Incidence, Predictors, and Outcomes of Cardiac Perforation During Pediatric Cardiac Catheterization: a Retrospective Observational Study from the Congenital Cardiac Interventional Study Consortium (CCISC).

INTRODUCTION: Cardiac perforation is a rare life-threatening complication of cardiac catheterization. There is very little published literature detailing risk factors for cardiac perforation and outcomes from this complication in children. MATERIALS AND METHODS: This was a retrospective study analyzing the cardiac catheterization case registry of the Congenital Cardiovascular Interventional Study Consortium. Children aged < 18 years were included during the study period of 9 years (January 2009-December 2017). The primary outcome measures were incidence of cardiac perforation, risk factors for and outcomes of patients who experience cardiac perforation during cardiac catheterization. RESULTS: Cardiac perforation occurred in 50 patients from a total of 36,986 (0.14%). Cardiac perforation was more likely to occur in younger, smaller patients undergoing urgent/emergent and interventional procedures (p < 0.01). Cardiac peroration risk was significantly different across diagnostic and procedure categories (p < 0.01). Higher CRISP score (Area Under Curve [AUC] = 0.87), lower age, and procedure category (radiofrequency perforation of pulmonary valve, AUC = 0.84) were independent predictors of cardiac perforation. Cardiac perforation was associated with a significantly higher rate of mortality (14%), further emergency procedure (42%), ECMO (14%), and cardiac arrest (6%), p < 0.01. CONCLUSIONS: Cardiac perforation during cardiac catheterization is a life-threatening complication with a range of associated secondary complications. Higher CRISP score, lower age, and radiofrequency perforation of pulmonary valve are independent predictors.

Barriers to initiating and maintaining participation in parkrun.

Interventions that increase population physical activity are required to promote health and wellbeing. parkrun delivers community-based, 5 km events worldwide yet 43% who register never participate in a parkrun event. This research had two objectives; i) explore the demographics of people who register for parkrun in United Kingdom, Australia, Ireland, and don't initiate or maintain participation ii) understand the barriers to participating in parkrun amongst these people. Mandatory data at parkrun registration provided demographic characteristics of parkrun registrants. A bespoke online survey distributed across the three countries captured the reasons for not participating or only participating once. Of 680,255 parkrun registrants between 2017 and 19, 293,542 (43%) did not participate in any parkrun events and 147,148 (22%) only participated in one parkrun event. Females, 16-34 years and physically inactive were more likely to not participate or not return to parkrun. Inconvenient start time was the most frequently reported barrier to participating, with females more likely than males to report the psychological barrier of feeling too unfit to participate. Co-creating strategies with and for people living with a chronic disease, women, young adults, and physically inactive people, could increase physical activity participation within parkrun.

Guideline for the management of hip fractures 2020: Guideline by the Association of Anaesthetists.

We convened a multidisciplinary Working Party on behalf of the Association of Anaesthetists to update the 2011 guidance on the peri-operative management of people with hip fracture. Importantly, these guidelines describe the core aims and principles of peri-operative management, recommending greater standardisation of anaesthetic practice as a component of multidisciplinary care. Although much of the 2011 guidance remains applicable to contemporary practice, new evidence and consensus inform the additional recommendations made in this document. Specific changes to the 2011 guidance relate to analgesia, medicolegal practice, risk assessment, bone cement implantation syndrome and regional review networks. Areas of controversy remain, and we discuss these in further detail, relating to the mode of anaesthesia, surgical delay, blood management and transfusion thresholds, echocardiography, anticoagulant and antiplatelet management and postoperative discharge destination. Finally, these guidelines provide links to supplemental online material that can be used at readers' institutions, key references and UK national guidance about the peri-operative care of people with hip and periprosthetic fractures during the COVID-19 pandemic.

Do psychosocial job stressors differentially affect the sleep quality of men and women? A study using the HILDA Survey.

The aim of this study was to investigate whether gender was an effect modifier of the relationship between three psychosocial job stressors and sleep quality, in a representative sample of 7280 employed Australians. We conducted linear regressions and effect measure modification analyses. Low job control, high job demands and low job security were associated with poorer sleep quality. There was evidence of effect modification of the relationship between job security and sleep quality by gender on the additive scale, indicating that the combined effect of being male and having low job security is greater than the summed interactive effect.

How do employment conditions and psychosocial workplace exposures impact the mental health of young workers? A systematic review.

PURPOSE: To assess the quality of the research about how employment conditions and psychosocial workplace exposures impact the mental health of young workers, and to summarize the available evidence. METHODS: We undertook a systematic search of three databases using a tiered search strategy. Studies were included if they: (a) assessed employment conditions such as working hours, precarious employment, contract type, insecurity, and flexible work, or psychosocial workplace exposures such as violence, harassment and bullying, social support, job demand and control, effort-reward imbalance, and organizational justice; (b) included a validated mental health measure; and (c) presented results specific to young people aged ≤ 30 years or were stratified by age group to provide an estimate for young people aged ≤ 30 years. The quality of included studies was assessed using the Risk of Bias in Non-randomized Studies of Exposures (ROBINS-E) tool. RESULTS: Nine studies were included in the review. Four were related to employment conditions, capturing contract type and working hours. Five studies captured concepts relevant to psychosocial workplace exposures including workplace sexual harassment, psychosocial job quality, work stressors, and job control. The quality of the included studies was generally low, with six of the nine at serious risk of bias. Three studies at moderate risk of bias were included in the qualitative synthesis, and results of these showed contemporaneous exposure to sexual harassment and poor psychosocial job quality was associated with poorer mental health outcomes among young workers. Longitudinal evidence showed that exposure to low job control was associated with incident depression diagnosis among young workers. CONCLUSIONS: The findings of this review illustrate that even better studies are at moderate risk of bias. Addressing issues related to confounding, selection of participants, measurement of exposures and outcomes, and missing data will improve the quality of future research in this area and lead to a clearer understanding of how employment conditions and psychosocial workplace exposures impact the mental health of young people. Generating high-quality evidence is particularly critical given the disproportionate impact of COVID-19 on young people's employment. In preparing for a post-pandemic world where poor-quality employment conditions and exposure to psychosocial workplace exposures may become more prevalent, rigorous research must exist to inform policy to protect the mental health of young workers.

Development of a Core Outcome Set for studies evaluating the effects of anaesthesia on perioperative morbidity and mortality following hip fracture surgery.

BACKGROUND: Perioperative studies of patients following hip fracture have large heterogeneity within their reported outcomes. This study aimed to develop a core outcome set for use in perioperative studies comparing the types of anaesthesia for hip fracture surgery. METHODS: The consensus process consisted of a systematic review of the literature, three rounds of a Delphi survey, two consensus webinars, and face-to-face patient meetings. RESULTS: The Delphi participants represented nine stakeholder groups. The numbers of participants completing Rounds 1-3 were 242, 186, and 169, respectively. Seventeen outcomes that met the predefined consensus criteria were considered at two consensus meetings. A final set of 10 core outcomes was agreed: mortality, time from injury to surgery, acute coronary syndrome, hypotension, acute kidney injury, delirium, pneumonia, orthogeriatric input, being out of bed at day 1, and pain. CONCLUSIONS: We generated a consensus-based set of core outcomes recommended for use in all perioperative trials evaluating the effects of anaesthesia for hip fracture surgery. An important next step is developing consensus-based consistency on how they should be measured. CLINICAL TRIAL REGISTRATION: http://www.comet-initiative.org/studies/details/757.

Perioperative outcomes in the context of mode of anaesthesia for patients undergoing hip fracture surgery: systematic review and meta-analysis.

BACKGROUND: Previous meta-analyses on the anaesthetic management of patients undergoing surgery for hip fracture have focused on randomized trials. Furthermore, heterogeneity in outcome reporting across the studies has made it difficult to inform best practice guidelines for patient care. METHODS: This systematic review examined how perioperative outcomes were reported and defined in the context of comparing modes of anaesthesia for hip fracture surgery. Outcomes were included from randomised and non-randomised studies published between January 2000 and July 2017. Meta-analyses were performed for regional versus general anaesthesia, with sensitivity analyses performed for spinal versus general anaesthesia. RESULTS: By including data from 15 large observational studies in this meta-analysis, we have increased the number of patients for whom outcomes were assessed from approximately 3000 to 202 000. There was no significant difference in 30-day mortality (OR 1.02; 95% CI 0.96, 1.07, I2 31%; n=200 616), prevalence of pneumonia (OR 1.07; 95% CI 0.94, 1.23, I2 34%; n=65 011), acute myocardial infarction (OR 0.96; 95% CI 0.88, 1.04, I2 0%, n=64 904), delirium (OR 1.07; 95% CI 0.72, 1.58, I2 93%, n=19 923), or renal failure (OR 0.94; 95% CI 0.54, 1.64, I2 0%, n=27 873) for regional compared with general anaesthesia [corrected]. There was a small statistically significant difference for length of stay (standardized mean difference -0.03; 95% CI -0.05, -0.02; I2 0%; n=78 711) favouring regional anaesthesia, which is unlikely to be clinically significant. Sensitivity analyses for the same outcomes examining spinal only vs general anaesthesia showed minor statistical significance for length of stay favouring spinal. We also present data highlighting the scale of the inconsistencies in reported outcomes across 32 studies, making evaluation in a standardized manner very difficult. As an example, mortality was reported in nine different ways throughout the studies. CONCLUSIONS: We highlight the need for agreement on outcome definitions and for a minimum core outcome set to be measured and reported in hip fracture studies. This would strengthen the evidence-based approach to delivering optimal care.

Transanal TATA/TME: a case-matched study of taTME versus laparoscopic TME surgery for rectal cancer.

BACKGROUND: Natural orifice translumenal endoscopic surgery (NOTES) has always made more sense in the colorectal field where the target organ for entry houses the pathology. To address the question whether an adequate total mesorectal excision (TME) for rectal cancer can be performed from a transanal bottoms-up approach, we performed a case-matched study. METHODS: Starting in 2009, transanal TME (taTME) surgery was selectively used for rectal cancer after neoadjuvant therapy and prospectively entered into a database. Between March 2012 and February 2014, 17 consecutive taTME rectal cancer patients were identified and case-matched to multiport laparoscopic TME (MP TME) based on age, body mass index, uT stage, radiation dose, level in the rectum, and procedure. Perioperative outcomes, morbidity, mortality, local recurrence, completeness of TME, and radial and distal margins were analyzed. Statistically significant differences were identified using Student's t test. RESULTS: There were 12 transanal abdominal transanal (TATA)/5 abdominoperineal resection procedures in each group. Data regarding overall/taTME/MP TME are as follows: % positive-circumferential margin: 2.9/0/5.9 % (p = 0.32). Distal margin: 0/0/0 %. Complete or near-complete TME: 97.1/100/94.1 % (p = 0.32). Incomplete TME 2.9/0/5.9 % (p = 0.32). Local recurrence: 2.9/5.9/0 % (p = 0.32). There were no perioperative mortalities. Morbidity in each group: 26.4/23.5/29.4 % (p = 0.79). There were no differences in perioperative or postoperative outcomes except days to clear liquids (1/2 days, p = 0.03) and largest incision length (1.3/2.6 cm, p = 0.05). CONCLUSIONS: We demonstrated no differences in perioperative/postoperative outcomes or pathologic TME outcomes of transanal or bottoms-up TME compared to standard laparoscopic TME. TaTME is a promising progressive approach to NOTES and deserves additional evaluation.

Blood eosinophils as a marker of likely corticosteroid response in children with preschool wheeze: time for an eosinophil guided clinical trial?

Childhood wheezing is common particularly in children under the age of 6 years and in this age group is generally referred to as preschool wheezing. Particular diagnostic and treatment uncertainties exist in these young children due to the difficulty in obtaining objective evidence of reversible airways narrowing and inflammation. A diagnosis of asthma depends on the presence of relevant clinical signs and symptoms and the demonstration of reversible airways narrowing on lung function testing, which is difficult to perform in young children. Few treatments are available and inhaled corticosteroids are the recommended preventer treatment in most international asthma guidelines. There is, however, considerable controversy about its effectiveness in children with preschool wheeze and a corticosteroid responder phenotype has not been established. These diagnostic and treatment uncertainties in conjunction with the knowledge of corticosteroid side effects, in particular the reduction of growth velocity, have resulted in a variable approach to inhaled corticosteroid prescribing by medical practitioners and a reluctance in carers to regularly administer the treatment. Identifying children who are likely responders to corticosteroid therapy would be a major benefit in the management of this condition. Eosinophils have emerged as a promising biomarker of corticosteroid responsive airways disease, and evaluation of this biomarker in sputum has successfully been employed to direct management in adults with asthma. Obtaining sputum from young children is time consuming and difficult, and it is hard to justify more invasive procedures such as a bronchoscopy in young children routinely. Recently, in children, interest has shifted to assessing the value of less invasive biomarkers of likely corticosteroid response and the biomarker 'blood eosinophils' has emerged as an attractive candidate. The aim of this review was to summarize the evidence for blood eosinophils as a predictive biomarker for corticosteroid responsive disease with a particular focus on the difficult area of preschool wheeze.

Organisational challenges to wellbeing in nuclear medicine technologists: Professionalism, burnout and pragmatic growth.

INTRODUCTION: Occupational risk for burnout in nuclear medicine technologists globally, and particularly during disaster demands on the profession, is poorly researched. This idiographic study explored the lived experience of nuclear medicine technologists during COVID-19 in a regional city in Australia. METHODS: Data was collected from five participants using semi-structured interviews and transcribed and analysed according to the protocols of Interpretative Phenomenological Analysis (IPA). RESULTS: Four group experiential themes were identified: Systemic Contraindications, Professional Strengths and Limitations, Pragmatic Growth, and Covid Rollercoaster. For these participants a dichotomous health care system, impacted by COVID-19, risked career longevity and burnout. Through empathic connection with vulnerable patients, they redefined their priorities, re-engaged in supportive connections with colleagues, and sought new pathways. CONCLUSION: Multiple workplace stressors compounded by COVID-19, risked mental wellbeing, in these participants. Nevertheless, these challenges provided opportunities for reflection around career trajectory and longevity precipitating personal growth, job satisfaction and work-life balance. IMPLICATIONS FOR PRACTICE: This study provided a lens on the risk factors inherent for nuclear medicine technologists in Australia, exacerbated by the COVID-19 pandemic. Current, and disaster protective practices, to ensure wellbeing and prevent burnout risk are recommended for future research.

Evaluation of DNA extraction methods for Bacillus anthracis spores isolated from spiked food samples.

AIMS: Nine commercial DNA extraction kits were evaluated for the isolation of DNA from 10-fold serial dilutions of Bacillus anthracis spores using quantitative real-time PCR (qPCR). The three kits determined by qPCR to yield the most sensitive and consistent detection (Epicenter MasterPure Gram Positive; MoBio PowerFood; ABI PrepSeq) were subsequently tested for their ability to isolate DNA from trace amounts of B. anthracis spores (approx. 6·5 × 10(1) and 1·3 × 10(2)  CFU in 25 ml or 50 g of food sample) spiked into complex food samples including apple juice, ham, whole milk and bagged salad and recovered with immunomagnetic separation (IMS). METHODS AND RESULTS: The MasterPure kit effectively and consistently isolated DNA from low amounts of B. anthracis spores captured from food samples. Detection was achieved from apple juice, ham, whole milk and bagged salad from as few as 65 ± 14, 68 ± 8, 66 ± 4 and 52 ± 16 CFU, respectively, and IMS samples were demonstrated to be free of PCR inhibitors. CONCLUSIONS: Detection of B. anthracis spores isolated from food by IMS differs substantially between commercial DNA extraction kits; however, sensitive results can be obtained with the MasterPure Gram Positive kit. SIGNIFICANCE AND IMPACT OF THE STUDY: The extraction protocol identified herein combined with IMS is novel for B. anthracis and allows detection of low levels of B. anthracis spores from contaminated food samples.

Development of a carbohydrate-supplemented semidefined medium for the semiselective cultivation of Lactobacillus spp.

The macronutrient and micronutrient compositions of traditional media used to cultivate Lactic Acid Bacteria (LAB) are largely undefined, which precludes their use in many metabolic bioassays. In order to address this deficiency, we developed MS: a carbohydrate-supplemented semidefined medium with low-background coloration. MS was designed to support the semiselective cultivation of a wide range of fastidious species belonging to the Lactobacillus clade of the LAB. When supplemented with 100 mM D-glucose, the MS medium stimulated the proliferation of 21 strains of LAB, including Pediococcus spp. and Lactobacillus spp. The MS medium supported biomass accumulation comparable with MRS, an undefined medium routinely used for the cultivation of lactobacilli. Interestingly, however, the novel MS medium exhibited greater semiselectivity against non-LAB than MRS. Together, these results suggest that MS is an acceptable alternative to MRS for use in metabolic and phenotypic bioassays that use a colorimetric reporter system or would benefit from a semidefined nutrient composition.

Genetic susceptibility to invasive meningococcal disease: MBL2 structural polymorphisms revisited in a large case-control study and a systematic review.

Invasive infection caused by Neisseria meningitidis is a worldwide public health problem. Previous reports have indicated that carriage of common 'defective' structural polymorphisms of the host mannose-binding lectin gene (MBL2) greatly increases an individual's risk of developing the disease. We report the largest case-control study so far to investigate the effect of these polymorphisms in meningococcal disease (296 PCR-positive cases and 5196 population controls, all of European ancestry) and demonstrate that no change in risk is associated with the polymorphisms overall or in any age-defined subgroup. This finding contrasts with two smaller studies that reported an increase in risk. A systematic review of all studies of MBL2 polymorphisms in people of European ancestry published since 1999, including 24,693 individuals, revealed a population frequency of the combined 'defective'MBL2 allele of 0.230 (95% confidence limits: 0.226-0.234). The past reported associations of increased risk of meningococcal disease were because of low 'defective' allele frequencies in their study control populations (0.13 and 0.04) that indicate systematic problems with the studies. The data from our study and all other available evidence indicate that MBL2 structural polymorphisms do not predispose children or adults to invasive meningococcal disease.

High concentrations of pepsin in bronchoalveolar lavage fluid from children with cystic fibrosis are associated with high interleukin-8 concentrations.

BACKGROUND: Gastro-oesophageal reflux is common in children with cystic fibrosis (CF) and is thought to be associated with pulmonary aspiration of gastric contents. The measurement of pepsin in bronchoalveolar lavage (BAL) fluid has recently been suggested to be a reliable indicator of aspiration. The prevalence of pulmonary aspiration in a group of children with CF was assessed and its association with lung inflammation investigated. METHODS: This was a cross-sectional case-control study. BAL fluid was collected from individuals with CF (n=31) and healthy controls (n=7). Interleukin-8 (IL-8), pepsin, neutrophil numbers and neutrophil elastase activity levels were measured in all samples. Clinical, microbiological and lung function data were collected from medical notes. RESULTS: The pepsin concentration in BAL fluid was higher in the CF group than in controls (mean (SD) 24.4 (27.4) ng/ml vs 4.3 (4.0) ng/ml, p=0.03). Those with CF who had raised pepsin concentrations had higher levels of IL-8 in the BAL fluid than those with a concentration comparable to controls (3.7 (2.7) ng/ml vs 1.4 (0.9) ng/ml, p=0.004). Within the CF group there was a moderate positive correlation between pepsin concentration and IL-8 in BAL fluid (r=0.48, p=0.04). There was no association between BAL fluid pepsin concentrations and age, sex, body mass index z score, forced expiratory volume in 1 s or Pseudomonas aeruginosa colonisation status. CONCLUSIONS: Many children with CF have increased levels of pepsin in the BAL fluid compared with normal controls. Increased pepsin levels were associated with higher IL-8 concentrations in BAL fluid. These data suggest that aspiration of gastric contents occurs in a subset of patients with CF and is associated with more pronounced lung inflammation.

Lower limb blocks.

The advances in regional techniques for blocks of the lower limb have been driven primarily by the need to produce effective analgesia in the postoperative period and beyond. These techniques are commonly performed before or after central neuraxial blockade when this technique is used to provide anaesthesia and analgesia for the surgical procedure. Increasingly, modern practice demands a shorter hospital stay, improved patient expectations and early mobilisation. This article describes the current methods and reasons for performing specific blocks to the lower limb and the management of these blocks particularly in the postoperative period.

Respiratory viral infection in lower airways of asymptomatic children.

AIM: The aim of this study was to determine if asthmatic children have viruses more commonly detected in lower airways during asymptomatic periods than normal children. METHODS: Fifty-five asymptomatic children attending elective surgical procedures (14 with stable asthma, 41 normal controls) underwent non-bronchoscopic bronchoalveolar lavage. Differential cell count and PCR for 13 common viruses were performed. RESULTS: Nineteen (35%) children were positive for at least one virus, with adenovirus being most common. No differences in the proportion of viruses detected were seen between asthmatic and normal 'control' children. Viruses other than adenovirus were associated with higher neutrophil counts, suggesting that they caused an inflammatory response in both asthmatics and controls (median BAL neutrophil count, 6.9% for virus detected vs. 1.5% for virus not detected, p = 0.03). CONCLUSIONS: Over one-third of asymptomatic children have a detectable virus (most commonly adenovirus) in the lower airway; however, this was not more common in asthmatics. Viruses other than adenovirus were associated with elevated neutrophils suggesting that viral infection can be present during relatively asymptomatic periods in asthmatic children.

Are radiographers an influencing factor in the radiation protection practices of speech-language therapists performing videofluoroscopic swallowing studies?

INTRODUCTION: A videofluoroscopic swallowing study (VFSS) is a fluoroscopic examination conducted by radiographers and speech-language therapists (SLTs) to assess dysphagia. Given the potential of SLTs to feed patients during the procedure, they may be exposed to radiation. The research aimed to assess radiation protection practices utilised by SLTs to determine if radiographers have a role in providing ongoing practical education. METHODS: An online questionnaire was distributed to SLTs from six countries (Australia, Canada, Ireland, New Zealand, United Kingdom and United States of America). Responses were analysed quantitatively using frequencies and chi-square analysis (p = 0.05) and supported by written comments. RESULTS: A total of 224 responses were analysed. Thyroid shields (94%) were used more frequently than full aprons (72%). Differences (p < 0.0001) were seen between Australian and USA participants regarding the use and position of radiation monitors; 43% of Australian participants stating they always used a monitor, compared to 75% of USA participants. Nearly all Australian SLTs wore monitors under shielding (92%) and at waist level (69%), while USA participants reported wearing them outside shielding (97%) and at thyroid level (94%). Participants' radiation practice was influenced primarily by other SLTs (64%), followed by radiographers (57%). However, written comments revealed the significance of the radiographer in providing training as "radiographers are excellent at ensuring we [use] right equipment, stand in the right places and use exposure monitoring". CONCLUSION: SLTs did not always adopt the ICRP principle of shielding and there were inconsistencies with regards to the use and placement of radiation monitors. Radiographers are well positioned to provide advice with regards to safe practice. IMPLICATIONS FOR PRACTICE: Opportunities to enhance radiation protection practices are evident, as is the advising role of radiographers.

Assessment of optic nerve cup-to-disk ratio changes in patients receiving multiple intravitreal injections of antivascular endothelial growth factor agents.

PURPOSE: To assess whether the transient intraocular pressure rise, frequent intraocular pressure fluctuations, or antivascular endothelial growth factor (VEGF) effects of repeated intravitreal injection of anti-VEGF agents can lead to changes in the optic nerve vertical cup-to-disk ratio (C/D). METHODS: Patients with a known history of glaucoma and those receiving triamcinolone acetonide were excluded from the study. Fundus photographs were cropped to optic disk images only, which were then randomized and independently graded by two glaucoma specialists. In patients who received treatments in only one eye, the fellow eye was used as a control. RESULTS: Twenty-three eyes of 21 patients met inclusion criteria. The mean change in C/D was -0.012 (95% confidence interval [CI], -0.053 to 0.029) for the treated group and -0.006 (95% CI, -0.106 to 0.095) for the control group, with no statistically significant difference (P = 0.90). The mean change in C/D for eyes receiving < or =5 injections (n = 9) was 0.003 (95% CI, -0.089 to 0.095) in the treated group and 0.054 (95% CI, -0.033 to 0.142) in the control group, with no statistically significant difference (P = 0.33). In eyes receiving >5 injections (n = 14), the mean change in C/D was -0.021 (95% CI, -0.095 to 0.052) in the treated group and -0.057 (95% CI, -0.231 to 0.116) in the control group, with no statistically significant difference (P = 0.70). CONCLUSION: There was no statistically significant change in the vertical C/D of optic nerves in patients receiving multiple intravitreal injections of anti-VEGF agents, regardless of whether they received fewer or more than five total injections. This suggests that the short-term intraocular pressure rise and frequent intraocular pressure fluctuation, as well as the anti-VEGF properties of these drugs, do not adversely change the optic nerve C/D. Additional prospective studies are warranted to confirm these conclusions.