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INTRODUCTION: Verbal feedback from trainees to supervisors is rare in medical education, although valuable for improvement in teaching skills. Research has mostly examined narrative comments on resident evaluations of their supervisors. This study aimed to explore supervisors' and residents' beliefs and experiences with upward feedback, along with recommendations to initiate and facilitate effective conversations.METHODS: Using 60-minute focus group discussions, a previous study explored opinions of internal medicine residents and clinical supervisors at the Brigham and Women's Hospital regarding the impact of institutional culture on feedback conversations. For this study, we conducted a thematic analysis of the transcribed, anonymous data to identify key concepts pertaining only to verbal upward feedback, through the theoretical lens of Positioning theory.RESULTS: Twenty-two supervisors and 29 residents participated in three and five focus groups, respectively. Identified themes were mapped to three research questions regarding (1) existing beliefs (lack of impact, risks to giving supervisors feedback, need for preparation and reflection), (2) experiences (nonspecific language, avoidance of upward feedback, bypassing the supervisor), and (3) recommended approaches (setting clear expectations, seeking specific feedback, emphasizing interest in growth).DISCUSSION: Study participants appeared to assume learner-teacher positions during feedback conversations, resulting in residents' concerns of adverse consequences, beliefs that supervisors will neither accept feedback nor change their behaviors, and avoidance of constructive upward feedback. Residents suggested that emphasis on mutual professional growth and regular feedback seeking by supervisors could encourage them to take on the role of feedback providers. Their recommendations could be a valuable starting point for faculty development initiatives on upward feedback.

Schwannomas of the sinonasal tract are rare, accounting for

The transcription factor or tumor suppressor protein p53 regulates numerous cellular functions, including cell proliferation, invasion, migration, senescence and apoptosis, in various types of cancer. HS-1793 is an analog of resveratrol, which exhibits anti-cancer effects on various types of cancer, including breast, prostate, colon and renal cancer, and multiple myeloma. However, to the best of our knowledge, the role of HS-1793 in lung cancer remains to be examined. The present study aimed to investigate the anti-cancer effect of HS-1793 on lung cancer and to determine its association with p53. The results revealed that HS-1793 reduced cell proliferation in lung cancer and increased p53 stability, thereby elevating the expression levels of the target genes p21 and mouse double minute 2 homolog (MDM2). When the levels of MDM2, a negative regulator of p53, are increased under normal conditions, MDM2 binds and degrades p53; however, HS-1793 inhibited this binding, confirming that p53 protein stability was increased. In conclusion, the findings of the present study provide new evidence that HS-1793 may inhibit lung cancer proliferation by disrupting the p53-MDM2 interaction.

Background The R2C2, a 4-phase feedback and coaching model, builds relationships, explores reactions, determines content and coaches for change, and facilitates formal feedback conversations between clinical supervisors/preceptors and residents. Formal discussions about performance are typically based on collated information from daily encounter sheets, objective structured clinical examinations, multisource feedback, and other data. This model has not been studied in settings where brief feedback and coaching conversations occur immediately after a specific clinical experience. Objective We explored how supervisors adapt the R2C2 model for in-the-moment feedback and coaching and developed a guide for its use in this context. Methods Eleven purposefully selected supervisors were interviewed in 2018 to explore where they used the R2C2 model, how they adapted it for in-the-moment conversations, and phrases used corresponding to each phase that could guide design of a new R2C2 in-the-moment model. Results Participants readily adapted the model to varied feedback situations; each of the 4 phases were relevant for conversations. Phase-specific phrases that could enable effective coaching conversations in a limited amount of time were identified. Data facilitated a revision of the original R2C2 model for in-the-moment feedback and coaching conversations and design of an accompanying trifold brochure to enable its effective use. Conclusions The R2C2 in-the-moment model offers a systematic approach to feedback and coaching that builds on the original model, yet addresses time constraints and the need for an iterative conversation between the reaction and content phases. The model enables supervisors to coach and co-create an action plan with residents to improve performance.

In 2015, the College of Family Physicians of Canada, in performing their commitment to supporting its members in their educational roles, created the Family Medicine Framework (FTA). It was designed to assist family medicine educators with an understanding of the core activities of educators: precepting, coaching, and teaching within or beyond clinical settings. Given that an examination of member awareness of FTA has not been previously undertaken, our primary objective was to conduct an evaluation on its utility and application.In partnership with College of Family Physicians of Canada Faculty Development Education Committee members, we used a practical participatory evaluation approach to conduct a two-phase mixed-methods evaluation of the FTA. We distributed an electronic survey in French and English languages to Canadian faculty development, program, and site directors in family medicine. We then conducted follow-up interviews with self-selected participants.Of the target populations, 12/15 (80%) faculty development directors (FDDs), 12/18 (66.7%) program directors, and 34/174 (19.5%) site directors completed the electronic survey. Subsequently, 6 FDDs, 3 program directors, and 3 site directors completed an interview (n = 12). Findings indicate that awareness of the FTA was highest among FDDs. Facilitators who encourage teachers to use the FTA and barriers for low uptake were also identified.This evaluation illuminated that varied levels of awareness of the FTA may contribute to the low uptake among education leaders. We also suggest future research to address possible barriers that hinder effective applications of the FTA in faculty development initiatives.

We demonstrate a monolithically integrated active topological photonic structure. Using a unique design with distributed gain/dielectric medium, we selectively address the topological mode to achieve robust and tunable continuous-wave single-mode emission at room temperature.

Background Although the gut microbiome dysbiosis have independently been shown to be associated with inflammatory bowel disease (IBD), less is known about the relationship between oral microbiota and IBD. This study aimed to elucidate unique microbiome patterns in saliva from patients with IBD and investigate potential oral microbial markers for differentiating Crohn’s disease (CD) and ulcerative colitis (UC). Methods A multicenter, prospective cohort study recruited patients with IBD (UC, n=175, CD, n=127) and unrelated healthy controls (HC, n=100) to examine microbiota within the oral microenvironments. We used 16S rRNA gene sequencing data as features in training machine learning models (sPLS-DA, Sparse Partial Least-Squares Discriminant Analysis) to classify CD and UC. Results The V3-V4 amplicon reads of the saliva 16S rRNA sequencing data were taxonomically classified to a total of 2839 taxa (2270 genera) using Kraken2 based on Silva 138.1 reference. The sequences that were not classifiable down to family level were removed, and the samples having sequence depth less than 30000 were also removed, resulting in 2616 taxa for 390 samples (UC, n=168, CD, n=124, HC, n=98). The alpha diversity analysis revealed that the microbiome in IBD patients were significantly less rich than the healthy controls, while CD samples were slightly richer then UC samples (Figure 1, Observed, P = 0.01, Shannon index, p=0.02, Chao index, P=0.0001). An sPLS-DA model with 470 taxa as features was able to distinguish IBD vs control with high performance (AUROC=0.9774), while a separate sPLS-DA model with 130 features classified CD vs UC with an AUROC of 0.8755 (Figure 2,3). Conclusion Collectively, oral microbial profiles can serve as a diagnostic marker to discriminate patients with IBD from HC, and patients with CD from UC. As obtaining oral samples is relatively easier than obtaining stool or intestinal biopsies, an opportunity exists to perform oral microbiome-based studies in larger cohort sizes, preferentially in a longitudinal fashion.

Supporting information is available online at https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.31983#support-information-section . From 2023 Hepatology is published by Wolters Kluwer Health on behalf of the American Association for the Study of Liver Diseases. Background and Aims Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of c-Jun N-terminal kinase (JNK) pathway is a key feature in ICC and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes ICC growth, and thus the key downstream effectors of this pathway remain unknown for their applicability as therapeutic targets. Our aim was to obtain a better mechanistic understanding of the role of JNK signalling in ICC that could open new therapeutic opportunities. Approach and Results Using loss- and gain-of-function studies in vitro and in vivo, we show that activation of the JNK pathway promotes ICC cell proliferation by affecting the protein stability of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), a key driver of tumorigenesis. PIN1 is highly expressed in ICC primary tumours, and its expression positively correlates with active JNK. Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. Moreover, pharmacological inhibition of PIN1 via all-trans retinoic acid (ATRA), an FDA-approved drug, impairs the growth of both cultured and xenografted ICC cells. Conclusions Our findings implicate the JNK-PIN1 regulatory axis as a functionally important determinant for ICC growth, and provide a rationale for therapeutic targeting of JNK activation via PIN1 inhibition. AMMF - The Cholangiocarcinoma Charity. Grant Number: 2014; Foundation for Liver Research. Grant Number: Start-up 2010; Guts UK. Grant Number: DGO2019_02; Rosetrees Trust. Grant Number: M894; Brunel University London. Grant Number: BRIEF LBL348; Blood Cancer UK. Grant Number: 17014; Faculty of Medicine and Health, University of Leeds. Grant Number: 250 ; Great Minds University Academic Fellowship 2016.

Introduction The continuous supply of personal protective equipment (PPE) in the National Health Service (NHS) is paramount in order to sustain a safe level of staffing and to reduce transmission of COVID-19 to patients, public and staff. Method A 16-question survey was created to assess the availability and personal thoughts of healthcare professionals regarding PPE supply in England. The survey was distributed via social media (Facebook © and Twitter ©) to all UK COVID-19 healthcare professional groups, with responses collected over 3 weeks in March 2020 during the beginning of the pandemic. Results A total of 121 responses from physicians in 35 different hospitals were collected (105 inpatient wards, 16 from intensive care units). In inpatient wards, eye and face protection were unavailable to 19.1% of respondents. Masks were available to 97.7% of respondents and gloves in all respondents (100%). Body protection was available primarily as a plastic apron (83.8%). All of respondents working in intensive care had access to full-body PPE, except FFP3 respirator masks (available in 87.5%). PPE is ‘Always’ available for 29.8% of all respondents, and ‘Never’ or ‘Almost Never’ in 11.6%. There was a statistically significant difference between London and non-London responders that ‘Always’ had PPE available (43.9% versus 19.0%, p = 0.003). Conclusions This is the first survey to evaluate PPE supply in England during the COVID-19 pandemic. Our survey demonstrated an overall lack of PPE volume supply in the UK, with preferential distribution in London. Eye and full body protection are in most lack of supply.

Background The overall global impact of COVID-19 in children and regional variability in pediatric outcomes are presently unknown. Methods To evaluate the magnitude of global COVID-19 death and intensive care unit (ICU) admission in children aged 0–19 years, a systematic review was conducted for articles and national reports as of December 7, 2020. This systematic review is registered with PROSPERO (registration number: CRD42020179696). Results We reviewed 16,027 articles as well as 225 national reports from 216 countries. Among the 3,788 global pediatric COVID-19 deaths, 3,394 (91.5%) deaths were reported from low- and middle-income countries (LMIC), while 83.5% of pediatric population from all included countries were from LMIC. The pediatric deaths/1,000,000 children and case fatality rate (CFR) were significantly higher in LMIC than in high-income countries (HIC) (2.77 in LMIC vs 1.32 in HIC; p < 0.001 and 0.24% in LMIC vs 0.01% in HIC; p < 0.001, respectively). The ICU admission/1,000,000 children was 18.80 and 1.48 in HIC and LMIC, respectively (p < 0.001). The highest deaths/1,000,000 children and CFR were in infants < 1 year old (10.03 and 0.58% in the world, 5.39 and 0.07% in HIC and 10.98 and 1.30% in LMIC, respectively). Conclusions The study highlights that there may be a larger impact of pediatric COVID-19 fatality in LMICs compared to HICs.

To investigate sports compression garment (CG)-induced recovery hemodynamics and their potential impact on subsequent cycling performance.In a randomized crossover design, 13 physically active men (20.9 ± 1.4 years; 65.9 ± 7.8 kg; 173.3 ± 4.8 cm; peak power output 254.2 ± 27.2 W) underwent 2 experimental trials. During each experimental trial, the subjects performed 20-min fatiguing preload cycling followed by 60-min passive recovery wearing either a sports CG (28.6 ± 9.4 mmHg) or gymnastic pants (CON). A 5-min all-out cycling performance test was subsequently conducted and power output and cadence were recorded. Cardiac output (CO) and stroke volume (SV) were measured using Doppler ultrasound (USCOM®). Heart rate (HR), blood lactate [BLaDuring the subsequent 5-min all-out cycling performance test, power output (215.2 ± 24.0 vs. 210.8 ± 21.5 W, CG vs. CON) and cadence (72.5 ± 3.8 vs. 71.2 ± 4.8 rpm, CG vs. CON) were higher in CG than CON (P 0.05). SV was higher at 15, 30 and 45 min (P 0.05), CO was higher at 5 and 45 min (P 0.05), HR was lower at 15 and 30 min (P 0.05) and [BLaSports CG improves subsequent cycling performance by enhancing hemodynamic responses and attenuating perceived muscle soreness during passive recovery in physically active men.

ObjectiveThe objective of our study was to explore the perspectives of patients and general practitioners (GPs) regarding interventions to increase initiation of cholesterol lowering medication (or statins), including a proposed laboratory-based facilitated relay intervention.DesignQualitative descriptive study using interviews and focus groups for data collection, and thematic analysis for data analysis.SettingPrimary care providers and patients in Calgary, Alberta, Canada.Participants17 GPs with primarily community-based, non-academic practices with at least 1 year of practice experience participated in semistructured interviews. 14 patients at high risk of cardiovascular disease participated in focus groups.Main outcome measuresExploration of strategies that might be used to enhance the prescription of, and adherence to statin therapy for patients with statin-indicated conditions.ResultsGPs proposed a variety of interventions to improve statin prescription, including electronic record audit solutions, GP directed education, and patient-oriented campaigns. Patients expressed that they may benefit from being provided access to their laboratory test results, as well as targeted education. Both parties provided positive feedback on the proposed laboratory-based facilitated relay intervention, while pointing out areas for improvement. Notably, GPs were concerned that the patient-directed component of the intervention might jeopardise therapeutic relationships, and patients were concerned about accidental disclosure of personal health information. Important considerations for the design of facilitated relay messaging should include brevity, simplicity and the provision of contact information for inquiries.ConclusionsGPs and patients described several suggestions for increasing statin initiation and welcomed the proposal of a laboratory-based facilitated relay strategy. These findings support further testing of this intervention which may enhance GPs’ ability to successfully engage patients in cardiovascular risk reduction through statin therapy.

Routine exercise has been established as an effective way to improve overall health. The value of exercise has been established in many diseases, however, there are no studies investigating the impact of exercise for individuals with primary immunodeficiency disease (PID). The purpose of this study was to investigate exercise perceptions and behaviors in individuals diagnosed with PID. An online survey was distributed over a four-week period. Of the 264 responses collected, most were females, 45–54 years old. Respondents reported a measurable loss of function impairing their daily activities due to loss of mobility/physical activity (41.32%), or loss of lung/pulmonary function (40.08%,). They felt exercise decreased stress level and improved their mental well-being (46.25%). Some indicated they participate in exercise (33.20%), while 36.84% had not participated in exercise for at least 1 year. Exercise was limited primarily due to fatigue (86.97%). Exercise is important for those with chronic medical conditions. Most individuals living with PID can participate in low/moderate physical activity, but struggle with vigorous physical activity, since fatigue is the greatest barrier. Respondents view exercise as beneficial, and would like to increase participation in an exercise program.

Background Patients with interstitial lung disease (ILD) constitute a substantial disease burden. Although ILD outcomes have been investigated, the risk of death due to ILD has not been studied in the light of confounders and comorbidities. In this nationwide, 11-year longitudinal, population-based study, we aimed to discover if ILD is an independent risk factor for mortality. Design Data on 1 031 392 (2.2%) randomly selected subjects from 47 279 373 Korean residents were collected from the 2002 Korean National Health Insurance database. The ILD group comprised patients with an initial diagnosis of ILD between January 2003 and December 2007. Each patient was followed until 2013. We used Cox proportional hazard regression analyses to calculate the risk of death adjusted for comorbidities and confounders. Results ILD developed in 783 of the 303 385 subjects during the 5-year period (51 per 100 000 person-years). Death occurred in 157 (23.2%) cases and 272 controls (10.4%). ILD was significantly associated with the risk of death (hazard ratio 2.1, 95% confidence interval [CI] 1.6-2.7) and for those aged 40-59, 60-69 and 70 years. A high proportion of patients with ILD died due to respiratory causes. Conclusion ILD patients had a significantly higher risk of death than matched controls, after adjustment for potential confounders and comorbidities.

Background Approved first-line treatments for patients with BRAF V600–mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). Patients and methods A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. Results In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. Conclusion Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months., Highlights • First-line treatments for BRAF V600-mutant melanoma include NIVO+IPI and BRAF/MEK inhibitors. • Results from prospective RCTs comparing NIVO+IPI and BRAF/MEK inhibitors have not yet been reported. • This MAIC evaluated NIVO+IPI versus BRAF/MEK inhibitors for BRAF-mutant advanced melanoma. • OS and PFS benefits were noted with NIVO+IPI versus BRAF/MEK inhibitors beginning at 12 months. • These findings may provide information relevant to the selection of treatments for BRAF-mutant advanced melanoma.

Although 53BP1 has been established well as a mediator in DNA damage response, its function in mitosis is not clearly understood. We found that 53BP1 is a mitotic-binding partner of the kinases Plk1 and AuroraA, and that the binding with Plk1 increases the stability of 53BP1 by accelerating its interaction with the deubiquitinase USP7. Depletion of 53BP1 induces mitotic defects such as chromosomal missegregation, misorientation of spindle poles and the generation of extra centrosomes, which is similar phenotype to USP7-knockdown cells. In addition, 53BP1 depletion reduces the levels of p53 and centromere protein F (CENPF), interacting proteins of 53BP1. These phenotypes induced by 53BP1 depletion were rescued by expression of wild-type or phosphomimic mutant 53BP1 but not by expression of a dephosphomimic mutant. We propose that phosphorylation of 53BP1 at S380 accelerates complex formation with USP7 and CENPF to regulate their stability, thus having a crucial role in proper centrosome positioning, chromosomal alignment, and centrosome number.

This abstract was withdrawn by the authors.

We establish a set of necessary conditions and a set of sufficient conditions for boundedness of a family of Brascamp-Lieb forms in Lorentz spaces and $L^p$-spaces with power weights. The conditions are close to optimal., 15 pages, updated version with minor changes suggested by referee. New material discussing multi-linear fractional integrals

Despite the amenability of early-stage prostate cancer to surgery and radiation therapy, locally advanced and metastatic prostate cancer is clinically problematic. Chemical castration is often used as a first-line therapy for advanced disease, but progression to the castration-resistant prostate cancer phase occurs with dependable frequency, largely through mutations to the androgen receptor (AR), aberrant AR signaling, and AR-independent mechanisms, among other causes. Semaphorin 3C (SEMA3C) is a secreted signaling protein that is essential for cardiac and neuronal development and has been shown to be regulated by the AR, to drive epithelial-to-mesenchymal transition and stem features in prostate cells, to activate receptor tyrosine kinases, and to promote cancer progression. Given that SEMA3C is linked to several key aspects of prostate cancer progression, we set out to explore SEMA3C inhibition by small molecules as a prospective cancer therapy. A homology-based SEMA3C protein structure was created, and its interaction with the neuropilin (NRP)-1 receptor was modeled to guide the development of the corresponding disrupting compounds. Experimental screening of 146 in silico‒identified molecules from the National Cancer Institute library led to the discovery of four promising candidates that effectively bind to SEMA3C, inhibit its association with NRP1, and attenuate prostate cancer growth. These findings provide proof of concept for the feasibility of inhibiting SEMA3C with small molecules as a therapeutic approach for prostate cancer.

This study including two parts investigates the influence of design parameters of tapered-spool restrictors and hydrostatic planar bearing on static characteristics of load capacity and static stiffness. The former part provides guides for the design of single-action and double-action tapered-spool restrictors. This part provides design guides for planar hydrostatic bearing and for matching up with tapered-spool restrictor. The equations of flow continuity are utilized to determine the film thickness for open-type planar bearing and worktable displacement for closed-type planar bearing with respect to the recess pressure, respectively. The load capacity can be obtained by multiplying recess pressure by effective area of bearing pad. Furthermore, the static stiffness can be obtained by differentiating the recess pressure with respect to film thickness or worktable displacement. The finding results give that the usage range of recess pressure, and the availability ranges of design parameters of restrictor and bearing parameters. Which are found for getting the maximum stiffness.

This paper is former part of serial studies to investigate the influence of design parameters of tapered-spool type restrictors on static characteristics of hydrostatic bearing. The flow rates passing restrictors can determine the static characteristics of hydrostatic bearings. In this part an analytical method which includes formulas and solving is utilized to simulate dimensionless flow rate in both single-action and double-action tapered-spool restrictors. The numerical results illustrate the variations of flow rates with respect to the change of pressure and pressure difference, respectively. The findings give that the design parameters of tapered-spool restrictors and the useful range of recess pressure. The following part will depend on this paper results to study load capacity and static stiffness of hydrostatic bearing compensated by tapered-spool restrictor.

The mortality rate in patients with haemodynamically unstable pelvic fractures is as high as 40–60%. Despite the new advances in trauma care which are in phase in trauma centres in Hong Kong, the management of haemodynamically unstable pelvic fracture is still heterogeneous. The aim of this study is to review the results of management of haemodynamically unstable pelvic fracture patients in Hong Kong over a five year period. This is a retrospective multi-centred cohort study of patients with haemodynamic and mechanically unstable pelvic fractures from 1 January 2010 to 31 December 2014. The primary outcome investigated is mortality of patients (including overall, 30-day, 7-day and 24-hour mortalities). Implementation of three-in-one pelvic damage control protocol was identified to be a significant independent predictive factor for overall, 30-day, seven-day and 24-hour mortalities. The overall in-hospital and 30-day mortality rates for patients managed with three-in-one protocol was 12.5%, while it was 11% for seven day mortality and 6% for 24 hour mortality. There were no significant differences in demographic characteristics, physiological measurements, types of pelvic fracture, severity and mechanism of injury between patients managed with or without three-in-one protocol. Implementation of the multidisciplinary three-in-one pelvic damage control protocol reduces mortality and therefore should be highly recommended. The results are convincing as it has eliminated the limitations of our previous single-centred trial.