Search Results for: GPG: Versione 5.7.5 (Novembre 2021)

Objective
To explore patient and healthcare professional perceptions about the acceptability and impact of a large-scale system for automated, real-time monitoring and feedback of shared decision-making (SDM) that has been integrated into surgical care pathways.

Design
Qualitative, semistructured interviews were conducted with patients and healthcare professionals between June and November 2021. Data were analysed using deductive and inductive approaches.

Setting
Large-scale monitoring of SDM has been integrated in NHS surgical care across two large UK National Health Service Trusts.

Participants
Adult surgical patients (N=18, 56% female), following use of an SDM real-time monitoring and feedback system, and healthcare professionals (N=14, 36% female) involved in their surgical care. Patient recruitment was conducted through hospital research nurses and professionals by direct approach from the study team to sample individuals purposively from seven surgical specialties (general, vascular, urology, orthopaedics, breast, gynaecology and urgent cardiac).

Results
10 themes were identified within three areas of exploration that described factors underpinning: (1) the acceptability of large-scale automated, real-time monitoring of SDM experiences, (2) the acceptability of real-time feedback and addressing SDM deficiencies and (3) the impact of real-time monitoring and feedback. There was general support for real-time monitoring and feedback because of its perceived ability to efficiently address deficiencies in surgical patients’ SDM experience at scale, and its perceived benefits to patients, surgeons and the wider organisation. Factors potentially influencing acceptability of large-scale automated, real-time monitoring and feedback were identified for both stakeholder groups, for example, influence of survey timing on patient-reported SDM scores, disease-specific risks, patients’ dissatisfaction with hospital processes. Factors particularly important for patients included concerns over digital exclusion exacerbated by electronic real-time monitoring. Factors unique to professionals included the need for detailed, qualitative feedback of SDM to contextualise patient-reported SDM scores.

Conclusions
This study explored factors influencing the acceptability of automated, real-time monitoring and feedback of patients’ experiences of SDM integrated into surgical practice, at scale among key stakeholders. Findings will be used to guide refinement and implementation of SDM monitoring and feedback prior to formal development, evaluation and implementation of an SDM intervention in the NHS.

Trial registration number
ISRCTN17951423.

The original protocol
doi: 10.1136/bmjopen-2023-079155.

Importance
Background rates are critical for contextualising safety signals arising from COVID-19-related interventions in investigational or real-world settings.

Objective
To estimate background rates of medical events of interest (MEI) for which COVID-19 infection and/or COVID-19 interventions may be risk factors in two US claims databases.

Design, setting and participants
This retrospective cohort study spans the pre-COVID-19 (2018–2019) and COVID-19 (2020–2021) periods. We constructed three cohorts, in each of Inovalon/HealthVerity (Inovalon/HV) and Optum databases: a COVID-19-positive adult cohort (2020–2021), a paediatric cohort (2018–2021) and a high-risk cohort (2018–2021) comprising patients at increased risk for severe COVID-19. Participants were indexed on the day they first qualified to enter each cohort during the study period. Background rates of 17 MEI were estimated per 1000 person-years (PY) with 95% CIs.

Main outcomes and measures
Annual incidence rates (IRs) of 17 MEI.

Results
Overall, 758 414 (COVID-19-positive adults; 57.8% women), 12 513 664 (high-risk adults; 56.8% women) and 8 510 627 (paediatric patients; 49.1% women) patients were identified in the HV database. IRs of MEI varied substantially by year, data source, study cohort and duration of follow-up. The IRs of MEI were highest among COVID-19-positive adults and lowest among paediatric patients. For example, IR of myocarditis/pericarditis per 1000 PY was 3.0 (95% CI: 2.6 to 3.4) in the COVID-19-positive adult cohort vs 0.36 (95% CI: 0.34 to 0.37) among high-risk adults and 0.05 (95% CI: 0.05 to 0.06) among paediatric patients. In the COVID-19-positive adult cohort, we observed higher IRs during 90-day follow-up (eg, IR of acute myocardial infarction (AMI) 26.5 (95% CI: 25.3 to 27.7)) vs 365-day follow-up (eg, IR of AMI 20.0 (95% CI: 9.2 to 20.8)) and during 2020 compared with 2021. IRs were higher in the high-risk adult and paediatric populations during the pre-COVID-19 period than during the COVID-19 pandemic.

Conclusions
Substantial variability was observed in IRs of MEI by study cohort, year, data source and follow-up duration. When generating background rates for contextualising safety signals from COVID-19 interventions, careful consideration must be given to the indicated subpopulation of interest, COVID-19-related temporal variations and data sources.

Stroke, Ahead of Print. BACKGROUND:National studies on reversible cerebral vasoconstriction syndrome (RCVS) point to differences between Asian and European patients. We investigated geographic variations in neurological complications, outcomes, and causes.METHODS:We conducted an exploratory analysis of pooled individual patient data from the Reversible Cerebral Vasoconstriction Syndrome International Collaborative network, a multicenter observational cohort study including patients with definite RCVS from 2 French, 32 Italian, 1 South Korean, and 1 Taiwanese centers. Data on demographics, precipitants, symptoms, imaging, treatment, and outcomes were collected. The primary end point was RCVS-associated brain lesions, including ischemic stroke, cortical subarachnoid hemorrhage, intracerebral hemorrhage, posterior reversible encephalopathy syndrome, and subdural hematoma. Secondary end points included unfavorable 3-month outcomes (modified Rankin Scale score ≥1) and causes (idiopathic versus secondary). Odds ratios and 95% CIs were calculated using multivariable logistic regression, adjusting for potential confounders.RESULTS:From 2009 to 2021, we included 1127 patients (528 European and 599 Asian). Recruitment occurred either through emergency settings or outpatient clinics, with most Asian patients recruited from outpatient clinics (65.8%) and most European patients from emergency settings (99.8%). Brain lesions were more frequent in European patients (29.2% versus 6.3%; odds ratio, 4.09 [95% CI, 2.66–6.30]). In a sensitivity analysis restricted to hospitalized patients (n=651), the association persisted. Unfavorable 3-month outcomes (5.5% versus 1.7%; odds ratio, 3.01 [95% CI, 1.35–6.68]) and secondary RCVS (50.4% versus 10.9%; odds ratio, 7.09 [95% CI, 5.14–9.76]) were also associated with European residency.CONCLUSIONS:RCVS presentations vary across regions, with higher lesion rates, more secondary forms, and worse outcomes in European patients. While these exploratory results may reflect selection bias from differing health care structures, further research is needed to determine the contribution of genetic, environmental, and societal factors.

Stroke, Ahead of Print. BACKGROUND:Familial hypercholesterolemia (FH) is characterized by elevated levels of LDL-C (low-density lipoprotein cholesterol) since birth. However, the association between FH and cerebrovascular diseases, including cerebral small vessel disease (CSVD), is controversial. To investigate the association between FH and CSVD, we compared the prevalence and severity of CSVD neuroradiological findings between patients with FH and control participants.METHODS:Patients with FH who visited the lipid clinic and underwent brain magnetic resonance imaging at the National Cerebral and Cardiovascular Center in Japan from November 2006 to April 2021 and control participants who voluntarily underwent brain magnetic resonance imaging as a checkup between December 2000 and December 2010 at the Health Science Center Shimane, Japan, were enrolled into the study. The prevalence and severity of CSVD neuroradiological findings were investigated in patients with FH and control participants, and potential risk factors for CSVD development were identified using multivariable logistic and quasi-Poisson regression analyses.RESULTS:A total of 151 patients with FH and 3172 control participants were enrolled in this study. FH was identified as an independent risk factor of prevalent lacunes (adjusted odds ratio, 1.60 [95% CI, 1.03–2.51];P=0.039) and increased number of lacunes (1.67 times [95% CI, 1.17–2.31];P=0.003). Furthermore, FH was also an independent risk factor of prevalent cerebral microbleeds (adjusted odds ratio, 9.42 [95% CI, 5.81–15.28];P

Objectives
To evaluate factors associated with clinic follow-up after traumatic spinal injury (TSI) in Tanzania, focusing on demographic, injury-related and hospital variables. We hypothesised that socioeconomic and injury-specific factors would predict follow-up adherence.

Design
Retrospective observational cohort study.

Setting
Tertiary government referral centre for neurosurgery and orthopaedics in Dar es Salaam, Tanzania.

Participants
443 adults with TSI admitted between September 2016 and October 2021. Inclusion criteria included survival to discharge and availability of the discharge date. Patients with missing data were excluded.

Primary and secondary outcome measures
Primary outcomes were any clinic follow-up and 1-year follow-up post-discharge. Secondary outcome was time to loss of follow-up. Logistic regression was used to identify factors associated with follow-up, and Kaplan-Meier survival analysis assessed follow-up duration.

Results
Of 443 patients (85.8% male, median age 34 years), 52.4% returned for follow-up. Independent factors associated with return included private insurance (adjusted OR (aOR) 2.69, 95% CI 1.38 to 5.45, p=0.005), involvement in a road traffic accident (aOR 2.15, 95% CI 1.22 to 3.83, p=0.009), lumbar injuries (aOR 2.26, 95% CI 1.30 to 4.00, p=0.004), neurological improvement at discharge (aOR 3.52, 95% CI 1.72 to 7.64, p=0.001) and hospital stays shorter than 24 days (aOR 1.63, 95% CI 1.07 to 2.47, p=0.022). Among those who returned, only 25.4% completed 1 year of follow-up. Predictors of 1-year follow-up included being female (aOR 4.87, 95% CI 2.31 to 10.56, p

Objectives
The New York City (NYC) HIV Care Coordination Programme (CCP) is designed to help people with HIV (PWH) overcome barriers to care and treatment engagement. We assessed preferences for CCP components among programme enrollees (’clients’) and providers. Our objective is to compare client and provider preferences, which were previously analysed separately.

Design
We used a discrete choice experiment to assess preferences for four CCP features (‘attributes’): Help with Adherence to Antiretroviral Therapy (ART), Help with Primary Care Appointments, Help with Issues other than Primary Care and Where Programme Visits Happen. Each of these attributes had 3–4 variants (‘levels’). In the original surveys, levels within Where Programme Visits Happen varied by participant type (client vs provider). We recoded the levels by visit location (VL) or by travel time (TT) to make them comparable and report results from both approaches.

Setting
25 Ryan White Part A-funded NYC CCPs participated.

Participants
152 providers and 181 clients completed the survey.

Primary and secondary outcome measures
Preferences were quantified using the relative importance of the attributes and utility of the levels.

Results
From January 2020 to March 2021, 152 providers and 181 clients completed the survey. Most of the providers (52%) were

In 2021, neurological disorders affected approximately 1 out of 3 people in China, according to new research published in Med. Using data from the Global Burden of Disease Study, researchers found that the aging population drove an increase from about 329 million cases in 1990 to about 468 million in 2021.

Introduction
The cardiovascular (circulatory) system is a closed-loop system. The dynamic interaction of the heart and vascular system plays a pivotal role in maintaining adequate cardiac output. Heart failure (HF) is commonly described as a problem of the pump, that is, mechanical myocardial failure causing poor perfusion to the body. Still, the contribution of the vasculature is often neglected. Acute decompensated heart failure (ADHF) carries a poor prognosis and is often accompanied by concomitant chronic kidney disease (CKD) and acute kidney injury (AKI), which inevitably lead to adverse outcomes. The interaction of the heart with the vasculature is conceptualised as ventricular–vascular (arterial) coupling. Arterial stiffness, a non-traditional risk factor for cardiovascular disease, can be measured non-invasively using carotid–femoral pulse wave velocity (cf-PWV). High cf-PWV values mimicking increased arterial stiffness could be a causational factor towards precipitating ADHF or AKI. This study aims to assess whether cf-PWV is higher during the hospitalisation phase of patients with HF (ADHF) and CKD (AKI in CKD) compared with stable compensated HF and stable CKD.

Methods and analysis
This prospective non-randomised observational study aims to recruit 120 patients aged≥60 years. Arterial stiffness will be assessed in three groups. These groups are decompensated HF with reduced ejection fraction (n=40), decompensated HF with preserved ejection fraction (n=40) and AKI in CKD stage 3a, 3b and 4, n=40. After 4 weeks from hospital discharge, patients in a stable, compensated state will be asked to attend a follow-up clinic visit to repeat the cf-PWV measurement. The primary outcome measure is variation in cf-PWV during hospitalisation against follow-up.

Ethics and dissemination
Ethical approval was granted in October 2021 (REC reference 21/EM/0239), recruitment started in February 2022 and the results are expected in late 2025. The findings will be published in peer-reviewed journals.

Trial registration number
NCT05012722.

Circulation, Ahead of Print. BACKGROUND:Combining antiplatelet therapy (APT) with conventional anticoagulants increases the risk of bleeding. In the AZALEA-TIMI 71 trial (Safety and Tolerability of Abelacimab [MAA868] vs Rivaroxaban in Patients With Atrial Fibrillation), the novel factor XI inhibitor abelacimab significantly reduced the risk of bleeding compared with rivaroxaban in patients with atrial fibrillation. Whether the safety of combination antithrombotic therapy differs in the context of factor XI inhibition has not been well characterized.METHODS:This prespecified analysis of AZALEA-TIMI 71 includes patients randomized between March and December of 2021 to 1 of 2 subcutaneous monthly abelacimab doses (90 or 150 mg) or oral rivaroxaban (20 mg daily, dose reduced to 15 mg in patients with creatinine clearance ≤50 mL/min), stratified by planned use of concomitant APT. The primary composite of major or clinically relevant nonmajor bleeding and other safety and efficacy outcomes were examined by concomitant APT and randomized treatment.RESULTS:Of 1287 patients (44% female; median age, 74 years [interquartile range, 69–78]), 318 (24.7%) were on APT at baseline with planned continuation (15.5% aspirin only, 7.5% P2Y12inhibitor only, and 1.6% dual APT). In the rivaroxaban arm, the rate of major or clinically relevant nonmajor bleeding was 10.6% per 100 patient-years with concomitant APT versus 7.7% per 100 patient-years without. In the abelacimab arms, the rates were 2.5% and 3.5% per 100 patient-years for the 90-mg and 150-mg doses, respectively, with concomitant APT and 2.7% and 3.1% per 100 patient-years without. Each abelacimab dose significantly reduced major or clinically relevant nonmajor bleeding compared with rivaroxaban, both in those with concomitant APT (adjusted hazard ratio, 0.26 [95% CI, 0.10–0.70] and hazard ratio, 0.30 [95% CI, 0.12–0.74] for 90 mg and 150 mg of abelacimab, respectively, versus rivaroxaban) and in those without concomitant APT (adjusted hazard ratio, 0.34 [95% CI, 0.19–0.60] and hazard ratio, 0.40 [95% CI, 0.23–0.68] for 90 mg and 150 mg of abelacimab, respectively;Pinteractions=0.56 and 0.60, respectively). Patients with concomitant APT tended to derive greater absolute risk reductions with abelacimab (8.1% and 7.1% for 90 mg and 150 mg of abelacimab, respectively, versus rivaroxaban) than those without concomitant APT (5.0% and 4.6%, respectively).CONCLUSIONS:Inhibition of factor XI with abelacimab consistently reduced bleeding compared with rivaroxaban regardless of concomitant APT use, with greater absolute reductions in bleeding in those requiring concomitant APT. These data suggest that factor XI inhibition may be a safe anticoagulant option in patients with atrial fibrillation requiring concomitant APT.REGISTRATION:URL:https://www.clinicaltrials.gov; Unique identifier: NCT04755283.

Objectives
To evaluate changes in oral corticosteroid (OCS) use after the publication of the 2014 Japanese clinical practice guidelines for myasthenia gravis (MG).

Design
Retrospective cohort study performed in three Japanese health insurance databases: the JMDC database between 2005 and 2021; the DeSC database covering the National Health Insurance (NHI) and the DeSC database covering the Late-Stage Elderly Healthcare Service (LSEHS) between 2014 and 2021. Achievement of OCS ≤5 mg/day was defined as ≥90 days of consecutive OCS ≤5 mg/day during follow-up, without any gap longer than 60 days between two consecutive claims. The time to achieve OCS ≤5 mg/day was estimated using Kaplan-Meier survival analysis.

Setting
Real-world treatment setting in Japan.

Participants
Patients aged ≥16 years with a record of MG (International Classification of Diseases 10th edition code: G70.0) with a serological test, who had baseline period ≥180 days before inclusion with no MG claim and who started immunotherapy (including OCS) within 90 days of MG diagnosis.

Outcome measures
Prescription of OCS and other therapies for MG.

Results
Overall, 811 patients were included. The mean age was 49 years in the JMDC, 61 years in the NHI and 80 years in the LSEHS. In the JMDC, the median time to achieve OCS ≤5 mg/day was significantly shorter (p=0.042; log-rank test) in patients included in 2015 or later (11.0 months) than in patients included before 2015 (17.9 months). The median time to achieve OCS ≤5 mg/day was shorter in the LSEHS (6.5 months) than in the JMDC (11.0 months) and the NHI (11.7 months).

Conclusions
Faster tapering of the OCS dose was observed in patients starting treatment after the publication of the 2014 guidelines, although use of higher-dose OCS remained widespread after this date. This highlights the need to improve awareness of guidelines by healthcare providers in order to decrease the burden of higher-dose OCS.

Trial registration number
Clinical Trials Registry (UMIN-CTR): UMIN000051155; Post-results.

Objective
To explore the association between biological rhythm and internalising disorders among children and adolescents.

Design, setting and participants
This cross-sectional study used data from the Baoxing Youth Mental Health cohort and included 2119 children and adolescents recruited in December 2021 from 21 primary and secondary schools in Baoxing County, Sichuan Province, China.

Exposure
Biological rhythm was assessed across four domains—eating habits, physical activity, social interactions and sleep behaviours—using a 22-item, self-constructed questionnaire. Principal component analysis was performed to identify the patterns of biological rhythm.

Main outcome measures
The 7-item Generalised Anxiety Disorder scale and the 9-item Patient Health Questionnaire were used to assess internalising disorders. Logistic regression analyses were conducted to examine the association between individual items and patterns of biological rhythm and internalising disorders.

Results
Among the participants, 47.9% were girls and the mean (SD) age was 12.4 (2.69) years. Seven distinct patterns of biological rhythm have been identified. Compared with low adherence level group, a high level of physical exercise (OR 0.43 (95%CI 0.33 to 0.56)), family meals for breakfast (0.53 (0.41 to 0.69)) and nutritious diet (0.48 (0.37 to 0.62)) were associated with a lower risk of internalising disorders. While high level of sedentary lifestyle (2.00 (1.53 to 2.62)), daytime tiredness (2.09 (1.61 to 2.71)) and unhealthy bedtime snacks (3.38 (2.57 to 4.44)) were associated with an increased risk of internalising disorders. Null results were observed for the pattern of social interactions in school (0.89 (0.69 to 1.16)). These associations were maintained for children and adolescents who were exposed to adverse childhood experiences.

Conclusions
The results of this study highlight the potential protective effects of physical exercise, family meals for breakfast and nutritious diet on youth mental health. Well-designed longitudinal studies are needed to further clarify the relationship between patterns of biological rhythm and internalising disorders.

Objectives
To identify clustered trajectories of self-reported disability following the initiation of care by a physical therapist in outpatient orthopaedic settings and to determine baseline factors that distinguish between different trajectories.

Design
Retrospective cohort study using electronic health record and patient-reported outcome data.

Setting
Data were extracted from the ATI Patient Outcomes Registry, encompassing patient encounters from over 900 ATI outpatient physical therapy clinics in 26 states across the USA.

Participants
Patients receiving physical therapy after surgery were excluded. The final analytical sample included 597 245 unique patients initiating care between 1 January 2016 and 31 December 2021 for management of a spine, upper extremity or lower extremity musculoskeletal condition.

Interventions
Patients received treatments which could include strengthening and range of motion exercises, manual therapy, education, functional training and pain-relieving modalities.

Primary and secondary outcome measures
The primary outcome was trajectory of self-reported, joint-specific disability measure scores up to 6 months following initial evaluation.

Results
Three distinct disability trajectory clusters were identified (proportion of sample; beta coefficient (95% CI)): significant immediate worsening (3.4%; –1.31 (–1.33, –1.28)), significant gradual improvement (61.4%; (0.36 (0.35, 0.36)) and minimal change (35.2%; –0.20 (–0.21, –0.19)). Results were similar when stratified by primary diagnosis of upper extremity, lower extremity or spine conditions, with small differences in the relative proportion of trajectory class membership by body region. Predictive factors for less favourable disability trajectories included older age, lower physical and mental health scores, body region, higher social deprivation index, insurance type and certain comorbidities.

Conclusions
Most patients showed improvement in disability after exposure to treatment by a physical therapist, but a notable proportion experienced minimal change or worsening. Multiple demographic, physical, mental and social health factors differentiated trajectory class membership, highlighting opportunities to improve how and to whom this type of guideline-supported non-pharmacological care is delivered.

Objectives
We aimed to analyse the disease burden and trends related to household air pollution (HAP) from 1990 to 2021 and to assess the correlation between development status and HAP burden using the Sociodemographic Index (SDI).

Design
Observational study using data from the global burden of disease (GBD) 2021.

Main outcomes and measures
The GBD results tool provided comprehensive data on disability-adjusted life years (DALYs) attributable to HAP, stratified by age, sex, year, and geographical location.

Results
A significant reduction of approximately 50% in global HAP-related DALYs was observed between 1990 and 2021. However, a minor increase in HAP-related DALYs was noted between 2020 and 2021. The highest burden was found in children under five. Males generally had higher DALY rates than females. A negative correlation was identified between SDI and HAP-related DALY rates, with the highest rate in Oceania and the lowest in high-income North America. Maternal and neonatal disorders, cardiovascular diseases, respiratory infections and tuberculosis, and chronic respiratory diseases were the leading causes of HAP-related DALYs.

Conclusion
The study highlighted the progress in reducing the global burden of HAP-related diseases, yet it also revealed persistent disparities that require targeted public health interventions. Continued efforts to promote cleaner energy solutions and address regional, age and gender-specific vulnerabilities are essential for further reducing the health impact of HAP. Future research should focus on understanding the contributing factors to these disparities and developing innovative mitigation strategies.

Objectives
This study aimed to evaluate the impact of the Charlson Comorbidity Index (CCI) on in-hospital outcomes in patients with aortic stenosis (AS) undergoing aortic valve replacement (AVR) and to compare the efficacy of transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in patients with different comorbidity burdens.

Setting
The National Clinical Research Center for Cardiovascular Diseases.

Participants
A retrospective analysis was conducted on 3380 AS patients who underwent AVR in Beijing Anzhen Hospital from January 2015 to October 2021.

Interventions
Patients were stratified into low (0–1) and high (≥2) CCI groups.

Primary and secondary outcome measures
The primary outcome was Valve Academic Research Consortium-2 (VARC-2) composite early safety endpoints.

Results
Patients with high CCI scores exhibited significantly higher rates of VARC-2 composite adverse outcomes compared with those with low scores (50.3% vs 44.2%, p=0.001). After adjusting for confounding factors, high CCI scores were independently associated with the VARC-2 composite adverse outcomes (OR=1.36, 95% CI 1.17 to 1.58, p

Objectives
Unplanned pneumonia readmissions increase patient morbidity, mortality and healthcare costs. Among pneumonia patients, the middle-aged and elderly (≥45 years old) have a significantly higher risk of readmission compared with the young. Given that the 14-day readmission rate is considered a healthcare quality indicator, this study is the first to develop survival machine learning (ML) models using emergency department (ED) data to predict 14-day readmission risk following pneumonia-related admissions.

Design
A retrospective multicentre cohort study.

Setting
This study used the Taipei Medical University Clinical Research Database, including data from patients at three affiliated hospitals.

Participants
11 989 hospital admissions for pneumonia among patients aged ≥45 years admitted from 2014 to 2021.

Primary and secondary outcome measures
The dataset was randomly split into training (80%), validation (10%) and independent test (10%) sets. Input features included demographics, comorbidities, clinical events, vital signs, laboratory results and medical interventions. Four survival ML models—CoxNet, Survival Tree, Gradient Boosting Survival Analysis and Random Survival Forest—were developed and compared on the validation set. The best performance model was tested on the independent test set.

Results
The RSF model outperformed the other models. Validation on an independent test set confirmed the model’s robustness (C-index=0.710; AUC=0.693). The most important predictive features included creatinine levels, age, haematocrit levels, Charlson Comorbidity Index scores, and haemoglobin levels, with their predictive value changing over time.

Conclusions
The RSF model effectively predicts 14-day readmission risk among pneumonia patients. The ED data-based model allows clinicians to estimate readmission risk before ward admission or discharge from the ED, enabling timely interventions. Accurately predicting short-term readmission risk might also further support physicians in designing the optimal healthcare programme and controlling individual medical status to prevent readmissions.