Drug-Induced dermatomyositis following COVID-19 vaccination.

Dermatomyositis (DM) is a multi-organ idiopathic inflammatory myopathy that presents with proximal symmetric muscle weakness accompanied by characteristic cutaneous findings. Most individuals present with skin manifestations prior to muscle involvement and its course can involve the blood vessels, joints, esophagus, and lungs and can be paraneoplastic, making a malignancy assessment imperative. Although its etiology is unknown, type I interferon appears to be a component in evoking the characteristic inflammatory response and patients with DM often have an increase in type I inducible genes. Suspected triggers for DM are environmental factors, drugs, viral infections, and vaccines. The association of DM with vaccination poses a new conundrum within the medical community as people continue to get vaccinated and boosted with SARS-CoV2 vaccines, though it is worth noting that the most common challenges arose as type I hypersensitivity reactions and new onset autoimmune disorders are rare. Presented here is a 53-year-old man who was diagnosed with DM after receiving the second dose of the Pfizer vaccine. His case highlights the importance of the potential onset of autoimmune diseases following the COVID-19 vaccine, a phenomenon that clinicians should be aware of as the discourse concerning the pandemic continues.

The Influence of "Super-Shoes" and Foot Strike Pattern on Metabolic Cost and Joint Mechanics in Competitive Female Runners.

PURPOSE: The objective of this study is to assess the influence of "super-shoes" on metabolic cost and joint mechanics in competitive female runners and to understand how foot strike pattern may influence the footwear effects. METHODS: Eighteen competitive female runners ran four 5-min bouts on a force instrumented treadmill at 12.9 km·h -1 in 1) Nike Vaporfly Next% 2™ (SUPER) and 2) Nike Pegasus 38™ (CON) in a randomized and mirrored order. RESULTS: Metabolic power was improved by 4.2% ( P < 0.001; d = 0.43) and metatarsophalangeal (MTP) negative work ( P < 0.001; d = 1.22), ankle negative work ( P = 0.001; d = 0.67), and ankle positive work ( P < 0.001; d = 0.97) were all smaller when running in SUPER compared with CON. There was no correlation between foot strike pattern and the between-shoe (CON to SUPER) percentage change for metabolic power ( r = 0.093, P = 0.715). CONCLUSIONS: Metabolic power improved by 4.2% in "super-shoes" (but only by ~3.2% if controlling for shoe mass differences) in this cohort of competitive female runners, which is a smaller improvement than previously observed in men. The reduced mechanical demand at the MTP and ankle in "super-shoes" are consistent with previous literature and may explain or contribute to the metabolic improvements observed in "super-shoes"; however, foot strike pattern was not a moderating factor for the metabolic improvements of "super-shoes." Future studies should directly compare the metabolic response among different types of "super-shoes" between men and women.

Increasing Breast Support is Associated With a Distal-to-Proximal Redistribution of Joint Negative Work During a Double-Limb Landing Task.

Female athletes exhibit greater rates of anterior cruciate ligament injury compared with male athletes. Biomechanical factors are suggested to contribute to sex differences in injury rates. No previous investigation has evaluated the role of breast support on landing biomechanics. This study investigates the effect of breast support on joint negative work and joint contributions to total negative work during landing. Thirty-five female athletes performed 5 landing trials in 3 breast support conditions. Lower-extremity joint negative work and relative joint contributions to total negative work were calculated. Univariate analyses of variance were used to determine the effect of breast support on negative joint work values. Increasing levels of breast support were associated with lower ankle negative work (P < .001) and ankle relative contributions (P < .001) and increases in hip negative work (P = .008) and hip relative contributions (P < .001). No changes were observed in total negative work (P = .759), knee negative work (P = .059), or knee contributions to negative work (P = .094). These data demonstrate that the level of breast support affects lower-extremity biomechanics. The distal-to-proximal shift in negative joint work and relative joint contributions may be indicative of a more protective landing strategy for anterior cruciate ligament injuries.

Increasing Trunk Mass Evokes Lower Extremity Biomechanical Plasticity during Stair Descent.

The purpose of this study was to investigate the influence of simulated changes in body mass on lower extremity joint work and relative joint contributions during stair descent. Ten healthy recreationally active college-age participants performed five stair descent trials in each of five loading conditions: no added load and with an additional 5%, 10%, 15% and 20% of their body weight. Three-dimensional ankle, knee and hip joint powers were calculated using a six degree-of-freedom model in Visual3D (C-Motion Inc., Germantown, MD, USA). Sagittal plane joint work was calculated as the joint power curve integrated with respect to time during the period between initial contact and toe off. Prism 9.0 (GraphPad Inc., San Diego, CA) was used to perform univariate 1 × 5 repeated measures analyses of variance to determine the effect of added mass on absolute and relative joint work values for total and for each lower extremity joint independently. Increasing added mass was associated with greater total lower extremity negative work during the stair descent task (p < 0.001). At the ankle, increasing added mass was associated with increasing magnitudes of negative joint work. Increasing added mass was associated with greater relative contributions of the ankle and reduced knee contributions to total negative lower extremity joint work (p = 0.014 and p = 0.006). The current findings demonstrated increases in ankle joint contributions to total lower extremity work while knee joint contributions to total lower extremity work were reduced in response to increasing added mass.

Interactions of arylhydroxylamines and alkylaldoximes with a rhodium porphyrin.

Heme enzymes are involved in the binding and metabolism of hydroxylamine (RNHOH) and aldoxime (RCH=NOH) compounds (R = H, alkyl, aryl). We report the synthesis and X-ray crystal structure of a metalloporphyrin in complex with an arylhydroxylamine, namely that of (TPP)Rh(PhNHOH)(C6H4Cl) (TPP = tetraphenylpophryinato dianion). The crystal structure reveals, in addition to N-binding of PhNHOH to Rh, the presence of an intramolecular H-bond between the hydroxylamine -OH proton and a porphyrin N-atom. Results from density functional theory (DFT) calculations support the presence of this intramolecular H-bond in this global minimum structure, and a natural bond order (NBO) analysis reveals that this H-bond comprises a donor π N=C (porphyrin) to acceptor σ* O-H (hydroxylamine) interaction of 2.32 kcal/mol. While DFT calculations predict the presence of similar intramolecular H-bond interactions in the related aldoxime complexes (TPP)Rh(RCH=NOH)(C6H4Cl) in their global minima structures, the X-ray crystal structure obtained for the (TPP)Rh(CH3(CH2)2CH=NOH)(C6H4Cl) complex is consistent with the local (non-global) minima conformation that does not have this intramolecular H-bond interaction.

Increasing breast support is associated with altered knee joint stiffness and contributing knee joint biomechanics during treadmill running.

Introduction: Greater breast support has been associated with improved running performance as measured by oxygen cost and running economy. Several candidate mechanisms have been proposed to underlie breast support-related improvements in running performance including increased knee joint stiffness. Greater knee joint stiffness has been associated with improved running performance (speed and metabolic cost), though the influence of breast support on knee joint stiffness has not been previously investigated. Therefore, the purpose of this study was to investigate the influence of increasing breast support on knee joint stiffness and its constituent components during treadmill running. Methods: Thirteen recreational runners performed a 3-min running bout at their preferred running velocity in each of three breast support conditions: bare chested (CON), low support (LOW) and high support (HIGH) sports bras. Three-dimensional kinematics and ground reaction forces were collected simultaneously using a 10-camera motion capture system (240 Hz, Qualisys Inc.) and instrumented treadmill (1,200 Hz, Bertec Inc.). Visual3D (C-Motion Inc.) was used to calculate knee joint excursions, moments, powers and work while custom software (MATLAB) was used to calculate knee joint stiffness and breast displacements during the stance phase of running in each experimental condition. A series of 1 × 3 repeated measures analysis of covariance with post-hoc t-tests was used to evaluate the effect of breast support on knee joint biomechanics during treadmill running. Results: Increasing levels of breast support were associated with greater knee joint stiffness (p = 0.002) as a result of smaller knee flexion excursions (p < 0.001). Increases in knee extension power (p = 0.010) were observed with increasing levels of breast support while no differences were observed in knee extension moments (p = 0.202) or work (p = 0.104). Conclusion: Greater breast support is associated with increased knee joint stiffness resulting from smaller joint excursions. These findings may provide insight into the biomechanical mechanisms underlying previously reported improvements in running performance including reduced oxygen consumption and greater running economy.

The Influence of Footwear Longitudinal Bending Stiffness on Running Economy and Biomechanics in Older Runners.

Purpose: This study assessed the effects of footwear longitudinal bending stiffness on running economy and biomechanics of rearfoot striking older runners. Methods: Nine runners over 60 years of age completed two running bouts at their preferred running pace in each of three footwear conditions: low (4.4 ± 1.8 N·m-1), moderate (5.7 ± 1.7 N·m-1), and high (6.4 ± 1.6 N·m-1) bending stiffness. Testing order was randomized and a mirror protocol was used (i.e., A,B,C,C,B,A). Expired gases, lower limb kinematics, and ground reaction forces were collected simultaneously and lower limb joint kinetics, running economy (i.e., VO2), leg stiffness, and spatio-temporal variables were calculated. Results: Running economy was not different among stiffness conditions (p = 0.60, p = 0.53 [mass adjusted]). Greater footwear stiffness reduced step length (p = 0.046) and increased peak vertical ground reaction force (p = 0.019) but did not change peak ankle plantarflexor torque (p = 0.65), peak positive ankle power (p = 0.48), ankle positive work (p = 0.86), propulsive force (p = 0.081), and leg stiffness (p = 0.46). Moderate footwear stiffness yielded greater peak negative knee power compared to low (p = 0.04) and high (p = 0.03) stiffness. Conclusions: These novel findings demonstrate that increasing footwear longitudinal bending stiffness using flat carbon fiber inserts does not improve running economy and generally does not alter lower limb joint mechanics of rearfoot strike runners over 60 years. Future studies should investigate how other footwear characteristics (e.g., midsole material, plate location, and sole curvature) influence economy and biomechanics in this population.

Influence of dynamic stretching on ankle joint stiffness, vertical stiffness and running economy during treadmill running.

The purpose of the present study was to investigate whether and how dynamic stretching of the plantarflexors may influence running economy. A crossover design with a minimum of 48 h between experimental (dynamic stretching) and control conditions was used. Twelve recreational runners performed a step-wise incremental protocol to the limit of tolerance on a motorised instrumented treadmill. The initial speed was 2.3 m/s, followed by increments of 0.2 m/s every 3 min. Dynamic joint stiffness, vertical stiffness and running kinematics during the initial stage of the protocol were calculated. Running economy was evaluated using online gas-analysis. For each participant, the minimum number of stages completed before peak O2 uptake (V̇O2peak) common to the two testing conditions was used to calculate the gradient of a linear regression line between V̇O2 (y-axis) and speed (x-axis). The number of stages, which ranged between 4 and 8, was used to construct individual subject regression equations. Non-clinical forms of magnitude-based decision method were used to assess outcomes. The dynamic stretching protocol resulted in a possible decrease in dynamic ankle joint stiffness (-10.7%; 90% confidence limits ±16.1%), a possible decrease in vertical stiffness (-2.3%, ±4.3%), a possibly beneficial effect on running economy (-4.0%, ±8.3%), and very likely decrease in gastrocnemius medialis muscle activation (-27.1%, ±39.2%). The results indicate that dynamic stretching improves running economy, possibly via decreases in dynamic joint and vertical stiffness and muscle activation. Together, these results imply that dynamic stretching should be recommended as part of the warm-up for running training in recreational athletes examined in this study.

The influence of surface and speed on biomechanical external loads obtained from wearable devices in rearfoot strike runners.

External load variables such as peak tibial acceleration (PTA), peak vertical ground reaction forces (GRF) and its instantaneous vertical loading rate (IVLR) may contribute to running injuries although evidence is conflicting given the influence of training load and tissue health on injuries. These variables are influenced by footwear, speed, surface and foot strike pattern during running. The purpose of this study was to assess the influence of four surfaces and two running speeds on external load variables in rearfoot strike (RFS) runners. Twelve RFS runners (confirmed with sagittal foot contact angle) completed a 2-min running bout on a treadmill and 50-m running bouts over the three surfaces (pavement, rubber track and grass) in standardised shoes at their preferred speed and 20% faster. PTA and vertical GRFs were collected using inertial measurement units and in-shoe force insoles. No interaction or surface effects were observed (p > 0.017). The faster speed produced greater axial PTA (+19.2%; p < 0.001), resultant PTA (+20.7%; p < 0.001), peak vertical GRF (+6.6%; p = 0.002) and IVLR (+16.5%; p < 0.001). These findings suggest that surface type does not influence PTA, peak vertical GRF and IVLR but that running faster increases the magnitude of these external loads regardless of surface type in RFS runners.

Greater Breast Support Is Associated With Reduced Oxygen Consumption and Greater Running Economy During a Treadmill Running Task.

Introduction: Breast pain is a major barrier to running for women. While breast support through the use of sports bras reduces breast-related discomfort, the effect of breast support on running performance is less understood. Therefore, the purpose of the current study was to evaluate the effect of greater breast support on oxygen consumption and running economy during a treadmill running task. Methods: Fifteen female recreational runners performed a 10-min treadmill running task at their preferred running speed in each of two sports bra conditions: low support and high support. Participants ran on an instrumented treadmill (1,200 Hz, Bertec) while indirect calorimetry was performed using a metabolic measurement system (100 Hz, TrueOne, ParvoMedics). Average VO2 (absolute and relative) from the third to 10th minutes was used to evaluate oxygen consumption. Running economy was calculated as the distance traveled per liter of oxygen consumed. Paired samples t-tests were used to compare mean oxygen consumption and running economy values between breast support conditions. Correlation analysis was performed to evaluate the relationship between breast size and change in running performance. Results: Greater breast support was associated with reductions in absolute (p < 0.001) and relative oxygen consumption (p < 0.001; LOW: 30.9 ± 7.1 ml/kg/min; HIGH: 28.7 ± 6.7 ml/kg/min). Greater breast support was associated with increases in running economy (p < 0.001; LOW: 88.6 ± 29.1 m/L O2; HIGH: 95.2 ± 31.1 m/L O2). No changes in temporospatial characteristics of running were observed including cadence (p = 0.149), step length (p = 0.300) or ground contact time (p = 0.151). Strong positive linear correlations were observed between the change in running performance metrics and breast size (Oxygen Consumption: p < 0.001, r = 0.770; Relative Oxygen Consumption: p < 0.001, r = 0769; Running Economy: p < 0.001, r = 0.807). Conclusions: Greater breast support was associated with reduced oxygen consumption and increased running economy. These findings demonstrate that greater breast support is not only associated with improved comfort but also improved running performance.

Greater Breast Support Alters Trunk and Knee Joint Biomechanics Commonly Associated With Anterior Cruciate Ligament Injury.

Objective: The female breast is a passive tissue with little intrinsic support. Therefore, women rely on external breast support (sports bras) to control breast motion during athletic tasks. Research has demonstrated that lower levels of breast support are associated with altered trunk and pelvis movement patterns during running, a common athletic task. However, no previous study has identified the effect of sports bra support on movement patterns during other athletic tasks including landing. Therefore, the purpose of this study was to examine the effects of breast support on trunk and knee joint biomechanics in female collegiate athletes during a double-leg landing task. Methods: Fourteen female collegiate athletes completed five double-leg landing trials in each of three different sports bra conditions: no support, low support, and high support. A 10-camera motion capture system (250 Hz, Qualisys, Goteburg, Sweden) and two force platforms (1,250 Hz, AMTI, Watertown, MA, USA) were used to collect three-dimensional kinematics and ground reaction forces simultaneously. Visual 3D was used to calculate trunk segment and knee joint angles and moments. Custom software (MATLAB 2021a) was used to determine discrete values of dependent variables including vertical breast displacement, knee joint and trunk segment angles at initial contact and 100 ms post-initial contact, and peak knee joint moments. A repeated measures analysis of covariance with post-hoc paired samples t-tests were used to evaluate the effect of breast support on landing biomechanics. Results: Increasing levels of breast support were associated with reductions in peak knee flexion (Right: p = 0.008; Left: p = 0.029) and peak knee valgus angles (Right: p = 0.011; Left: p = 0.003) as well as reductions in peak knee valgus moments (Right: p = 0.033; Left: p = 0.013). There were no changes in peak knee extension moments (Right: p = 0.216; Left: p = 0.261). Increasing levels of breast support were associated with greater trunk flexion angles at initial contact (p = 0.024) and greater peak trunk flexion angles (p = 0.002). Conclusions: Lower levels of breast support are associated with knee joint and trunk biomechanical profiles suggested to increase ACL injury risk.

Selection of Noninvasive Features in Wrist-Based Wearable Sensors to Predict Blood Glucose Concentrations Using Machine Learning Algorithms.

Glucose monitoring technologies allow users to monitor glycemic fluctuations (e.g., blood glucose levels). This is particularly important for individuals who have diabetes mellitus (DM). Traditional self-monitoring blood glucose (SMBG) devices require the user to prick their finger and extract a blood drop to measure the blood glucose based on chemical reactions with the blood. Unlike traditional glucometer devices, noninvasive continuous glucose monitoring (NICGM) devices aim to solve these issues by consistently monitoring users' blood glucose levels (BGLs) without invasively acquiring a sample. In this work, we investigated the feasibility of a novel approach to NICGM using multiple off-the-shelf wearable sensors and learning-based models (i.e., machine learning) to predict blood glucose. Two datasets were used for this study: (1) the OhioT1DM dataset, provided by the Ohio University; and (2) the UofM dataset, created by our research team. The UofM dataset consists of fourteen features provided by six sensors for studying possible relationships between glucose and noninvasive biometric measurements. Both datasets are passed through a machine learning (ML) pipeline that tests linear and nonlinear models to predict BGLs from the set of noninvasive features. The results of this pilot study show that the combination of fourteen noninvasive biometric measurements with ML algorithms could lead to accurate BGL predictions within the clinical range; however, a larger dataset is required to make conclusions about the feasibility of this approach.

Zinc Ammonio-dodecaborates: Synthesis, Lewis Acid Strength, and Reactivity.

Two series of zinc salts, [EtZn][A] and Zn[A]2, with weakly coordinating anions [A]- as counterions have been prepared, and their activities as catalysts for hydrosilylation reactions of 1-hexene, benzophenone, and acetophenone have been investigated. The counterions and per- and partially chlorinated 1-ammonio-closo-dodecaborate anions [Me3NB12Cl11]- [1]-, [Pr3NB12H5Cl6]- [2]-, [Bu3NB12H4Cl7]- [3]-, and [Hex3NB12H5Cl6]- [4]- were chosen as potential and more readily available alternatives to carborate anions such as [CHB11Cl11]- and [HexCB11Cl11]-. The basicity of anion [4]- was determined as being close to that of the triflimide anion [N(SO2CF3)2]-, and the fluoride ion affinities (FIAs) of compounds [EtZn][2] and Zn[2]2 are lower than those of the Lewis acids B(C6F5)3 and Zn[HexCB11Cl11]2. The higher anion basicity and the resulting lower Lewis acidity of the zinc centers result in low activity in 1-hexene hydrosilylation catalysis and only moderate activity in the hydrosilylation catalysis of benzophenone and acetophenone.

Interactions of N-hydroxyamphetamine with an iron porphyrin: A unique intramolecular H-bond probed by DFT calculations.

Hydroxylamine (NH2OH) and its N-substituted derivatives (RNHOH) are important biological intermediates in the global N cycle. Heme plays a central role in the binding and activation of these hydroxylamines. We report the crystal structures of N-hydroxyamphetamine (AmphNHOH) in complex with Fe and Co heme models. We demonstrate a previously unrecognized internal H-bond interaction between a hydroxylamine RNHO-H group and a porphyrin N-atom. We utilize density functional theoretical (DFT) calculations to show that the conformations with the internal H-bond represent global minima along the potential energy surfaces for both the Fe and Co heme models. A natural bond orbital (NBO) analysis reveals a donor π (porN=C) to acceptor σ* (O-H) interaction of 3.04 kcal/mol for Fe, accounting for 11% of the total heme-AmphNHOH interaction energy. Our DFT calculations with the parent Fe-NH2OH suggests that the presence of internal H-bonds between hydroxylamine (R/H)NHOH moieties and heme N-atoms may be more common than previously recognized.

Insights into the Observed trans-Bond Length Variations upon NO Binding to Ferric and Ferrous Porphyrins with Neutral Axial Ligands.

NO is well-known for its trans effect. NO binding to ferrous hemes of the form (por)Fe(L) (L = neutral N-based ligand) to give the {FeNO}7 (por)Fe(NO)(L) product results in a lengthening of the axial trans Fe-L bond. In contrast, NO binding to the ferric center in [(por)Fe(L)]+ to give the {FeNO}6 [(por)Fe(NO)(L)]+ product results in a shortening of the trans Fe-L bond. NO binding to both ferrous and ferric centers involves the lowering of their spin states. Density functional theory (DFT) calculations were used to probe the experimentally observed trans-bond shortening in some NO adducts of ferric porphyrins. We show that the strong σ antibonding interaction of d z 2 and the axial (L) ligand p orbitals present in the Fe(II) systems is absent in the Fe(III) systems, as it is now in an unoccupied orbital. This feature, combined with a lowering of spin state upon NO binding, provides a rationale for the observed net trans-bond shortening in the {FeNO}6 but not the {FeNO}7 derivatives.

Case-control analysis of prehospital death and prolonged field care survival during recent US military combat operations.

BACKGROUND: Quantification of medical interventions administered during prolonged field care (PFC) is necessary to inform training and planning. MATERIALS AND METHODS: Retrospective cohort study of Department of Defense Trauma Registry casualties with maximum Abbreviated Injury Scale (MAIS) score of 2 or greater and prehospital records during combat operations 2007 to 2015; US military nonsurvivors were linked to Armed Forces Medical Examiner System data. Medical interventions administered to survivors of 4 hours to 72 hours of PFC and nonsurvivors who died prehospital were compared by frequency-matching on mechanism (explosive, firearm, other), injury type (penetrating, blunt) and injured body regions with MAIS score of 3 or greater. Covariates for adjustment included age, sex, military Service, shock, Glasgow Coma Scale, transport team, MAIS and Injury Severity Score (ISS). Sensitivity analysis focused on US military subgroup with AIS/ISS assigned to nonsurvivors after autopsy. RESULTS: The total inception cohort included 16,202 casualties (5,269 US military, 10,809 non-US military), 64% Afghanistan, 36% Iraq. Of US military, 734 deaths occurred within 30 days, nearly 90% occurred within 4 hours of injury. There were 3,222 casualties (1,111 US military, 2,111 non-US military) documented for prehospital care and died prehospital (691) or survived 4 hours to 72 hours of PFC (2,531). Twenty-five percent (815/3,222) received advanced airway, 18% (583) ventilatory support, 9% (281) tourniquet. Twenty-three percent (725) received blood transfusions within 24 hours. Of the matched cohort (1,233 survivors, 490 nonsurvivors), differences were observed in care (survivors received more warming, intravenous fluids, sedation, mechanical ventilation, narcotics, antibiotics; nonsurvivors received more intubations, tourniquets, intraosseous fluids, cardiopulmonary resuscitation). Sensitivity analysis focused on US military (732 survivors, 379 nonsurvivors) showed no significant differences in prehospital interventions. Without autopsy information, the ISS of nonsurvivors significantly underestimated injury severity. CONCLUSION: Tourniquets, blood transfusion, airway, and ventilatory support are frequently required interventions for the seriously injured. Prolonged field care should direct resources, technology, and training to field technology for sustained resuscitation, airway, and breathing support in the austere environment. LEVEL OF EVIDENCE: Prognostic, Level III.

A high fat western diet attenuates phasic dopamine release.

Natural rewards, such as food and social interaction, as well as drugs of abuse elicit increased mesolimbic dopamine release in the nucleus accumbens (NAc). Drugs of abuse, however, increase NAc dopamine release to a greater extent and are known to induce lasting changes on the functioning of the mesolimbic dopamine pathway. Less is known about the long-term effects of diet composition on this reward pathway. In the present study, two diets were compared: a higher-fat diet (Western Diet: WD) and a control diet (standard lab chow) on their effect on the mesolimbic dopamine system. Twenty male C57BL/6 J mice were placed on one of these diets at 7 weeks old. After twelve weeks on the diet, in vivo fixed potential amperometry was used to measure real-time stimulation-evoked dopamine release in the NAc of anesthetized mice before and after an i.p. injection of the dopamine transporter (DAT) inhibitor nomifensine. Results indicated that diet altered mesolimbic dopamine functioning. Mice that consumed the WD demonstrated a hypodopaminergic profile, specifically reduced baseline dopamine release and an attenuated dopaminergic response to DAT inhibition compared to the control diet group. Thus, diet may play a role in mediating dopamine-related behavior, disorders associated with dopamine dysfunction, and pharmacological treatments aimed at altering dopamine transmission.