Sevoflurane Posttreatment Attenuates Lung Injury Induced by Oleic Acid in Dogs.
In animal models, both sevoflurane and propofol protect against acute lung injury (ALI), especially when administered prior to ALI onset. We hypothesized that when compared to propofol, sevoflurane administration after the onset of acute respiratory distress syndrome would mitigate oleic acid (OA)-induced ALI in dogs. Dogs were randomly assigned to receive intravenous OA to induce ALI (n = 7 for each OA group) or saline as an OA control (n = 6 for each control). Dogs were then mechanically ventilated for 6 hours during which propofol (5 mg/kg/h) or sevoflurane (1.0 minimum alveolar concentration) was administered for sedation. Study end points included PO2/FIO2 ratio, pulmonary arterial pressure, pulmonary edema, histology, and tumor nuclear factor-α. In OA-injured animals, oxygenation was worse at 1, 2, 3, and 4 hours after 6-hour mechanical ventilation in sevoflurane-sedated animals compared with propofol-sedated animals, with mean difference (95% confidence interval; propofol minus sevoflurane) of 75 (39-111), 87 (55-119), 66 (44-87), and 67 (27-107) mm Hg for the respective time points. However, sevoflurane reduced the elevated pulmonary arterial pressure and vascular resistance, attenuated pulmonary edema as evidenced by reduced extravascular lung water index, and decreased tumor nuclear factor-α and diffuse alveolar damage score compared with propofol in the OA-injured lungs. When compared with propofol, sevoflurane attenuates OA-induced lung damage. However, despite this effect on lung histology and inflammation, sevoflurane worsened oxygenation in OA-induced ALI, possibly via inhibition of hypoxic pulmonary vasoconstriction.


Effects of shrimp-aquaculture reclamation on sediment nitrate dissimilatory reduction processes in a coastal wetland of southeastern China.
The conversion of natural saltmarshes to shrimp aquaculture ponds can potentially influence the biogeochemical cycling of nutrients in coastal wetlands, but its impact on the dynamics of sediment dissimilatory nitrate (NO3-) reduction remains poorly understood. In this study, three sediment NO3- reduction processes including denitrification (DNF), anaerobic ammonium oxidation (ANAMMOX), and dissimilatory NO3- reduction to ammonium (DNRA) were examined simultaneously in a natural saltmarsh and two shrimp culture ponds (5- and 18-year-old) in July and November, using nitrogen (N) isotope-tracing experiments. Our results showed that sediment potential DNF, ANAMMOX and DNRA rates were generally higher in the shrimp culture ponds than the natural saltmarsh in the two seasons. The rates of all three processes generally increased with the age of shrimp ponds, with the magnitude of increase being less pronounced for DNF and ANAMMOX than DNRA. The contribution of DNRA to total NO3- reduction increased significantly following saltmarsh conversion to shrimp ponds, suggesting that DNRA became an increasingly important biogeochemical process under shrimp culture. DNRA competed with DNF and limited reactive N loss to some extent after natural saltmarshes converted to shrimp culture ponds. The results of redundancy analysis revealed that the availability of substrates and sulfides in sediments, rather than the bacteria gene abundance, were the most important factor influencing the NO3- reduction processes. Overall, our findings highlighted that shrimp-aquaculture reclamation may aggravate nitrogen loading in coastal wetlands by promoting the production of bioavailable ammonium.


[The antiproliferative effects associated with vincristine and human interferons in experimental in vitro systems].
Cytotoxic potential of suboptimal doses of vincristine associated with human interferon was studied in two cell lines of tumoral origin, as compared to the action of or gamma type interferon preparations. Results show that the vincristine cytotoxic effect may be synergistically augmented in both culture types by simultaneous interferon administration.


COVID - 19 related knowledge and preventive practices early in the outbreak among health care workers in selected public health facilities of Illu aba Bor and Buno Bedelle zones, Southwest Ethiopia.
Novel-coronavirus 2019 (COVID-19) disease is currently a worldwide health risk and public health emergency concern. The virus is transmitted from an infected person to another person through close contact and droplets. Frontline health care workers are the most at risk of infection, and so a WHO interim guidance document was issued by the World Health Organization (WHO) which underscores the importance of proper sanitation and waste management practices for COVID- 19 in health-care settings. This study aimed at assessing knowledge and preventive practices towards Covid-19 among health care providers in selected health facilities of Illu Aba Bor and Buno Bedele zones, Southwest Ethiopia. An institution-based cross-sectional study was conducted from April to May 2020 among 330 health workers in selected health facilities of Illu Aba Bor and Buno-Bedelle Zones, Southwest Ethiopia. Data were collected using a self-administered structured questionnaire. The collected data were entered into Epidata version 3.1 and exported to SPSS version 23 for analysis. Bivariate and multivariable logistic regression analysis was used to identify independent predictors of preventive practices towards Covid-19. Statistical significance was declared at a p-value of < 0.05. The majority of respondents (93.3%) demonstrated good knowledge of COVID-19, and the mean (SD) knowledge score was 9.04 ± 1.06. Nearly two-thirds (64.2%) of the study participants had good infection prevention practices. Being male (AOR = 3.65, 95% CI: (1.96, 6.80)), education level (AOR = 1.82, 95% CI (1.02, 3.22)), profession (AOR = 3.17, 95% CI (1.08, 9.33)), service year (5-10 years) (AOR = 2.00 (1.02, 3.92)) and more than 10 years (AOR = 3.14 (1.51, 6.52)), availability of personal protective equipment (AOR = 1.96 (1.06, 3.61)) and Knowledge level (AOR = 2.61 (1.48, 4.62)) were independent predictors of COVID-19 preventive practices. The overall level of knowledge of HCWs was good. However, the practice was relatively low. Gender, educational status, profession, year of service, knowledge towards COVID-19, and availability of personal protective equipment were independent predictors of good infection prevention practices. Optimizing the infection prevention and control loop of the health facilities is recommended.


Optimized CRISPR-mediated gene knockin reveals FOXP3-independent maintenance of human Treg identity.
Regulatory T cell (Treg) therapy is a promising curative approach for a variety of immune-mediated conditions. CRISPR-based genome editing allows precise insertion of transgenes through homology-directed repair, but its use in human Tregs has been limited. We report an optimized protocol for CRISPR-mediated gene knockin in human Tregs with high-yield expansion. To establish a benchmark of human Treg dysfunction, we target the master transcription factor FOXP3 in naive and memory Tregs. Although FOXP3-ablated Tregs upregulate cytokine expression, effects on suppressive capacity in vitro manifest slowly and primarily in memory Tregs. Moreover, FOXP3-ablated Tregs retain their characteristic protein, transcriptional, and DNA methylation profile. Instead, FOXP3 maintains DNA methylation at regions enriched for AP-1 binding sites. Thus, although FOXP3 is important for human Treg development, it has a limited role in maintaining mature Treg identity. Optimized gene knockin with human Tregs will enable mechanistic studies and the development of tailored, next-generation Treg cell therapies.


Elevated pleural fluid pH in Proteus mirabilis empyema.
Three cases of Proteus empyema were associated with elevated pleural fluid pH values. The elevated pH is likely due to ammonia production by Proteus organisms.


A Mouse Model of Neurodegeneration Induced by Blade Penetrating Stab Wound to the Hippocampus.
Traumatic brain injury (TBI) is closely associated with the later development of neurodegenerative and psychiatric diseases which are still incurable. Although various animal TBI models have been generated, they usually have weaknesses in standardization, survivability and/or reproducibility. In the present study, we investigated whether applying a blade penetrating stab wound to the hippocampus would create an animal model of cognitive deficits. Open-field, Morris water maze and Barnes maze tests were used to evaluate the animal behaviors. The immunofluorescence staining of NeuN, GFAP, IBA1, and TUNEL was conducted to analyze the changes in neurons, astrocytes, and microglia, as well as cell death. Mice with a hippocampal blade stab injury (HBSI) displayed the activation of microglia and astrocytes, inflammation, neuronal apoptosis, and deficits in spatial learning and memory. These findings suggest that HBSI is an easy approach to generate a reliable in vivo model of TBI to capture hemorrhage, neuroinflammation, reactive gliosis, and neural death, as well as cognitive deficits observed in human patients.


Mirror, mirror on the wall, when are inequalities higher, after all? Analysis of breast and cervical cancer screening in 30 European countries.
Screening for breast and cervical cancer is strongly related with a reduction in cancer mortality but previous evidence has found socioeconomic inequalities in screening. Using up-to-date data from the second wave of the European Health Interview Survey (2013-2015), this study aims to analyse income-related inequalities in mammography screening and Pap smear test in 30 European countries. We propose a framework that combines age group and screening interval, identifying situations of due-, under-, and over-screening. Coverage rates, standard and generalised concentration indices are calculated. Overall, pro-rich inequalities in screening persist though there are varied combinations of prevalence of screening attendance and relative inequality across countries. Bulgaria and particularly Romania stand out with low coverage and high inequality. Some Baltic and Mediterranean countries also present less favourable figures on both accounts. In general, there are not marked differences between mammography and Pap smear test, for the recommended situation ('Due-screening'). 'Extreme under-screening' is concentrated among lower income quintiles in basically all countries analysed, for both screenings. These women, who never screened, are at risk of entering the group of 'Lost opportunity', once they reach the upper-limit age of the target group. At the same time, there are signals of 'Over-screening', within target group, due to screening more frequently than recommended. In several countries, 'Over-screening' seems to be concentrated among richer women. This is not only a waste of resources, but it can also cause harms. The inequalities found in 'Extreme under-screening' and 'Over-screening' raise concerns on whether women are making informed choices.


Long-term surgical outcomes after resection of presacral tumours and risk factors associated with recurrence.
The incidence of presacral tumours is low and pertinent data on the management and outcomes after surgery are sparse. The aim of this study was to identify the risk factors for recurrence in patients with presacral tumours undergoing surgery at our institution. Patients undergoing resection of a presacral tumour between 2009 and 2019 were identified from a prospectively maintained database. Demographics, clinicopathological features, preoperative imaging, operative details, morbidity, mortality, recurrence and survival were investigated. A total of 122 patients were identified. There were 95 women (77.9%) and the median age was 34 years. The most common presenting symptoms included pelvic pain (n = 60, 49.2%) and recurrent abscesses or fistulas (n = 40, 32.8%). The accuracy of preoperative magnetic resonance imaging (MRI) in distinguishing malignant from benign tumours was 93.9%. Six patients underwent three-dimensional computed tomography angiography (3D-CTA) and preoperative interventional embolization. Procedures were performed using transabdominal (n = 9), posterior (n = 99) and combined abdominal and posterior (n = 14) approaches. There were 21 (17.2%) malignant and 101 (82.8%) benign tumours. The local recurrence rate was 33.3% for malignant tumours and 9.9% for benign tumours. Multivariate analysis revealed that recurrence of malignant tumours was associated with R1 resection while recurrence of benign tumours was associated with secondary resections and intraoperative lesion rupture. Presacral tumours continue to be a diagnostic and therapeutic challenge. A multidisciplinary team, informed by modern imaging modalities, is essential for the management of presacral tumours.


Response properties of periodontal mechanosensitive fibers in the superior dental nerve of the cat.
Periodontal mechanosensitive units were detected as single nerve fibers from the anterior branches of five cats, and their receptive fields and optimal stimulus directions were examined. Of 801 units detected, 759 units (95%) responded to movement of only one tooth (single-tooth unit), and 42 units (5%) responded to movement of two or three teeth (multitooth unit). Eighty percent of the single-tooth units were of the sustained type which discharged during more than 1 s to a long-lasting pressure applied to the tooth, and 20% were of the transient type which adapted in less than 1 s to the pressure. The majority (93%) of the sustained type exhibited directional selectivity to stimulation, but only 35% of the transient type showed it. More than half of the single-tooth units had their receptive fields in the canine tooth, stimulation of which produced the largest mass discharge in the nerve bundle. The optimal stimulus direction for many single-tooth units was the same as that for the mass discharge in the nerve bundle. The receptive fields of the multitooth units were observed mainly in the incisor teeth adjacent to each other.


Fibroblast Activation Protein Inhibitor Theranostics: Preclinical Considerations.
Fibroblast activation protein (FAP) was first reported in 1986. However, FAP is not expressed in normal fibroblasts, normal or malignant epithelial cells, or the stroma of benign epithelial tumors. FAP is a cell membrane-bound serine peptidase overexpressed on the surface of cancer-associated fibroblasts and, as such, is a novel target for molecular imaging of several tumors. FAP inhibitors (FAPI) are potential theranostic molecular probes for various cancers. A tumor model expressing FAP was used to verify or confirm the usefulness of FAPI experimentally.


Identification of candidate genes responsible for chasmogamy in wheat.
The flowering biology of wheat plants favours self-pollination which causes obstacles in wheat hybrid breeding. Wheat flowers can be divided into two groups, the first one is characterized by flowering and pollination within closed flowers (cleistogamy), while the second one possesses the ability to open flowers during processes mentioned above (chasmogamy). The swelling of lodicules is involved in the flowering of cereals and among others their morphology, calcium and potassium content differentiate between cleistogamic and non-cleistogamous flowers. A better understanding of the chasmogamy mechanism can lead to the development of tools for selection of plants with the desired outcrossing rate. To learn more, the sequencing of transcriptomes (RNA-Seq) and Representational Difference Analysis products (RDA-Seq) were performed to investigate the global transcriptomes of wheat lodicules in two highly chasmogamous (HCH, Piko and Poezja) and two low chasmogamous (LCH, Euforia and KWS Dacanto) varieties at two developmental stages-pre-flowering and early flowering. The differentially expressed genes were enriched in five, main pathways: "metabolism", "organismal systems", "genetic information processing", "cellular processes" and "environmental information processing", respectively. Important genes with opposite patterns of regulation between the HCH and LCH lines have been associated with the lodicule development i.e. expression levels of MADS16 and MADS58 genes may be responsible for quantitative differences in chasmogamy level in wheat. We conclude that the results provide a new insight into lodicules involvement in the wheat flowering process. This study generated important genomic information to support the exploitation of the chasmogamy in wheat hybrid breeding programs.


Clinical efficacy, safety, and pharmacokinetics of indapamide in renal impairment.
The efficacy and safety of a new diuretic-antihypertensive drug, indapamide (2.5 mg/day), were evaluated in hypertensive patients with normal renal function, in patients with various degrees of chronic renal failure, and in hypertensive patients undergoing long-term maintenance hemodialysis. The results obtained from single-blind, placebo-controlled studies indicate that indapamide is a safe and effective agent to use in lowering the blood pressure of hypertensive patients with normal renal function, those with various degrees of renal impairment, and those who are undergoing long-term maintenance hemodialysis. No significant side or toxic effects were noted in these studies. Furthermore, indapamide does not accumulate in the bloodstream of patients with renal impairment and is not dialyzable.


Communication culture in cancer nursing care: an ethnographic study.
This study aimed to explore the communication culture in nursing care of patients with cancer. This ethnographic study was conducted in 2018-2019. Data were collected through participatory observation (318 h of observing nurses, patients, and family behaviors), semi-structured interviews (8 interviews with nurses), and informal interactions. Data were analyzed using Spradley's framework. The study results in five cultural components of "communication determinants," "experimental acquisition of communication skills," "gradual empathetic communication," "avoidant communication with patient," and "communication with family as caregiver." "Communication between nurse, patient and family is an experimental, gradual and avoidant relationship" was the study's cultural statement. In this study, the nurse-patient communication was influenced by factors related to the patient, the nurse and the care environment, and nurses acquired communication skills experimentally. There were two patterns of empathetic and avoidant communication between the nurse and the patient. For having high-quality care, nurses' behavioral patterns must be improved and changed in some cases. Nursing professors, managers, and nurses can use these results in training, hiring, orienting novice nurses, and empowering oncology nurses. Training communication skills to nurses and changing managers and nurses' approach to move from task-oriented care to holistic care help improve nurses' communication patterns.


MicroRNA-145-5p regulates the proliferation of epithelial ovarian cancer cells via targeting SMAD4.
Epithelial ovarian cancer (EOC) is one of the most prevalent malignancies affecting females worldwide; however, its etiology mechanism remains unclear. In various malignancies, miR-145-5p is a widely accepted and versatile miRNA. Therefore, our research focused on exploring the activity and etiology of miR-145-5p in the modulation of metastasis, migration, and proliferation of EOC cells. The direct reactions between the 3'UTRs of SMAD4 mRNA and miR-145-5p were verified using dual luciferase reporter test. SKOV-3 cells were subsequently transfected using miR-145-5p mimics. Cell migration, death, and proliferation were evaluated using MTT, flow cytometry, and Transwell test. In addition, SMAD4 transcription and translation were evaluated using qRT-PCR and Western blot. We found that miR-145-5p expression was repressed prevalently in EOC tissues, apart from SMAD4 upregulation. Excessive miR-145-5p expression remarkably reinforced EOC cell death and repressed EOC cell proliferation. Furthermore, upregulated miR-145-5p expression noticeably repressed migration via MMP-2 and MMP-9 downregulation. Moreover, SMAD4 was downregulated via miR-145-5p transfection. The dual luciferase test revealed that miR-145-5p directly targeted SMAD4. Our research suggests that miR-145-5p serves as a malignancy repressor and exerts an essential impact on inhibiting malignancy generation and reinforcing EOC death via targeting SMAD4. MiR-145-5p application could serve as a promising strategy to treat EOC.


[The efficacy of outpatient monitoring of children and adolescents with type 1 diabetes with regular use of professional continuous glucose monitoring].
According to research, only 38% of patients reach glycated hemoglobin targets. It is possible to improve the effectiveness of medical care for children with T1D using modern technologies, including continuous glucose monitoring (CGM). To evaluate the effectiveness of outpatient monitoring of children and adolescents with T1D with regular use of professional continuous glucose monitoring. The inclusion criteria: age 8−12 years; T1D at least 1 year; insulin therapy by multiple injections of insulin; inadequate glycemic control of T1D: НbА1с level of 7.5% and higher and / or children and adolescents with frequent episodes of hypoglycemia (usually 4 times a week) or with a history of severe hypoglycemia; signed informed consent. All patients initially and 12 weeks after inclusion in the study conducted a study of the level of НbА1с, and also performed CGM for 6 days. Based on the results of CGM, glycemia indicators and daily doses of insulin were recorded, treatment was evaluated and corrected, and recommendations for self-monitoring were made. Glucose monitoring was carried 120−144 hours using the blind method iPro2 (Medtronic, USA). In all, 99 children aged 8−18 years were included in the study in all centers. The decrease in the level of НbА1с by the end of the study was 0.72%, while the proportion of patients who reached the target level of НbА1с (defined as <7.5%) was statistically significantly higher at the end of the study (15.5% and 2%, respectively; p<0.05). During the study, patients showed a trend towards a decrease in the average level and variability of glycemia by the end of the study, however, statistical significance was achieved only in relation to the average level of glycemia (p=0.04). Conducted insulin therapy, determined by the average daily doses of long-acting and short-acting insulin, did not statistically significantly change at the end of the study. The frequency of DKA episodes and severe hypoglycemia did not statistically significantly differ from the initial level. For children with poor glycemic control of T1D, the use of professional CGM is effective in terms of glycemic control and a safe method.


CTHRC1 Knockdown Promotes Inflammatory Responses Partially by p38 MAPK Activation in Human Periodontal Ligament Cells.
Collagen triple helix repeat containing 1 (CTHRC1), a secreted glycoprotein, is widely expressed in many tissues. It has been recently defined as a novel marker for rheumatoid arthritis (RA), a systemic inflammatory disorder. However, the precise role of CTHRC1 in other chronic inflammatory diseases, like periodontal disease, remains unclear. This research aimed to explore the presence of CTHRC1 in periodontal inflammation, determine the precise role in inflammatory response modulation in periodontal ligament cells (PDLCs), and explore its underlying mechanisms. In vivo gingival crevicular fluid (GCF) and gingivae were obtained from healthy people and chronic periodontitis patients. Maxillary tissues of mice with or without ligature-induced periodontitis were immunostained for CTHRC1. In vitro human PDLCs were treated with tumor necrosis factor alpha (TNF-α) to mimic the inflammatory environment. Small interfering RNA (siRNA) was used to silence CTHRC1. SB203580 was used to inhibit the p38 mitogen-activated protein kinase (MAPK) pathway. CTHRC1 was highly expressed in GCF and gingival tissues of periodontitis patients. Animal models also revealed the same tendency. CTHRC1 knockdown promoted inflammatory cytokine production and activated the p38 MAPK signaling pathway in PDLCs. Inhibiting the p38 MAPK signaling pathway partially attenuated the inflammatory responses. This study revealed that CTHRC1 was highly expressed in periodontitis and suggested that CTHRC1 might play an important role in modulating periodontal inflammation.


Communicative participation with public authorities: Experiences of people with aphasia, people who stutter, and employees of public authorities.
Several studies have examined the communicative participation of people with communication disorders (PWCD). Hindering and facilitating factors were analyzed in different population groups considering various private and public communication contexts. However, knowledge about (a) the experiences of persons with different communication disorders, (b) communication with public authorities, and (c) the perspective of communication partners in this area remains limited. Therefore, this study aimed to explore the communicative participation of PWCD with public authorities. We analyzed communicative experiences (hindering and facilitating factors) and suggestions for improving communicative access described by persons with aphasia (PWA) and persons who stutter (PWS) as well as by employees of public authorities (EPA). In semi-structured interviews, PWA (n = 8), PWS (n = 9), and EPA (n = 11) reported specific communicative encounters with public authorities. The interviews were analyzed using qualitative content analysis, focusing on hindering/facilitating experiences and suggestions for improvement. The personal experiences of the participants during authority encounters were represented by the interwoven themes of familiarity and awareness, attitudes and behavior, and support and autonomy. The perspectives of the three groups overlap in several areas; however, the results also indicate specific differences between PWA and PWS as well as between PWCD and EPA. The results indicate a need to improve awareness/knowledge about communication disorders and communicative behavior in EPA. Moreover, PWCD should actively engage in encounters with authorities. In both groups, awareness must be raised about how each communication partner can contribute to successful communication, and avenues to achieve this goal must be demonstrated.


Analysis of the temporal events in blood and tissues following fecal peritonitis in mice.
The kinetics of systemic responses triggered by bacterial peritonitis were analysed in the blood, bronchoalveolar lavage (BAL) and several organs. The murine model of cecal ligation and puncture was employed. The parameters were analysed at different periods of time (4 to 72 h). Fecal peritonitis triggered a progressive, but not significant, decline of blood leukocytes between 4 and 6 h, becoming significant at 24 to 48 h (p<0.05). This profile was closely associated with the enhancement of leukocytes both in the abdomen (p<0.05) and in the BAL (p<0.05). A significant abdominal exudation was detected between 4 and 72 h (p<0.01), whereas maximal growth of aerobic bacteria in the blood and lungs was observed 24 and 72 h after. Maximal exudation in the studied tissues occurred at different time points (heart=24 h, spleen and kidney=48 h, liver and lung= 72 h). Using this model, evidence of sepsis can be easily measured in different body systems.


Possible neuroleptic malignant syndrome related to concomitant treatment with paroxetine and alprazolam.
A 74-year-old man with depressive symptoms was admitted to a psychiatric hospital due to insomnia, loss of appetite, exhaustion, and agitation. Medical treatment was initiated at a daily dose of 20 mg paroxetine and 1.2 mg alprazolam. On the 10th day of paroxetine and alprazolam treatment, the patient exhibited marked psychomotor retardation, disorientation, and severe muscle rigidity with tremors. The patient had a fever (38.2 degrees C), fluctuating blood pressure (between 165/90 and 130/70 mg mm Hg), and severe extrapyramidal symptoms. Laboratory tests showed an elevation of creatine phosphokinase (2218 IU/L), aspartate aminotransferase (134 IU/L), alanine aminotransferase (78 IU/L), and BUN (27.9 mg/ml) levels. The patient received bromocriptine and diazepam to treat his symptoms. 7 days later, the fever disappeared and the patient's serum CPK levels were normalized (175 IU/L). This patient presented with symptoms of neuroleptic malignant syndrome (NMS), thus demonstrating that NMS-like symptoms can occur after combined paroxetine and alprazolam treatment. The adverse drug reaction score obtained by the Naranjo algorithm was 6 in our case, indicating a probable relationship between the patient's NMS-like adverse symptoms and the combined treatment used in this case. The involvement of physiologic and environmental aspects specific to this patient was suspected. Several risk factors for NMS should be noted in elderly depressive patients whose symptoms often include dehydration, agitation, malnutrition, and exhaustion. Careful therapeutic intervention is necessary in cases involving elderly patients who suffer from depression.


Survival of forensic trace evidence on improvised explosive devices: perspectives on individualisation.
Improvised Explosive Devices (IEDs) are weapons of modern times, used by terrorist groups and thereby causing substantial damage to communities. There is a widespread misconception that destructive conditions like heat, water or pressure destroy all forensic evidence. Moreover, the plausibility to detect identifiable fingermarks and DNA on components of IEDs is insufficiently known. Therefore, this study investigated the effects of neutralisation and explosion on latent fingerprints and touch DNA. In a majority of the cases, comparative fingermark- and DNA testing resulted in individualisation. In some cases, despite extremely low amounts of contact DNA detected after deployment of render-safe tools or detonation, full STR profiles could be constituted, even after applying fingerprint development techniques. This research shows that latent fingerprints and touch DNA on improvised explosives can be successfully detected after destructive conditions and possibly be linked to the perpetrators of such crimes. This individualising power offers perspectives to enhance forensic investigations of terrorism-related crimes.


Flattening of the interventricular septum (D-shaped left ventricle) in addition to high right ventricular tracer uptake and increased right ventricular volume found on gated SPECT studies strongly correlates with right ventricular overload.
Flattening of the interventricular septum (D-shaped left ventricle) detected during echocardiographic examination is correlated with significant right ventricular (RV) overload. There are no reports of this finding with cardiac gated single photon emission computed tomography (SPECT) imaging. We report an observational study correlating this finding with the presence of RV overload. Retrospectively, we compared 8 cases with flattening of the interventricular septum on cardiac gated SPECT imaging for which echocardiographic correlations and clinical data were available regarding the presence of RV overload. All patients but 1 had pulmonary hypertension ranging from 42 to 52 mm Hg measured by echocardiographic Doppler studies. All patients but 1 had reasons for RV overload (chronic obstructive pulmonary disease in 3, history of atrial septal defect in 3, pulmonary embolism in 1, and obstructive sleep apnea in 1). Septal flattening present on gated SPECT images was seen in 50% of the cases by echocardiography. Other signs of RV overload (RV enlargement, RV hypertrophy) were observed by echocardiography in 5 patients and by the gated SPECT in 7 patients. The presence of interventricular septal flattening on gated SPECT studies correlates with RV overload and should be routinely assessed during interpretation of gated SPECT studies.


Tuberculosis outbreak in rhesus monkeys immunosuppressed with antithymocyte globulin.
Tuberculosis lesions were found in necropsied monkeys used in studies involving immunosuppression. Correlations were made between the demonstration of reduced numbers of circulating T cells, the duration of allograft survival and the appearance of T cell-dependent tuberculin sensitivity. The immunosuppressed state of these monkeys may have resulted in false tuberculin reactions. The report confirms the necessity for sequential tuberculin tests on rhesus monkeys prior to their being used in experiments.


Ultrasonography in inflammatory rheumatic disease: an overview.
Modern ultrasonography enables clinicians to sensitively assess the progression of inflammatory joint and tendon disease, and to investigate vasculitides, connective tissue diseases and nerve lesions. Despite the advantages of musculoskeletal ultrasonography for diagnostic, prognostic and monitoring purposes, fewer than 10% of European rheumatologists use this technique in routine clinical practice. The reliability and limitations of rheumatic ultrasonography remain a concern, although good interobserver and intraobserver agreement in results from ultrasonography have been demonstrated among experienced sonographers. International recommendations for assessments and ultrasonography training courses are available, and will improve the standardization of the use of these techniques. In clinical practice, ultrasonography can complement the diagnostic evaluation of patients with rheumatic disease and might have value in confirming and extending clinical findings. Musculoskeletal ultrasonography can also be a valuable follow-up tool to monitor disease activity and support treatment decisions for specific patients. Furthermore, ultrasonography-guided articular injections provide better precision and a higher success rate for synovial fluid aspiration than clinically-guided injections. In the future, three-dimensional ultrasonography techniques, the fusion of ultrasonography and other imaging methods, and real time sonoelastography will be interesting new fields of investigation.


Hybrid repair of complex thoracic aortic arch pathology: long-term outcomes of extra-anatomic bypass grafting of the supra-aortic trunk.
Hybrid repair constitutes supra-aortic debranching before thoracic endovascular aortic repair (TEVAR). It offers improved short-term outcome compared with open surgery; however, longer-term studies are required to assess patient outcomes and patency of the extra-anatomic bypass grafts. A prospectively maintained database of 380 elective and urgent patients who had undergone TEVAR (1997-2011) was analyzed retrospectively. Fifty-one patients (34 males; 17 females) underwent hybrid repair. Median age was 71 (range, 18-90) years with mean follow-up of 15 (range, 0-61) months. Perioperative complications included death: 10 % (5/51), stroke: 12 % (6/51), paraplegia: 6 % (3/51), endoleak: 16 % (8/51), rupture: 4 % (2/51), upper-limb ischemia: 2 % (1/51), bypass graft occlusion: 4 % (2/51), and cardiopulmonary complications in 14 % (7/51). Three patients (6 %) required emergency intervention for retrograde dissection: (2 aortic root repairs; 2 innominate stents). Early reintervention was performed for type 1 endoleak in two patients (2 proximal cuff extensions). One patient underwent innominate stenting and revision of their bypass for symptomatic restenosis. At 48 months, survival was 73 %. Endoleak was detected in three (6 %) patients (type 1 = 2; type 2 = 1) requiring debranching with proximal stent graft (n = 2) and proximal extension cuff (n = 1). One patient had a fatal rupture of a mycotic aneurysm and two arch aneurysms expanded. No bypass graft occluded after the perioperative period. Hybrid operations to treat aortic arch disease can be performed with results comparable to open surgery. The longer-term outcomes demonstrate low rates of reintervention and high rates of graft patency.


The absence of real-time pulmonary vein isolation during cryoballoon ablation is associated with atrial fibrillation recurrence and pulmonary vein reconnection : Insights from the Middelheim-PVI Registry 2.
Absence of real-time pulmonary vein (PV) isolation (PVI) occurring in 15-40% of PVs during cryoballoon ablation (CBA) of atrial fibrillation (AF) raises doubt about adequate PVI. Aim of the present study is to determine whether real-time PVI during CBA is predictive of long-term clinical outcome and durability of PVI. Eight hundred three AF patients (64 ± 10 years, 68% males) undergoing CBA were studied. The cohort was divided in 4 groups according to the number of PVs without real-time PVI: none (N = 252 [31.4%]), 1 (N = 255 [31.8%]), 2 (N = 159 [19.8%]), and 3-4 (N = 137 [17.1]). At 3 years, 279 (34.7%) patients had recurrence of AF of which 188 underwent repeat ablation. A vein without real-time PVI was associated with AF recurrence (HR = 1.275; 95% CI 1.134-1.433; p < 0.01), independent of persistent AF type (HR = 2.075; 95% CI 1.584-2.738; p < 0.01), left atrial diameter (HR = 1.050; 95% CI 1.028-1.072; p < 0.01), and diagnosis-to-ablation time (HR = 1.002; 95% CI 1.000-1.005; p = 0.04). Highest success was achieved with present real-time PVI in all veins (77.4%), gradually decreasing per increasing number of absent real-time PVI: 66.3% for 1 vein, 58.5% for 2, and 48.9% for 3-4 veins (p < 0.001). At repeat ablation (N = 188), PV reconnection was seen in 99/430 (23.0%) versus 83/288 (28.8%) veins with and without real-time PVI, respectively (p = 0.08). Right inferior PVs (RIPVs) with real-time PVI were less reconnected than RIPVs without real-time PVI: 29.7% versus 43.7% (p = 0.047). The absence of real-time PVI during CBA independently predicts AF recurrence with a 30% gradual decrease in outcome per increase in veins without real-time PVI. Real-time PVI is particularly important for the RIPV to achieve durable PVI.


Thermal ablation in adrenal disorders: a discussion of the technology, the clinical evidence and the future.
To summarise the emerging role of thermal ablation as a therapeutic modality in the management of functioning adrenal tumours and metastases to the adrenal gland. Observational evidence has demonstrated the benefit of thermal ablation in (i) resolving adrenal endocrinopathy arising from benign adenomas, (ii) treating solitary metastases to the adrenal and (iii) controlling metastatic adrenocortical carcinoma and phaeochromocytoma/paraganglioma. Microwave thermal ablation offers a promising, minimally invasive therapeutic modality for the management of functioning adrenocortical adenomas and adrenal metastases. Appropriate technological design, treatment planning and choice of imaging modality are necessary to overcome technical challenges associated with this emerging therapeutic approach.


[Diagnosis and management of alcohol-use disorders].
With the publication of the DSM-5, the alcoholic disease becomes Alcohol-use disorders taking into account dependence and damages according to a gradient of severity. This conceptual evolution should improve the screening of people affected by this chronic and progressive disease associated with a heavy impact on morbidity and mortality. This identification is provided by the clinical interview and examination. Its sensitivity can be improved by questionnaires and biological markers. Damage and related pathologies have to be systematically revealed. In this context, the MoCA test allows the early detection of cognitive disorders. Care management aims for a change in consumption and consists in supporting the patient in his/her approach. Care management should be personalized, appropriated to the patient's informed choice and graded according to disorders' severity. This includes a psychosocial intervention which can be associated with drugs. Abstinence is no longer the only alternative: decreasing consumption with the aim of regulation has been shown interesting in the reduction of harmful consumption. When therapeutic withdrawal turns out to be necessary, use of a treatment should not be systematic. If necessary, benzodiazepines remain the first-line treatment with a limited duration of prescription. According to his/her profile, the patient can receive a long-term treatment to help to maintain abstinence, prevent relapse or reduce consumption. There is evidence that identifying and involving patients in their care significantly improve their health. Effective treatments are available for treating alcohol-use disorders. However, only a relatively small number of patients receive specific management appropriated to their needs and according to concrete goals.


The role of nuclear receptors in controlling the fine balance between proliferation and differentiation of neural stem cells.
In the central nervous system (CNS) of vertebrates a large variety of cell types are specified from a pool of highly plastic neural stem/progenitor cells (NSCs) via a combined action of extrinsic morphogenetic cues and intrinsic transcriptional regulatory networks. Nuclear receptors and their ligands are key regulators of fate decisions in NSCs during development and adulthood, through their ability to control transcription of downstream genes. In the last few years considerable progress has been made towards the understanding of the actions of nuclear receptors in NSCs as well as elucidating the mechanistic basis for these actions. Here we summarize recent progress in the role of nuclear receptors in the biology of NSCs. These studies highlight the importance of this family of transcriptional regulators in CNS development and function in health and disease. Furthermore, they raise the intriguing possibility of using nuclear receptors as therapeutic targets for nervous system related diseases and traumas.


The radiological characteristics of childhood intussusception including unusual features and rare pathological lead points.
To describe the radiological characteristics for childhood intussusceptions including unusual radiological features and rare pathological lead points (PLP). The medical records of all childhood intussusceptions between 1/1/2010 -1/10/2020 were retrospectively reviewed. 95 cases were identified in 82 patients. The demographic data, presenting symptoms, diagnostic and treatment methods, radiological features, and PLPs among the different types of intussusception were analyzed. Ileocolic intussusception (ICI) represented 53.7% (51/95). The average age for ICI was 1.87 years. Males constituted 72.1% (31/43). 29.4% (15/51) were treated primarily surgically due to peritonitis. Small bowel intussusception (SBI) represented 40% (38/95) in which females constituted 51.5% (17/33). Ileo-ileal represented 63.2% (24/38). 81.8% (27/33) were transient. On ultrasound; There was a statistically significant difference in the size of the outer diameter of ICI compared to SBI (P-value 0.00012). Ileo-ileocolic and colo-colic intussusceptions constituted 3.2% (3/95); each and were more common in females. Vomiting was the most common symptom for intussusception and ultrasound was diagnostic in the majority of cases. PLPs were seen in 36.6% (30/82) of the patients of which the average age was 7 years. PLPs/risk factors were benign in 80% (24/30). A case of colo-colic intussusception was seen in a 16-year-old female due to clear cell sarcoma which was not reported before. 12.2% patients (10/82) had recurrent intussusception. Our study showed that ICI is the most commonly encountered type. SBIs are mostly transient. It is important to radiologically determine the type of intussusception and to identify PLPs or unusual radiological features to avoid unnecessary intervention and significant patient morbidity.


Accuracy of transrectal ultrasonography to evaluate pathologic prostate weight: correlation with various prostate size groups.
To report the accuracy of transrectal ultrasonography (TRUS) to measure prostate size before robotic-assisted radical prostatectomy using the prolate ellipsoid formula and its correlation to the weight of the postoperative prostate specimen, for different prostate size groups. Preoperative prostate size estimated by TRUS and the weight of postoperative prostate specimens were collected from 440 men undergoing robotic-assisted radical prostatectomy. Patients were grouped according to preoperative prostate size: <30, 30-60, 60-80, and ≥80 g. To evaluate accuracy, the mean absolute percentage of error was used. The mean percentage of error was used to indicate whether the estimation of TRUS had a tendency to overestimate or underestimate prostate size. The correlation between both measurements was analyzed for each size group. Accuracy of TRUS estimation was associated with increased prostate size. TRUS estimation was more accurate for larger prostates. The mean absolute percentage of error of each group was 38.64% (<30 g), 21.33% (30-60 g), 13.23% (60-80 g), and 14.96% (≥80 g). Correlation followed a similar size-dependent trend, with a stronger r coefficient for larger prostates: 0.174 (<30 g), 0.327 (30-60 g), 0.457 (60-80 g), and 0.839 (≥80 g). Interestingly, smaller prostates were underestimated, whereas larger glands (≥80 g) had a tendency to be overestimated by TRUS. This study demonstrates that the accuracy of the prolate ellipsoid formula for TRUS varies according to prostate size. Although this formula is fairly accurate for assessing larger prostates, it shows some limitations for smaller prostates. This must be taken into account when evaluating treatment modalities such as transurethral incision of the prostate and brachytherapy.


Total and out-of-pocket costs for PARP inhibitors among insured ovarian cancer patients.
To evaluate total and out-of-pocket costs for poly(ADP-ribose) polymerase (PARP) inhibitors and differences based on insurance characteristics. We identified ovarian cancer patients who were prescribed niraparib, olaparib, or rucaparib from the MarketScan (2014-2017) and Surveillance, Epidemiology, and End Results (SEER)-Medicare (2014-2016) databases. Drug costs were estimated for a 30-day supply. Descriptive statistics and Wilcoxon rank sum tests were performed. 590 commercially insured beneficiaries from MarketScan and 213 SEER-Medicare beneficiaries were prescribed PARP inhibitors for a median 112 days. For commercially insured beneficiaries, median total cost was $13,342 (IQR $12,022-$14,256). Median out-of-pocket cost was $44 (IQR $0-$120) and PARP inhibitors accounted for a median 90.8% of patients' total out-of-pocket drug spending. High-deductible health plan was not associated with higher out-of-pocket costs (N = 570; median $0 vs. $45, P = 0.87). For SEER-Medicare beneficiaries, median total cost was $12,798 (IQR $11,704-$13,180). Median out-of-pocket cost was $370 (IQR $2-$1234) and PARP inhibitors accounted for a median 99.0% of patients' total out-of-pocket drug spending. Out-of-pocket costs were lower for dual-eligible patients with supplemental Medicaid prescription coverage (N = 209; median $1 vs. $911, P < 0.001). Although insurers are responsible for a large proportion of PARP inhibitor costs, out-of-pocket costs for PARP inhibitors account for a majority of patients' drug spending. SEER-Medicare beneficiaries had higher out-of-pocket costs than patients with commercial insurance, which was offset for those with supplemental Medicaid prescription coverage.


Mechanisms giving rise to triploid zygotes during assisted reproduction.
To review information on the origin of triploid zygotes as gathered from assisted reproduction techniques. Identification of relevant literature by a MEDLINE search and own experience on the basis of cytogenetic studies of abnormally fertilized oocytes. None. None. None. None. Penetration of two haploid spermatozoa or of a single diploid spermatozoon into the oocyte causes diandric triploidy. The first case can be discerned by formation of a total of three pronuclei, whereas the second process will remain undetected, because it involves a female and a single but diploid male pronucleus. Digynic triploidy after intracytoplasmic sperm injection is characterized by nonextrusion of the second polar body and formation of three pronuclei. Digyny can also result from the fertilization of diploid giant oocytes. Depending on how maturation of these gametes proceeds, three or only two pronuclei will be observed. Thus, the size of the pronuclear stage must be considered for a successful identification of the abnormality. Endoreduplication within the female pronucleus is not detectable and may represent another, albeit rare, origin of digynic triploidy. Routine inspection of the number of pronuclei is not an absolutely reliable tool for excluding the development of triploid embryos. Observations during assisted reproduction may yield valuable information on the origin of triploidy.


Delaying Urgent Exploration in Neonatal Testicular Torsion May Have Significant Consequences for the Contralateral Testis: A Critical Literature Review.
To assess the optimal management strategy for boys with neonatal testicular torsion (NTT) in the first 30 days of life, and to stratify outcomes for prenatal, postnatal, unilateral, synchronous, and asynchronous events METHODS: All articles including case reports published between 1946 and 2020 in Embase/Scopus/Medline/Pubmed and Web of Science that had a defined diagnosis of NTT within the first 30 days of life were reviewed. Data and outcomes were analyzed individually, and together as pooled data, using a random effect model. There was a total of 152 studies representing 1336 patients. Outcome data was available on 974 patients (1121 testes). NTT was unilateral in 829 cases, synchronous bilateral in 80 cases, and asynchronous in 66 cases. There were a total of 1107 orchiectomies, and 229 salvage orchiopexies. A total of 2.5% synchronous NTT underwent successful salvage. A total of 95.7% of prenatal unilateral torsions underwent orchiectomy, compared with 92% postnatal torsions. 11.8% of all NTT events were asynchronous with a median time to second torsion of 1 day (Range 1-8). The contralateral orchiectomy rate in this group was 31.8%, with a 40% atrophy rate following orchiopexy. The number needed to treat to avoid bilateral orchiectomy was 1.6, and the number needed to treat to avoid solitary atrophy was 2.6. NTT is an important condition carrying a significant risk for testicular loss and endocrine insufficiency. Given the potential catastrophic risk of asynchronous extravaginal torsion, we recommend urgent, safe, surgical intervention with both unilateral and bilateral NTT.


A Prospective Comparison of the Effects of Instrument Tracking on Time and Radiation During Minimally Invasive Lumbar Interbody Fusion.
Minimally invasive surgical techniques have resulted in improved patient outcomes. One drawback has been the increased reliance on fluoroscopy and subsequent exposure to ionizing radiation. We have previously shown the efficacy of a novel instrument tracking system in cadaveric and preliminary clinical studies for commonplace orthopedic and spine procedures. In the present study, we examined the radiation and operative time using a novel instrument tracking system compared with standard C-arm fluoroscopy for patients undergoing minimally invasive lumbar fusion. The radiation emitted, number of radiographs taken, and time required to complete 2 tasks were recorded between the instrument tracking systems and conventional C-arm fluoroscopy. The studied tasks included placement of the initial dilator through Kambin's triangle during percutaneous lumbar interbody fusion and placement of pedicle screws during both percutaneous lumbar interbody fusion and minimally invasive transforaminal lumbar interbody fusion with or without instrument tracking. A total of 23 patients were included in the analysis encompassing 31 total levels. For the task of placing the initial dilator into Kambin's triangle, an average of 4.21 minutes (2.4 vs. 6.6 minutes; P = 0.002), 15 fluoroscopic images (5.4 vs. 20.5; P = 0.002), and 8.14 mGy (3.3 vs. 11.4; P = 0.011) were saved by instrument tracking. For pedicle screw insertion, an average of 5.69 minutes (3.97 vs. 9.67; P < 0.001), 14 radiographs (6.53 vs. 20.62; P < 0.001), and 7.89 mGy (2.98 vs. 10.87 mGy; P < 0.001) were saved per screw insertion. Instrument tracking, when used for minimally invasive lumbar fusion, leads to significant reductions in radiation and operative time compared with conventional fluoroscopy.


Vascular selective calcium entry blockers in the treatment of cardiovascular disorders: focus on felodipine.
Calcium entry through L-type calcium channels is essential for contraction of both arterial smooth muscle and the myocardium, and is important in cardiac conduction. First-generation calcium entry blockers lack or have a modest degree of vascular selectivity and inhibit cardiac function at doses producing therapeutic arterial dilatation. Such agents may cause deterioration in patients with left ventricular dysfunction, and their combination with a beta-adrenergic blocker may adversely affect cardiac contractility and conduction. Development of newer agents has focused on obtaining a higher degree of vascular selectivity. Felodipine is a highly vascular selective calcium entry blocker, with a vascular selectivity ratio greater than 100, as shown experimentally. Isradipine and nicardipine are also vascularly selective calcium entry blockers. Hemodynamic studies in patients with hypertension, coronary artery disease, congestive heart failure, or in patients receiving beta-adrenergic blockade, show that felodipine can produce profound arteriolar dilatation without the negative effects of left ventricular systolic performance. Furthermore, felodipine alone or when added to a beta-adrenergic blocker does not interfere with cardiac conduction. The primary mechanism that accounts for the efficacy of dihydropyridine calcium entry blockers in hypertension and angina pectoris is arterial dilation, whereas nondihydropyridines may also derive part of their effect from inhibition of cardiac performance. As some of these patients, most commonly the elderly, have concomitant left ventricular dysfunction, it should be advantageous to avoid myocardial depression in the treatment of their primary disease. Preliminary studies in patients with heart failure indicate that felodipine and amlopidine may improve hemodynamics, reduce neurohormonal activation, and increase exercise tolerance, but final conclusions must await the randomized clinical trials now underway.


N-way sensitivity analysis: a verification and stability-assessment technique for completely subjective decision analysis trees.
The purpose of this paper is to describe the development of N-way sensitivity analysis, a modified version of traditional sensitivity analysis that was created for the purpose of verifying the stability of decisions made by a completely subjective decision-analytic tree. The technique was developed during research that addressed whether nurses make clinical decisions that coincide with those recommended by a decision-analytic model. Since all parameters of the model were derived from subjective assessment, traditional one-way or two-way sensitivity analysis was deemed inappropriate. Consequently, N-way sensitivity analysis was developed and used for the verification of the decision model's results.


DNA damage induces expression of WWP1 to target ΔNp63α to degradation.
ΔNp63αplays key roles in cell survival and proliferation. So its expression is always tightly controlled in cells. We previously reported that DNA damage down-regulates transcription of ΔNp63αin FaDu and HaCat cells, which contributes to cell apoptosis. In the present study, we found that DNA damage induces down-regulation of ΔNp63αvia facilitating its proteasomal degradation in cell lines such as MDA-MB-231 and MCF10A. Further investigation revealed that transcription of WWP1 is stimulated by DNA damage in these cells. Knock-down of WWP1 abrogates DNA damage-induced down-regulation of ΔNp63αand partially rescues cell apoptosis. Interestingly, DNA damage may stimulate WWP1 through different mechanisms in different cell types: it up-regulates transcription of WWP1 in a p53-dependent manner in MCF10A and HEK293 cells, while miR-452 may be involved in DNA damage-induced up-regulation of WWP1 in MDA-MB-231 cells. Our study demonstrates a novel pathway which regulates ΔNp63αupon cellular response to chemotherapeutic agents.


[The structure of macronutrient consumption by the population of various regions of Russian Federation].
The article presents data on the consumption of macronutrients by the population of large cities of all eight Federal Districts of the Russian Federation. Dietary intake assessment was investigated using method of 24-hour recall. The analyzed sample consisted of 11 850 people. The criterion for not inclusion was people working in harmful working conditions and engaged in heavy physical labor. In each of the four age groups (12-17, 18-30, 31-45, 46-60 years), there were at least 150 subjects surveyed for each gender. It has been established that in all districts of Russia the level of consumption of total fats (33.2-38.8% of the energy value of the diet) was exceeded. The level of protein intake was 9.3-11.5% with a rate of 12% of the caloric intake. The share of carbohydrates in the caloric content of the diet was 50.3-56.4% with the recommended rates of 50-60%.


Detecting the "O-GlcNAc-ome"; detection, purification, and analysis of O-GlcNAc modified proteins.
The modification of Ser and Thr residues of cytoplasmic and nuclear proteins with a monosaccharide of O-linked beta-N-acetylglucosamine is an essential and dynamic post-translational modification of metazoans. Deletion of the O-GlcNAc transferase (OGT), the enzyme that adds O-GlcNAc, is lethal in mammalian cells highlighting the importance of this post-translational modification in regulating cellular function. O-GlcNAc is believed to modulate protein function in a manner analogous to protein phosphorylation. Notably, on some proteins O-GlcNAc and O-phosphate modify the same Ser/Thr residue, suggesting that a reciprocal relationship exists between these two post-translational modifications. In this chapter we describe the most robust techniques for the detection and purification of O-GlcNAc modified proteins, and discuss some more specialized techniques for site-mapping and detection of O-GlcNAc during mass spectrometry.


Dexmedetomidine Restores Autophagic Flux, Modulates Associated microRNAs and the Cholinergic Anti-inflammatory Pathway upon LPS-Treatment in Rats.
Infections and perioperative stress can lead to neuroinflammation, which in turn is linked to cognitive impairments such as postoperative delirium or postoperative cognitive dysfunctions. The α2-adrenoceptor agonist dexmedetomidine (DEX) prevents cognitive impairments and has organo-protective and anti-inflammatory properties. Macroautophagy (autophagy) regulates many biological processes, but its role in DEX-mediated anti-inflammation and the underlying mechanism of DEX remains largely unclear. We were interested how a pretreatment with DEX protects against lipopolysaccharide (LPS)-induced inflammation in adult male Wistar rats. We used Western blot and activity assays to study how DEX modulated autophagy- and apoptosis-associated proteins as well as molecules of the cholinergic anti-inflammatory pathway, and qPCR to analyse the expression of autophagy and inflammation-associated microRNAs (miRNA) in the spleen, cortex and hippocampus at different time points (6 h, 24 h, 7 d). We showed that a DEX pretreatment prevents LPS-induced impairments in autophagic flux and attenuates the LPS-induced increase in the apoptosis-associated protein cleaved poly(ADP-ribose)-polymerase (PARP) in the spleen. Both, DEX and LPS altered miRNA expression and molecules of the cholinergic anti-inflammatory pathway in the spleen and brain. While only a certain set of miRNAs was up- and/or downregulated by LPS in each tissue, which was prevented or attenuated by a DEX pretreatment in the spleen and hippocampus, all miRNAs were up- and/or downregulated by DEX itself - independent of whether or not they were altered by LPS. Our results indicate that the organo-protective effect of DEX may be mediated by autophagy, possibly by acting on associated miRNAs, and the cholinergic anti-inflammatory pathway. Preventive effects of DEX on LPS-induced inflammation. DEX restores the LPS-induced impairments in autophagic flux, attenuates PARP cleavage and alters molecules of the cholinergic system in the spleen. Furthermore, DEX alters and prevents LPS-induced miRNA expression changes in the spleen and brain along with LPS.


The expanding field of non-canonical RNA capping: new enzymes and mechanisms.
Recent years witnessed the discovery of ubiquitous and diverse 5'-end RNA cap-like modifications in prokaryotes as well as in eukaryotes. These non-canonical caps include metabolic cofactors, such as NAD+/NADH, FAD, cell wall precursors UDP-GlcNAc, alarmones, e.g. dinucleotides polyphosphates, ADP-ribose and potentially other nucleoside derivatives. They are installed at the 5' position of RNA via template-dependent incorporation of nucleotide analogues as an initiation substrate by RNA polymerases. However, the discovery of NAD-capped processed RNAs in human cells suggests the existence of alternative post-transcriptional NC capping pathways. In this review, we compiled growing evidence for a number of these other mechanisms which produce various non-canonically capped RNAs and a growing repertoire of capping small molecules. Enzymes shown to be involved are ADP-ribose polymerases, glycohydrolases and tRNA synthetases, and may potentially include RNA 3'-phosphate cyclases, tRNA guanylyl transferases, RNA ligases and ribozymes. An emerging rich variety of capping molecules and enzymes suggests an unrecognized level of complexity of RNA metabolism.


Associations between interferon regulatory factor-1 polymorphisms and Behçet's disease.
Interferon regulatory factor-1 (IRF-1) is a transcription factor that regulates the functions of type I and II interferons and plays a role in host protection. Behçet's disease (BD) is an idiopathic systemic vasculitis that is often complicated with thrombotic features, and infectious agents have long been postulated to be a disease-triggering factor in its pathogenesis. The authors investigated the distributions of IRF-1 promoter -415 C/A, -410 A/G, and -300 A/G, and 3'-untranslated region (UTR) A/G polymorphisms in 105 BD patients (mean age 41.7 +/- SEM 1.1 years, 44 male and 61 female) and in 105 gender- and age-matched healthy controls. The frequencies of individual alleles and genotypes were not different between the control and BD groups. However, the frequency of AGGG haplotype was significantly higher (73.5% vs 60.2%, odds ratio [OR] = 1.842, 95% confidence interval [95% CI] = 1.219-2.783, p(c) = 0.036) and that of the CAAG haplotype was significantly lower (2.2% vs 9.5%, OR = 0.195, 95% CI = 0.068-0.559, p(c) = 0.02) in BD patients than in healthy controls. In addition, the frequency of the AGGG haplotype was significantly higher (80.3% vs 57.4%, OR = 3.033, 95% CI = 1.716-5.360, p(c) = 0.001) and that of the CAAG haplotype was significantly lower (0.8% vs 12.3%; OR = 0.059, 95% CI = 0.010-0.357, p(c) = 0.005) in female BD patients than female controls. By subgroup analyses, the CAAA haplotype tended to be more common in BD patients with moderate or severe disease than in those with mild disease (25.4% vs 13.6%, OR = 2.158, 95% CI = 1.046-4.440, p = 0.037 before Bonferroni correction). When BD patients were subclassified by a history of deep vein thrombosis (DVT), the CAAA haplotype was found to be significantly increased the risk of DVT (42.1% vs 15.7%, OR = 3.906, 95% CI = 1.836-8.324, p(c) = 0.0015) and the AGGG haplotype tended to reduce this risk (57.9% vs 77.3%, OR = 0.403, 95% CI = 0.195-0.834, p(c) = 0.0685). Furthermore, the frequency of the CAAA haplotype was significantly higher in BD patients that had experienced a thrombotic event than in those that had not (40.5% vs 15.5%, OR = 3.7147, 95% CI = 1.778-7.770, p(c) = 0.0015). These results suggest that IRF-1 is a novel susceptibility gene in BD, especially in women, and furthermore, that IRF-1 polymorphisms may be related to thrombosis in BD patients.


Bootstrap-based methods for testing factor-by-curve interactions in generalized additive models: assessing prefrontal cortex neural activity related to decision-making.
In many situations the effect of a continuous covariate on response varies across groups defined by levels of a categorical variable. This paper addresses generalized additive models incorporating the so-called factor-by-curve interaction. A local scoring algorithm based on local linear kernel smoothers was used to estimate the model. Two different types of bootstrap-based procedures are proposed for testing interaction terms, namely, the likelihood ratio test, and a procedure based on an estimate of the interaction terms. Given the high computational cost involved, binning techniques were used to speed up computation in the estimation and testing processes. A simulation study was conducted to assess the validity of these bootstrap-based tests. This methodology was applied to studying prefrontal cortex neural activity associated with decision-making in monkeys. The proposed statistical procedure proved very useful in revealing the neural activity correlates of decision-making strategies adopted by monkeys in accordance with different behavioural tasks.


FoxK1 splice variants show developmental stage-specific plasticity of expression with temperature in the tiger pufferfish.
FoxK1 is a member of the highly conserved forkhead/winged helix (Fox) family of transcription factors and it is known to play a key role in mammalian muscle development and myogenic stem cell function. The tiger pufferfish (Takifugu rubripes) orthologue of mammalian FoxK1 (TFoxK1) has seven exons and is located in a region of conserved synteny between pufferfish and mouse. TFoxK1 is expressed as three alternative transcripts: TFoxK1-alpha, TFoxK1-gamma and TFoxK1-delta. TFoxK1-alpha is the orthologue of mouse FoxK1-alpha, coding for a putative protein of 558 residues that contains the forkhead and forkhead-associated domains typical of Fox proteins and shares 53% global identity with its mammalian homologue. TFoxK1-gamma and TFoxK1-delta arise from intron retention events and these transcripts translate into the same 344-amino acid protein with a truncated forkhead domain. Neither are orthologues of mouse FoxK1-beta. In adult fish, the TFoxK1 splice variants were differentially expressed between fast and slow myotomal muscle, as well as other tissues, and the FoxK1-alpha protein was expressed in myogenic progenitor cells of fast myotomal muscle. During embryonic development, TFoxK1 was transiently expressed in the developing somites, heart, brain and eye. The relative expression of TFoxK1-alpha and the other two alternative transcripts varied with the incubation temperature regime for equivalent embryonic stages and the differences were particularly marked at later developmental stages. The developmental expression pattern of TFoxK1 and its localisation to mononuclear myogenic progenitor cells in adult fast muscle indicate that it may play an essential role in myogenesis in T. rubripes.


Distribution of essential heavy metals in the aquatic ecosystem of Lake Manzala, Egypt.
Lake Manzala is the largest and most productive lake of Egypt's northern coastal lakes and has socio-economic impacts. Pollution by heavy metals is the most significant type of pollution worldwide, particularly in Lake Manzala, which receives mixed discharges from densely populated areas. Water samples were collected at twelve sites around the lake in winter and summer of 2015. Samples of Eichhornia crassipes were collected in the winter, and Oreochromis niloticus samples were collected at two sites (8 and 10). V, Cr, Mn, Fe, Co, Ni, Cu, and Zn were analysed in these samples using inductively coupled plasma-mass spectrometry. The average metal concentrations were below the internationally accepted upper permissible limits and are improved compared to those in previous studies. However, the metal concentrations at the eastern and southeastern sites were higher than the allowable limits due to multiple waste discharges. Pollution assessment using pollution risk indicators indicated low to moderate concentrations of metal enrichment in the sediment and biota of the lake, except at sites near the eastern and southeastern drains; these latter sites were considered to be hazardous and should be taken into account in the current development efforts of the lake. Complete removal of floating plants transported by drains is recommended.


MRI-guided selection of patients for treatment of acute ischemic stroke.
To summarize what is known about the use of MRI in acute stroke treatment (predominantly thrombolysis), to examine the assumptions and theories behind the interpretation of magnetic resonance images of acute ischemic stroke and how they are used to select patients for therapies, and to suggest directions for future research. Recent studies have been contradictory about the usefulness of MRI in selecting patients for treatment. New MRI models for selecting patients have emerged that focus not only on the ischemic penumbra but also on the infarct core. Fixed time-window selection parameters are being replaced by timing-based individualized MRI stroke features. New ways to interpret traditional MRI stroke sequences are emerging. Although the efficacy of acute stroke treatment is time dependent, the use of fixed time windows cannot account for individual differences in infarct evolution, which could potentially be detected with MRI. Although MRI shows promise for identifying patients who should be treated, as well as excluding patients who should not be treated, definitive evidence is still lacking. Future research should focus on validating the use of MRI to select patients for intravenous therapies in extended time windows.


Mechanism study of CoS2/Fe(III)/peroxymonosulfate catalysis system: The vital role of sulfur vacancies.
Peroxymonosulfate (PMS) activation methods have attractive advantages in advanced oxidation process (AOPs) due to their powerful ability of directly or indirectly generating various reactive oxygen species (ROS). Herein, trace amount of Fe(III) ions were added into the commercial-CoS2/PMS system to improve the CoS2/PMS decomposition for organics removal. The organics removal efficiency could reach >90% towards methylene blue (MB), diclofenac sodium (DCF), sulfamethoxazole (SMX) and bisphenol A (BPA) in the CoS2/Fe(III)/PMS system, with the kinetic apparent rate constant kobs of 0.141, 0.206, 0.247 and 0.091 min-1, respectively. The synergistic effect between Fe(III) ions and sulfur-vacancies on CoS2 for PMS degradation were revealed for the first time in cobalt sulfides/PMS system. Quenching experiments and ESR analysis proved that 1O2 was the major ROS and was produced mainly by the hydrolysis of SO5•-. Besides, the high degradation efficiency was obtained by the contribution of SO4•- and •OH. Electron spin-resonance spectroscopy (ESR), cyclic voltammetry (CV) and Raman spectrum data revealed that the addition of Fe(III) ions could optimize the intensity of sulfur vacancies on the CoS2 surface, which hindered the PMS reduction ability of Co(II), but accelerated the PMS oxidation to form 1O2. The degradation path of MB was analyzed by liquid chromatograph-mass spectrometer (LC-MS). The mechanism studies speculated that the sulfur vacancies of CoS2 provided the binding sites for Fe(III) ions with Co(II), which facilitated the PMS activation by Co(III).


Risk factors for intensive care delirium: a systematic review.
Delirium has been a recognised syndrome in the intensive care unit for some years. This systematic review reports risk factors for delirium studied in the intensive care unit. Four predisposing and 21 precipitating factors, including nine laboratory blood values and seven items relating to the use or the administration of medication, were found to influence the onset of delirium in the intensive care unit in six publications. The APACHE II score and hypertension were the only factors reported twice. Risk factors for the development of intensive care delirium were understudied and underreported in the literature.


Probability distributions of the electroencephalogram envelope of preterm infants.
To determine the stationary characteristics of electroencephalogram (EEG) envelopes for prematurely born (preterm) infants and investigate the intrinsic characteristics of early brain development in preterm infants. Twenty neurologically normal sets of EEGs recorded in infants with a post-conceptional age (PCA) range of 26-44 weeks (mean 37.5 ± 5.0 weeks) were analyzed. Hilbert transform was applied to extract the envelope. We determined the suitable probability distribution of the envelope and performed a statistical analysis. It was found that (i) the probability distributions for preterm EEG envelopes were best fitted by lognormal distributions at 38 weeks PCA or less, and by gamma distributions at 44 weeks PCA; (ii) the scale parameter of the lognormal distribution had positive correlations with PCA as well as a strong negative correlation with the percentage of low-voltage activity; (iii) the shape parameter of the lognormal distribution had significant positive correlations with PCA; (iv) the statistics of mode showed significant linear relationships with PCA, and, therefore, it was considered a useful index in PCA prediction. These statistics, including the scale parameter of the lognormal distribution and the skewness and mode derived from a suitable probability distribution, may be good indexes for estimating stationary nature in developing brain activity in preterm infants. The stationary characteristics, such as discontinuity, asymmetry, and unimodality, of preterm EEGs are well indicated by the statistics estimated from the probability distribution of the preterm EEG envelopes.


A qualitative study of the characteristics and representation of fatigue in a French speaking population of cancer patients and healthy subjects.
The aim of this study was to explore the differences in the representation of fatigue between cancer patients and healthy subjects; identify the concepts, dimensions and terminology of fatigue specific to patients with cancer-related fatigue (CRF) and healthy persons; examine some of the strategies used in illness and in health to overcome fatigue. A qualitative research design, using grounded theory was used. Twenty-four cancer patients were recruited in outpatients or the wards of a cancer institute and 24 healthy subjects among the hospital personnel or the investigator's entourage. Data were collected through individual audio-taped, open-ended interviews. The transcripts of the interviews were reviewed, and the participants' responses analysed thematically and grouped into major categories and sub-categories. This study demonstrated differences in the intensity, variability, duration and temporality of fatigue between patients and healthy subjects. Analysis resulted in the categorisation of fatigue into three major dimensions, physical, affective and cognitive, common to both patients and healthy subjects, although the frequency and occurrence of themes within these categories differed slightly in the two groups. A fourth category, distress, was identified in the patient group. The linguistic descriptions of fatigue confirmed the differing perceptions of fatigue between patients and healthy individuals and a heightened concern for the negative aspects of fatigue and suffering among patients. A four-step conceptual model for fatigue was developed explaining the different stages in individual responses to fatigue.


Multiple Pools of Nuclear Actin.
While nuclear actin was reported ~50 years ago, it's in vivo prevalence and structure remain largely unknown. Here, we use Drosophila oogenesis, that is, follicle development, to characterize nuclear actin. We find that three different reagents-DNase I, anti-actin C4, and anti-actin AC15-recognize distinct pools of nuclear actin. DNase I labels monomeric or G-actin, and, during follicle development, G-actin is present in the nucleus of every cell. Some G-actin is recognized by the C4 antibody. In particular, C4 nuclear actin colocalizes with DNase I to the nucleolus in anterior escort cells, follicle stem cells, some mitotic follicle cells, and a subset of nurse cells during early oogenesis. C4 also labels polymeric nuclear actin in the nucleoplasm of the germline stem cells, early cystoblasts, and oocytes. The AC15 antibody labels a completely distinct pool of nuclear actin from that of DNase I and C4. Specifically, AC15 nuclear actin localizes to the chromatin in the nurse and follicle cells during mid-to-late oogenesis. Within the oocyte, AC15 nuclear actin progresses from localizing to puncta surrounding the DNA, to forming a filamentous cage around the chromosomes. Together these findings reveal that nuclear actin is highly prevalent in vivo, and multiple pools of nuclear actin exist and can be recognized using different reagents. Additionally, our localization studies suggest that nuclear actin may regulate stemness, nucleolar structure and function, transcription, and nuclear structure. Such findings call for further studies to explore the prevalence, diversity, and functions of nuclear actin across tissues and organisms. Anat Rec, 301:2014-2036, 2018. © 2018 Wiley Periodicals, Inc.


A heritable syndrome of craniosynostosis, short thin hair, dental abnormalities, and short limbs: cranioectodermal dysplasia.
Five children are reported with dolichocephaly (with sagittal suture synostosis in three), sparse, slow-growing, fine hair, epicanthal folds, hypodontia and/or microdontia, short span, brachydactyly and brachypodia, and narrow thoraces. Radiologic abnormalities were noted chiefly in the skull, chest, and limbs. Intelligence was normal. The pattern of inheritance is compatible with an autosomal recessive trait.


Interrogating the 5'UTR tandem repeats of retrotransposon roo of Drosophila about horizontal transfer.
Horizontal transfer in Drosophila has been inferred for several families of transposable elements. Specifically, the retroelement roo has been suggested to have been horizontally transferred between the species D. melanogaster, D. simulans, D. sechellia and D. yakuba. The inferences were based on the observation that divergence between transposable elements in different species was lower than the divergence found in typical nuclear genes and in the incongruence of phylogenies of the species and their TEs. Here, we address the question of the possible horizontal transfer of roo between species of the Drosophila genus by studying the presence absence of a duplication of 99 bp in the 5'UTR of the transposon, as well as comparing the sequences of the paralogous and orthologous duplicated repeats within and between species. First, the repeats were only found in five species of the melanogaster subgroup. Second, the date of occurrence of the duplication event originating the repeats was posterior to the split of the subgroup. The duplication date suggests an origin previous to the split of D. simulans and D. sechellia and close to the divergence of D. melanogaster from the D. simulans complex. These data point to horizontal transfer to the afrotropical species D. yakuba and D. erecta from one of the cosmopolitan species D. melanogaster or D. simulans. We propose that the parasitoid wasp Leptopilina could have been the vector of horizontal transfer after the observation that a sequence of 845 bp with high homology to a fragment of roo was isolated from this wasp.


Imino [4+4] cycloaddition products as exclusive and biologically relevant acrolein-amine conjugates are intermediates of 3-formyl-3,4-dehydropiperidine (FDP), an acrolein biomarker.
We demonstrated synthetically that the eight-membered heterocycles 2,6,9-triazabicyclo[3.3.1]nonanes and 1,5-diazacyclooctanes are the initial and exclusive products of the reaction, through an imino [4+4] cycloaddition, of biologically relevant amines with acrolein. The stabilities of the aminoacetals within the eight-membered heterocycles determined whether the product was subsequently transformed gradually into the 3-formyl-3,4-dehydropiperidine (FDP), which is widely used as an oxidative stress marker. The reactivity profiles discovered in this study suggested that some of the imino [4+4] cycloaddition products are reactive intermediates of FDP and contribute to the mechanisms underlying the oxidative stress response to acrolein.


Nervous regulation: beta-2-adrenergic signaling in immune homeostasis, cancer immunotherapy, and autoimmune diseases.
Beta-2-adrenergic receptor (β2-AR) mediates neural signaling from the sympathetic nervous system (SNS) to the immune system to modulate immunogenic and immunosuppressive responses for maintaining immune homeostasis. β2-AR regulates various cellular activities on the innate and adaptive immune cells through differential signaling to modulate activation, proliferation, differentiation, and cytokine production. This signaling pathway has been found to be critical for regulating anti-tumor immune responses and autoimmune responses. Recently, β2-AR has also been implicated in the mobilization of immune cells in peripheral blood and ex-vivo expansion of cytotoxic T cells from donor blood that has clinical implications for improving cancer immunotherapy. This review attempts to provide a comprehensive overview of the established and emerging roles of β2-AR signaling in immune homeostasis, cancer immunotherapy, and autoimmune diseases.


The physical and mental burden of dry eye disease: A large population-based study investigating the relationship with health-related quality of life and its determinants.
This large cross-sectional population-based study investigated the relationship between dry eye disease (DED) and health-related quality of life (HR-QoL). Dry eye and HR-QoL were assessed in 78,165 participants (19-94 yrs, 59.2% female) from the Dutch population-based Lifelines cohort, using the WHS and the SF36 questionnaire, respectively. Logistic regression was used to assess the relationship between DED and below median Physical Component Summary (PCS) and Mental Component Summary (MCS) score, corrected for age, sex, education, BMI, and 52 comorbidities. Overall, 8.9% of participants had DED. Participants with DED had an increased risk of low PCS (OR 1.54 (95% CI 1.46-1.62)) and MCS scores (OR 1.39 (95% CI 1.32-1.46)), corrected for age and sex. This risk remained significant after correction for comorbidities (P < 0.0005). Increasing DED symptom frequency was associated with decreasing HR-QoL (P < 0.0005). Undiagnosed DED subjects had a significantly increased risk of low mental HR-QoL with increasing dry eye symptoms compared to diagnosed subjects (P < 0.0005). Compared to allergic conjunctivitis, glaucoma, macular degeneration and retinal detachment, DED showed the highest risk of low HR-QoL. Compared to other common systemic and chronic disorders, such as depression, rheumatoid arthritis, and COPD, DED was distinctive by having a substantial reduction in both PCS and MCS. DED is associated with substantial reductions in both physical and mental HR-QoL, also after correction for associated comorbidities. Not having a diagnosis is associated with worse mental HR-QoL in subjects with severe DED. Our results underline the importance of recognizing dry eye as a serious disorder.


Myocardial structure and matrix metalloproteinases.
Metalloproteinases (MMPs) are enzymes which enhance proteolysis of extracellular matrix proteins. The pathophysiologic and prognostic role of MMPs has been demonstrated in numerous studies. The present review covers a wide a range of topics with regards to MMPs structural and functional properties, as well as their role in myocardial remodeling in several cardiovascular diseases. Moreover, the clinical and therapeutic implications from their assessment are highlighted.


Osseous autografts. I. Clinical responses to bone blend or hip marrow grafts.
A clinical evaluation was undertaken to compare regeneration of osseous defects following implantation of either osseous coagulum-bone blend from intraoral sources or autogenous iliac marrow-cancellous bone. Thirty-two transplants were performed in 15 male patients. The intraosseous defects in which marrow was placed (initial average depth = 7.18 mm) filled 60.7% (average fill = 4.36 mm). Defects in which osseous coagulum-bone blend was placed (initial average depth 4.0 mm) filled 73% (average fill = 2.93 mm). The difference in results between the two materials was not statistically significant. Therefore, similar levels of osseous regeneration apparently took place regardless of graft material used.


No Strong Association between the Apolipoprotein E E4 Allele and Glaucoma: A Multicohort Study.
To elucidate a potential association between the apolipoprotein E (APOE) E4 allele and glaucoma prevalence in large cohorts. A cross-sectional analysis of baseline and prospectively collected cohort data. UK Biobank (UKBB) participants of genetically determined European ancestry (n = 438 711). Replication analyses were performed using clinical and genotyping data collected from European participants recruited to the Canadian Longitudinal Study of Aging (CLSA; n = 18 199), the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG; n = 1970), and the Blue Mountains Eye Study (BMES; n = 2440). Apolipoprotein E alleles and genotypes were determined, and their distributions were compared on the basis of glaucoma status. Similar analyses were performed using positive control outcomes associated with the APOE E4 allele (death, dementia, age-related macular degeneration) and negative control outcomes not associated with the APOE E4 allele (cataract, diabetic eye disease). Outcome phenotypes were also correlated with Alzheimer's dementia (AD), a clinical outcome highly associated with the APOE E4 allele. Results of APOE E4 genotype-phenotype comparisons were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Replication analyses investigated APOE E4 associations in 2 replication cohorts (CLSA and ANZRAG/BMES). The APOE E4 allele was inversely associated with glaucoma (OR, 0.96; 95% CI, 0.93-0.99; P = 0.016) and both negative controls (cataract: OR, 0.98; 95% CI, 0.96-0.99; P = 0.015; diabetic eye disease: OR, 0.92; 95% CI, 0.87-0.97; P = 0.003) in the UKBB cohort. A paradoxical positive association was observed between AD and both glaucoma (OR, 1.30; 95% CI, 1.08-1.54; P < 0.01) and cataract (OR, 1.15; 1.04-1.28; P = 0.018). No association between the APOE E4 allele and glaucoma was observed in either replication cohort (CLSA: OR, 1.03; 95% CI, 0.89-1.19; P = 0.66; ANZRAG/BMES: OR, 0.97; 95% CI, 0.84-1.12; P = 0.65). A small negative association observed between APOE E4 and glaucoma within the UKBB was not evident in either replication cohort and may represent an artifact of glaucoma underdiagnosis in APOE E4 carriers. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Risk of Low Energy Availability, Disordered Eating, and Menstrual Dysfunction in Female Collegiate Runners.
Collegiate female distance runners may be at risk for low energy availability (LEA) due to increased exercise energy expenditure with or without decreased energy intake. Furthermore, this population has increased risk of disordered eating (DE), which can lead to LEA and negative health consequences, such as menstrual dysfunction (MD). 1) investigate risk of LEA and DE, 2) compare DE, training volume, and weight dissatisfaction among female collegiate runners at risk vs not at risk for LEA, and 3) compare risk for LEA between NCAA (National Collegiate Athletics Association) Division I, II, and III female collegiate runners. Cross-sectional study. Free-living. Female runners (n = 287) who competed on an NCAA (National Collegiate Athletics Association) Division I, II, or III cross-country and/or track team. A 45 question questionnaire was completed which included the Low Energy Availability in Females Questionnaire (LEAF-Q) and the Disordered Eating Screening Assessment (DESA-6). 54.5% (n = 156) of runners were at risk for LEA (score ≥ 8 on LEAF-Q), and 40.8% (n = 117) were at risk for DE (DESA-6 score ≥ 3), and 56.5% (n = 162) reported MD (LEAF-Q subsection MD score ≥ 4). Athletes "at risk" for LEA had significantly higher DESA-6 scores than athletes "not at risk" for LEA (p < 0.001). Athletes "at risk" for LEA had significantly greater weight dissatisfaction than those not at risk for LEA (X23, 156 = 15.92, p = 0.001). Higher weekly training volumes was not associated with risk for LEA (X22, 156 = 4.20, p = 0.112). A substantial percentage of collegiate female runners were found to be at risk for LEA, DE, and report MD. These findings demonstrate that risk for DE, MD, and weight dissatisfaction are associated with risk for LEA.


Establishment of a pediatric HSCT program in a public hospital in Chile.
In Chile, survival estimates for pediatric patients with cancer are comparable to those in the United States and Western Europe. Approximately 80% of these patients are treated at government-supported centers, and an estimated 65% are cured. We reasoned that cure rates could be further improved if transplantation with hematopoietic stem cells were available for patients with chemotherapy-resistant malignancy. Physicians and nurses were selected to be trained in international centers, and a transplantation unit was developed at Luis Calvo Mackenna Hospital in Santiago. Between October 1999 and December 2003, 59 patients received transplants. Of these, 42 were from HLA-matched family members and 11 were autologous. The 3-year event-free survival estimate was 72 +/- 10% overall, and it was 81 +/- 10% for the subgroup treated with matched related transplants. Peritransplant mortality was 6.6%. The average cost for an allogeneic transplant in our unit was 50,000 US dollars. We are encouraged by this experience as well as by the overall survival rates and hope to expand the program. Our goal is to extend treatment to all children in the country for whom HSCT is indicated, including those who do not have HLA-identical family donors.


Use of different thresholds of prior antimicrobial use in defining exposure: impact on the association between antimicrobial use and antimicrobial resistance.
Although many studies have explored the association between antimicrobial use and antimicrobial resistance, definitions of "exposure" (i.e., prior antimicrobial use) differ across such studies. Specifically, it has been noted that some studies define "exposure" as any antimicrobial use, while others require the administration of at least 24 or 48 h of an antimicrobial to constitute "exposure." The impact of different definitions of exposure on final study results is unknown. We conducted the current study to determine the impact of varying the minimum threshold of prior antimicrobial use to define exposure status in studies of antimicrobial resistance. We used a dataset from a prior study of risk factors for fluoroquinolone (FQ) resistant Pseudomonas aeruginosa (FQRPA) to address the study aim. Four separate multivariable models of risk factors for FQRPA were built. Each model defined a different threshold for the duration of antimicrobial administration to determine "exposure" to that antimicrobial: (1) no threshold (i.e., a subject is considered exposed if any use of the antimicrobial was documented); (2) >24 h of use of the antimicrobial is necessary to be considered exposed; (3) >48 h of use is required; and (4) >72 h of use is required. Except for these definitions, the four multivariable models were built in exactly the same way, each using prior FQ use as the primary risk factor of interest. Among 872 P. aeruginosa isolates included in the original dataset, 332 (38.2%) were FQ-resistant. Each of the four multivariable models identified prior FQ use as an independent risk factor for FQRPA. However, as increasingly strict thresholds were used, the association between FQ use and FQRPA increased. Furthermore, prior use of an agent with activity against anaerobic bacteria was associated with FQRPA in models 2, 3 and 4, but not in model 1. The use of different thresholds to define prior "exposure" to antimicrobials altered the associations between antimicrobial use and resistance. Stricter thresholds resulted in a higher estimate of the association between antimicrobial use and resistance. Furthermore, different risk factors may be identified depending on how exposure is defined. Greater attention to this issue is necessary to optimize identification of modifiable risk factors for resistance as well as accurately compare results across studies.


Can general surgery interns accurately measure their own technical skills? Analysis of cognitive bias in surgical residents' self-assessments.
Accurate self-assessment of knowledge and technical skills is key to self-directed education required in surgical training. We aimed to investigate the presence and magnitude of cognitive bias in self-assessment among a cohort of surgical interns. First-year general surgery residents self-assessed performance on a battery of technical skill tasks (knot tying, suturing, vascular anastomosis, Fundamentals of Laparoscopic Skills peg transfer and intracorporeal suturing) at the beginning of residency. Each self-assessment was compared to actual performance. Bias and deviation were defined as arithmetic and absolute difference between actual and estimated scores. Spearman correlation assessed covariation between actual and estimated scores. Improvement in participant performance was analyzed after an end-of-year assessment. Participants (N = 34) completed assessments from 2017 to 2019. Actual and self-assessment scores were positively correlated (0.55, P < .001). Residents generally underestimated performance (bias -4.7 + 8.1). Participants who performed above cohort average tended to assess themselves more negatively (bias -7.3 vs -2.3) and had a larger discrepancy between self and actual scores than below average performers (deviation index 9.7 + 8.2 vs 3.8 + 3.1, P < .05). End-of-year total scores improved in 31 (91.2%) participants by an average of 11 points (90 possible). Least accurate residents in initial self-assessments (deviation indices >75th percentile) improved less than more accurate residents (median 5 vs 16 points, P < .05). All residents with a deviation index >75 percentile underestimated their performance. Cognitive bias in technical surgical skills is apparent in first-year surgical residents, particularly in those who are higher performers. Inaccuracy in self-assessment may influence improvement and should be addressed in surgical training.


Association between prolonged corticosteroids use in COVID-19 and increased mortality in hospitalized patients: a retrospective study with inverse probability of treatment weighting analysis.
Previous studies have demonstrated a beneficial effect of early use of corticosteroids in patients with COVID-19. This study aimed to compare hospitalized patients with COVID-19 who received short-course corticosteroid treatment with those who received prolonged-course corticosteroid treatment to determine whether prolonged use of corticosteroids improves clinical outcomes, including mortality. This is a retrospective cohort study including adult patients with positive testing for Sars-CoV-2 hospitalized for more than 10 days. Data were obtained from electronic medical records. Patients were divided into two groups, according to the duration of treatment with corticosteroids: a short-course (10 days) and a prolonged-course (longer than 10 days) group. Inverse probability treatment weighting (IPTW) analysis was used to evaluate whether prolonged use of corticosteroids improved outcomes. The primary outcome was in-hospital mortality. Secondary outcomes were hospital infection and the association of different doses of corticosteroids with hospital mortality. Restricted cubic splines were used to assess the nonlinear association between mortality and dose and duration of corticosteroids use. We enrolled 1,539 patients with COVID-19. Among them, 1127 received corticosteroids for more than 10 days (prolonged-course group). The in-hospital mortality was higher in patients that received prolonged course corticosteroids (39.5% vs. 26%, p < 0.001). The IPTW revealed that prolonged use of corticosteroids significantly increased mortality [relative risk (RR) = 1.52, 95% confidence interval (95% CI): 1.24-1.89]. In comparison to short course treatment, the cubic spline analysis showed an inverted U-shaped curve for mortality, with the highest risk associated with the prolonged use at 30 days (RR = 1.50, 95% CI 1.21-1.78). Prolonged course of treatment with corticosteroids in hospitalized patients with COVID-19 was associated with higher mortality.


A Decision Support System for Economically Sustainable Sheep and Goat Farming.
The European sheep and goat sector is characterized by low professionalization and management training. Moreover, it is fragmented in terms of production aims and farming systems. Here, iSAGEDSS, a web-based application allowing dairy and meat small ruminant farmers in different countries to make annual management plans by testing future scenarios, is presented. Data were obtained for the meat sheep (United Kingdom and Spain), dairy sheep (France and Greece) and dairy goat production systems (Greece) from partners of the Innovation for Sustainable Sheep and Goat Production in Europe (iSAGE) project. These were used to set default values and ranges for all important farm parameters in each system and country. An algorithm was developed assessing nutritional management and its impact on production and financial performance. Reports focus on profitability, productivity and environmental sustainability. A case study in three dairy sheep farms in Greece was performed. In each case, an evaluation scenario was created using actual farm data that were compared with the estimated ones. Two scenarios testing management decisions for gross margin maximization and milk pricing fluctuations were created. Application results showed high prediction accuracy for gross margin and production estimation (error of circa 9% and 4%, respectively). Moreover, the ability to promote financial, production and grazing management efficiency was demonstrated.