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Moreover arrhythmia light headed hydrochlorothiazide 12.5 mg buy cheap on-line, in sufferers with severe metabolic acidosis blood pressure normal limit 12.5 mg hydrochlorothiazide fast delivery, the serum potassium may also be lowered with an infusion of 50�100 mmol of sodium bicarbonate blood pressure x large cuff generic hydrochlorothiazide 12.5 mg without prescription. Also blood pressure medication used for withdrawal hydrochlorothiazide 12.5 mg purchase fast delivery, if repeated doses are wanted, sufferers may obtain large quantities of sodium which can be undesirable, particularly in patients with heart failure and/or renal failure. Thus, hyperkalaemic states due to potassium overload must be handled by measures resulting in enhanced potassium elimination. In patients with preserved diuresis, renal excretion could additionally be enhanced using loop and thiazide diuretics. Moreover, enteral potassium elimination can be achieved by oral application of an ion exchange resin (with a laxative to prevent constipation) and/or an enema containing ion change resins. The concern of change resins has provoked a current controversy with respect to efficacy and unwanted aspect effects (Sterns et al. However, haemodialysis primarily affects the extracellular component that incorporates < 2% of exchangeable potassium and may thus only take away a restricted amount of total body potassium. Consequently, redistribution of potassium (which could have been shifted to the intracellular area with insulin prior to dialysis therapy) could happen after dialysis. Therefore, potassium levels need to be checked repeatedly even after initially successful management of hyperkalaemia. Calcium Physiology Calcium (see also Chapters 26, 37, 38) is essential for the normal function of many intracellular techniques, muscle contraction (including the heart), nerve conduction, and coagulation pathways. Hypocalcaemia Hypocalcaemia is defined as a complete serum calcium focus of < 2. Patients could complain of perioral numbness (often seen in respiratory alkalosis due to hyperventilation) and distal paraesthesias. If hyperphosphataemia is current, quick correction of calcium carries the danger of soft tissue calcifications. In such a state of affairs phosphate binders must be considered and calcium supplementation should be postponed for as long as attainable. With serum calcium rising additional, non-specific signs corresponding to malaise, nausea, vomiting, weak point, and abdominal pain might happen. Management the management of hypercalcaemia relies on enough (re) hydration with saline infusions, elevated calcium excretion through the kidneys, inhibition of bone turnover, and treatment of the underlying disease. After correction of volume depletion, loop diuretics (but not thiazides, as they increase calcium reabsorption in the kidney) should be given to maintain hydration status and also enhance renal calcium excretion. Moreover, bisphosphonates are an efficient mode of therapy to lower calcium mobilization from bones. In patients with vitamin D intoxication, lymphoma, sarcoidosis, or multiple myeloma, steroids are obligatory as they decrease calcitriol production (Gardner, 2001). Treatment results with both steroids and bisphosphonates might, nonetheless, be delayed by 2�4 days. Calcitonin acts very rapidly (usually within 4�6 hours) and should safely be given in the meantime. In patients with extreme symptomatic hypercalcaemia, haemodialysis in opposition to a low calcium dialysate could also be indicated, particularly in sufferers with renal and/or heart failure. Sepsis Decreased absorption: � Chronicdiarrhoea � VitaminDdeficiency Renal losses: � Osmoticdiuresis � Renaltransplantation � Hyperparathyroidism � Steroidtherapy Other losses: � Burns � Pancreatitis � Renalreplacementtherapy Transcellular shifts: � Alkalosis � Hormonal(calcitonin,insulin) � Hungrybonesyndromeleukaemic crisis � Hypothermia Renal failure Tumour calcinosis syndrome Bisphosphonates Rhabdomyolysis Tumour lysis syndrome Malignant hyperthermia Lactic acidosis Hyperphosphataemia Hypophosphataemia Hypophosphataemia is uncommon, however some sufferers are at higher risk. In this setting, phosphate must be monitored on a daily basis and supplemented if wanted. Management In common, delicate hypophosphataemia could be managed with oral supplements. The extent of the possible phosphate deficit is unpredictable and repletion therapy have to be empiric. One ought to be cautious, nonetheless, when the serum calcium is grossly elevated due to the danger of soppy tissue calcification. Calcium and phosphate repletion must be strictly separated, as precipitation could set off anaphylactic reactions. Careful monitoring of phosphate and prevention of hypophosphataemia is due to this fact a lot safer than intravenous infusions. It is important for the mineralization of the bone and cellular capabilities together with energy metabolism and genetic encoding. Hyperphosphataemia In critical sickness, acute hyperphosphataemia might occur as a consequence of severe cell or tissue harm, for example, in tumour lysis syndrome or rhabdomyolysis. Acid�base problems the kidneys and the lung play the elemental function in sustaining acid�base stability. The actual mechanisms of acid�base handling of the kidney and its mobile penalties are described in Chapters 24 and 35. To better perceive acid�base imbalances, the clinician ought to look at the real changes in H+ concentrations rather than merely looking at the calculated bicarbonate degree. It is outlined as the distinction of the plasma sodium concentration and the sum of bicarbonate plus chloride concentrations. One ought to keep in mind, nevertheless, that a discount of serum albumin by 1 g/L will result in a lower within the anion hole by as a lot as 2. From a scientific point of view the anion hole could be very helpful in differentiating metabolic acidosis and detecting the presence of organic or mixed metabolic acidosis. Causes of high anion hole acidosis are ketoacidosis (diabetes, alcohol, starvation), intoxications (methanol, ethylene glycol, salicylates), and lactic and uraemic acidosis. Given a normal respiration this will correspond to the next decreases in bicarbonate concentrations: >20 mmo/L, 10�19 mmol/L, and <10 mmol/L, respectively. It is important to elaborate the underlying problem to have the ability to target helpful remedy. In normal (non-) anion hole acidosis the bicarbonate concentration falls and the chloride focus rises. This is the case, for instance, when bicarbonate is lost through the gastrointestinal tract or the kidneys. In high anion-gap acidosis, however, bicarbonate is lowered by a achieve of acid with its unmeasured anion being answerable for the rise in the anion hole. Acids similar to lactic or uraemic acids or ketones are probably the most common causes of high anion-gap acidosis (Table 230. In non-anion hole acidosis the loss of bicarbonate is a rationale to administer base. In patients with values above this limit, the treatment of the underlying sickness. Inadequate oxygen supply to the cells leads to increased glycolysis without oxidative phosphorylation resulting in an accumulation of lactate that binds protons causing acidosis. As these problems are usually not reversed within a couple of hours, remedy could take longer. Base administration would Approach to a affected person with acute metabolic acidosis the therapy of metabolic acidosis is based on two ideas: therapy of the underlying situation. This strategy is, however, only sensible when the underlying situation could be treated. Haemofiltration has been advocated for the therapy of lactic acidosis, on the basis of anecdotal experiences. The best therapy is to cease acid manufacturing by treating the underlying disorder (Luft, 2001; Kraut and Madias, 2014). The most essential imbalances of electrolyte homeostasis embrace disorders of sodium, potassium, calcium, and phosphate. Hyponatraemia and hyperkalaemia are the commonest issues and require immediate and protected correction, once the prognosis is made and the underlying illness is identified. Thus, the main emphasis is on the causes and management of electrolyte abnormalities. Patients with hyponatraemia are at excessive danger of cerebral oedema, whereas hyperkalaemia may result in life-threatening cardiac arrhythmia. The differentiation of regular or high anion-gap acidosis is clinically important, because the underlying diagnoses are very totally different. Prompt recognition and effective administration of these issues will limit the danger of life-threatening consequences.

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In sufferers with extra generalized neurological pathology corresponding to a quantity of sclerosis arteria appendicularis purchase hydrochlorothiazide 12.5 mg without prescription, signs could additionally be more non-specific such as elevated fatigue blood pressure medication and pregnancy cheap 12.5 mg hydrochlorothiazide, deterioration in neurological operate heart attack grill calories purchase hydrochlorothiazide 12.5 mg line, or growing urinary incontinence heart attack vol 1 pt 4 hydrochlorothiazide 12.5 mg buy discount online. Pyuria (identified by urinalysis or a leucocyte esterase dipstick test) can additionally be current in lots of sufferers with asymptomatic bacteriuria and like constructive tradition is in keeping with, however not diagnostic of, infection. Similarly, the absence of pyuria has a excessive unfavorable predictive worth and a urinalysis without pyuria makes urinary infection using microbiologically primarily based definitions less likely. An assessment of the severity of the underlying urological abnormality and its effect on renal perform may even inform the prognosis and determination on therapy. However, where the clinical standing of the affected person necessitates that early empirical therapy is initiated, the antimicrobial choice ought to be reassessed as quickly as culture results become obtainable (typically 2�3 days). While there are a variety of medical trials of remedy in difficult urinary an infection, small pattern measurement, variability in cohorts, and exclusion of patients with resistant strains has made it troublesome to translate findings into sensible steerage for management. It is essential to search local microbiological steerage and local or nationwide antibiotic insurance policies ought to provide steerage. For symptomatic an infection without instant menace to life or health then fluoroquinolones similar to ciprofloxacin are effective. This class of antibiotic has a wide spectrum of bactericidal activity that covers most of the doubtless pathogens, they usually reach high concentrations in both urogenital tissues and urine. In addition, most sufferers with symptomatic infection may be treated successfully with oral remedy as excessive plasma concentrations may be attained (Mombelli et al. Unfortunately, widespread and maybe indiscriminate use of fluoroquinolones is resulting in quickly growing bacterial resistance and can be implicated in bacterial ecological change and public health concern concerning the emergence of extremely resistant strains of Escherichia coli. Fever with out local signs is a extra reliable indicator of infection however lacks specificity. In addition to urological abnormalities other co-morbidities such as diabetes are regularly current as additional danger factors and may be implicated in the causation of the underlying urinary tract abnormality. As well as confirming the infection, this pattern may also help determine the micro organism concerned, their antibiotic susceptibilities, and doubtlessly their virulence elements. For an asymptomatic affected person, two consecutive urine cultures (at least 24 hours apart) yielding 105 cfu/mL or 104 cfu/mL of the same microorganism are required. In populations with a excessive prevalence of asymptomatic bacteriuria such as the aged and those residing in establishments or those with indwelling urological units such as urethral catheters or ureteric stents, a optimistic urine tradition has a low optimistic predictive worth for symptomatic an infection (Orr et al. The other alternatives are subsequently second-generation cephalosporins such as cephalexin and medicines that may counter beta-lactamase exercise similar to amoxicillin/clavulanic acid (co-amoxiclav). For folks presenting with life- or health-threatening infection and people with marked systemic symptoms, parenteral therapy must be used with the co-administration of gentamicin when acceptable. With all parenteral medication the agent and dosage ought to be adjusted based on culture outcomes and clinical response and step-down to oral therapy should take place as soon as possible. Successful first-line antimicrobial therapy will often ameliorate signs rapidly, with substantial scientific improvement in 2�3 days. However, the place initial remedy has failed or in clinically extreme infections, different broader-spectrum antibiotics with anti-pseudomonal activity ought to be considered. Options include fluoroquinolones (if not used for preliminary therapy), ureidopenicllins with a beta-lactamase inhibitor, for example, piperacillin and tazobactam (Naber et al. However, where the medical scenario dictates, a course may be extended for as much as 21 days (Grabe et al. Role of fluoroquinolones in the treatment of great bacterial urinary tract infections. Comparison of intravenous fleroxacin with ceftazidime for remedy of complicated urinary tract infections. Once-daily fleroxacin versus twice-daily ciprofloxacin in the treatment of difficult urinary tract infections. Preoperative evaluation of the affected person and danger factors for infectious issues and tentative classification of surgical area contamination of urological procedures. Bacteriuria and the diagnosis of infections of the urinary tract; with observations on using methionine as a urinary antiseptic. Oral vs intravenous ciprofloxacin in the preliminary empirical management of severe pyelonephritis or complicated urinary tract infections: a potential randomized clinical trial. Double-blind, randomized comparability of 24 weeks of norfloxacin and 12 weeks of norfloxacin adopted by 12 weeks of placebo within the therapy of difficult urinary tract an infection. Bacteriuria in ladies with long-term catheters: paired comparability of indwelling and substitute catheters. A potential microbiologic examine of bacteriuria in patients with persistent indwelling urethral catheters. Typically sufferers with long-term ureteric stents, non-removable stones, or immunosuppression such as for renal transplantation may be thought-about for this sort of administration. There is proof displaying the efficacy for norfloxacin, a quinolone, in this regard though the concerns regarding opposed private and neighborhood results must be thought of (Sheehan et al. Patients frequently receive concomitant antibiotics and immunosuppression tends to suppress clinical signs and indicators of urosepsis. The urinary tract is protected against ascending an infection in a variety of ways including the physiochemical antibacterial effects of urine (acidic and hyperosmolar), urine flow, and full voiding. Urine also incorporates inhibitors of bacterial adhesion and progress (lactoferrin, low-molecular-weight oligosaccharides, mucopolysaccharides, and Tamm�Horsfall protein). Uroepithelial defence mechanisms include antibacterial peptides and FimH-mediated exfoliation of contaminated superficial epithelial cells. Finally, the innate immune system is important in combating urosepsis by way of neutrophils and pro-inflammatory cytokines. However, in transplantation most of the above pure defences in opposition to ascending an infection shall be impaired, particularly within the setting of delayed or poor graft perform. Prospectively screening asymptomatic transplant sufferers, Fiorante and co-workers detected bacteriuria in 51% (Fiorante et al. This vastly increased threat pertains to recipient, donor, surgical, and immunological factors, only a few of which are modifiable (Box 179. They may present with fulminant and life-threatening sepsis significantly in the first weeks after a transplant. However, as many as 50% of sufferers have asymptomatic bacteriuria (Fiorante et al. Infection might end in unexplained graft dysfunction, anaemia, or persistent acute part response. The difference is made up with an increasing proportion of Gram-positive in addition to much less virulent and atypical organisms. In some cases there could also be evidence of polymicrobial infections, perhaps dominated by a extra prosaic organism (Domann et al. Investigations As infections can be clinically covert it is important to preserve lively surveillance and have a high index of suspicion. An ultrasound is helpful to exclude an obstructed system and critical in assessing bladder emptying. A retrospective evaluation of 189 patients demonstrated that 50% had asymptomatic bacteriuria. A current meta-analysis of six trials of antibiotic prophylaxis totalling 545 patients demonstrated a 60% reduction in bacteriuria and an 87% reduction in bacteraemia (Green et al. It is clearly critical to exclude obstruction acutely and to have close liaison with microbiology relating to native resistance profiles to ensure the appropriate antibiotic is given intravenously to an acutely unwell patient. It seems prudent to also guarantee high fluid consumption, good diabetic management, and rapid removing of urinary catheter or ureteric stent if present (with culture). It is essential to be sure that appropriate antibiotics have already began at the time of stent elimination. If the affected person fails to respond rapidly, has extremely resistant organisms, or has a speedy relapse with the same organism then significantly prolonging the course of antibiotics is prudent. In this setting, good imaging of the bladder, transplant, and native kidneys to exclude stones, obstruction, or a localized collection is mandatory. The implication from this is that prophylaxis might be a great factor within the first weeks or months of a transplant. However the optimum length of prophylaxis is way from clear; resistance rates to widespread antibiotics are already extremely high on this setting, and only a few research assess the incidence of Clostridium difficile or allergy with long-term antibiotics. Relatively few of the chance components are modifiable but reducing catheter time, tradition of perfusion fluid, and early removal of ureteric stent (especially if infection present) all appear sensible. Urine cytokines profile in renal transplant sufferers with asymptomatic bacteriuria. Nosocomial infections in renal transplant sufferers: risk components and treatment implications associated with urinary tract and surgical website infections.

Specifications/Details

Large-volume crystalloid fluid resuscitation could also be sophisticated by hyperchloraemic metabolic acidosis blood pressure chart new zealand hydrochlorothiazide 12.5 mg purchase overnight delivery, particularly when close to isotonic saline resolution (NaCl 0 arrhythmia electrophysiology hydrochlorothiazide 25 mg purchase. Despite its description as close to isotonic arteria iliolumbalis 25 mg hydrochlorothiazide purchase overnight delivery, this fluid has an virtually 50% greater chloride concentration in comparability with arteria ulnaris purchase 25 mg hydrochlorothiazide visa the traditional plasma in humans (154 mmol/L compared to a hundred and five mmol/L). Several elements may play a job within the acute phase, together with decreased kidney perfusion, inflammation, quantity overload, intra-abdominal hypertension, rhabdomyolysis, and the type of fluid used for resuscitation. Development and validation of a mannequin for prediction of mortality in sufferers with acute burn harm. Outcome and modifications over time in survival following extreme burns from 1985 to 2004. Outcome of acute kidney damage in extreme burns: a scientific evaluation and meta-analysis. Severe burn damage in Europe: a scientific evaluation of the incidence, etiology, morbidity, and mortality. Serum cystatin C is an early biomarker for evaluation of renal perform in burn patients. Continuous renal substitute therapy improves survival in severely burned navy casualties with acute kidney damage. Continuous venovenous hemofiltration in severely burned patients with acute kidney damage: a cohort research. Objective estimates of the incidence and consequences of a number of organ dysfunction and sepsis after burn trauma. Surviving Sepsis Campaign: worldwide guidelines for management of extreme sepsis and septic shock: 2012. Increased fluid resuscitation can lead to antagonistic outcomes in major-burn injured sufferers, but low mortality is achievable. A prospective, randomized evaluation of intra-abdominal pressures with crystalloid and colloid resuscitation in burn patients. Amplified cytokine response and lung harm by sequential hemorrhagic shock and abdominal compartment syndrome in a laboratory mannequin of ischemia-reperfusion. Resuscitation fluid quantity and abdominal compartment syndrome in patients with main burns. Epidemiology of burn accidents in the East Mediterranean Region: a scientific evaluation. Effects of norepinephrine on renal perfusion, filtration and oxygenation in vasodilatory shock and acute kidney injury. Systemic inflammatory response secondary to belly compartment syndrome: stage for multiple organ failure. Markers of tubular and glomerular damage in predicting acute renal harm end result in thermal burn patients: a prospective study. Predicting acute kidney damage among burn patients within the 21st century: a classification and regression tree evaluation. The intrinsic renal compartment syndrome: new views in kidney transplantation. Plasma neutrophil gelatinase-associated lipocalin as early biomarker for acute kidney injury in burn sufferers. Assessment of renal operate in lately admitted critically sick sufferers with regular serum creatinine. Relation between proteinuria and acute kidney injury in patients with extreme burns. Peak worth of blood myoglobin predicts acute renal failure induced by rhabdomyolysis. Elevated cytokine levels in peritoneal fluid from burned patients with intra-abdominal hypertension and abdominal compartment syndrome. A pilot study comparing percutaneous decompression with decompressive laparotomy for acute belly compartment syndrome in thermal injury. Circulating plasma components induce tubular and glomerular alterations in septic burns patients. Early acute kidney harm predicts progressive renal dysfunction and higher mortality in severely burned adults. Pathophysiology of renal hemodynamics and renal cortical microcirculation in a porcine model of elevated intra-abdominal strain. The influence of opioid administration on resuscitation volumes in thermally injured sufferers. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration technique and kidney injury in critically unwell adults. Bargman 255 Haemodialysis: overview Jonathan Himmelfarb 2173 2176 267 Overview of dialysis patient management and future instructions 2290 Allen R. Nissenson, John Moran, and Robert Provenzano 256 Haemodialysis: vascular access Michael Allon 257 Haemodialysis: principles 2188 Claudio Ronco and William R. Clark 268 Cardiovascular issues in end-stage renal illness patients: pathophysiological elements Gerard M. London 2296 258 Haemodialysis: prescription and assessment of adequacy 2199 Scott D. Bieber and Jonathan Himmelfarb 269 Bacterial and fungal infections in sufferers on haemodialysis 2304 2218 2229 259 Haemodialysis: acute problems Victor F. Jaber Laura Labriola, Eric Goffin, and Michel Jadoul 260 Haemofiltration and haemodiafiltration Francesco Locatelli, Celestina Manzoni, Giuseppe Pontoriero, and Salvatore Di Filippo 270 Bacterial and fungal infections in sufferers on peritoneal dialysis 2310 Eric Goffin, Laura Labriola, and Michel Jadoul 271 Virus infections in patients on dialysis 2238 2314 261 Dialysis withdrawal and palliative care Arkadiy Pinkhasov, Michael J. Cohen Michel Jadoul, Laura Labriola, and Eric Goffin 272 Cognitive function, melancholy, and psychosocial adaptation 2316 Manjula Kurella Tamura, Mark L. This ultimately results in the malfunctioning of the complete body, and as signs turn into extra prominent, survival and quality of life can solely be maintained by changing kidney perform by dialysis or transplantation. The practical disturbances are to a big extent attributed to the retention of uraemic solutes, which, with normal renal operate, are faraway from the physique by the conventional kidneys through the urine. The uraemic syndrome consists of a myriad of useful disturbances, corresponding to anaemia, metabolic bone disease, insulin resistance, inflammation, hypercoagulation, fluid overload, and hypertension. Most necessary uraemic retention solutes Several uraemic retention solutes affect biological features. It should be acknowledged that inorganic compounds corresponding to water and potassium exert toxicity as nicely. Low-molecular-weight molecules Non-protein-bound molecules Creatinine Creatinine belongs to the larger group of guanidines (see below) but because of its specific value as a marker of renal operate, this compound is mentioned separately. Increased guanidine levels have been decided in serum, urine, cerebrospinal fluid, and brains of uraemic patients (De Deyn et al. Moreover, these compounds have been associated to decreased protein binding of homocysteine, another compound with vessel-damaging potential (Perna et al. An further function can be attributed to changes in tubular secretion, reabsorption, and metabolic breakdown, which all are altered when renal mass decreases. Renal and non-renal metabolism of solutes and non-renal clearance could in flip be inhibited following uraemic retention. They can additional be subdivided into protein-bound and non-protein-bound molecules. Whereas the small water-soluble compounds are simply removed by whatever dialysis technique, the protein-bound toxins and center molecules require extra sophisticated strategies. Purines Uric acid, xanthine, and hypoxanthine are crucial purines retained in uraemia. Xanthine and hypoxanthine have been implicated as modulators of neurotransmission, poor urge for food, and weight reduction (Simmonds et al. Dialytic elimination of xanthine and hypoxanthine exhibits no correlation with that of urea and creatinine (Vanholder et al. Urea Urea is a 60 Da water-soluble compound which is taken into account probably not poisonous by itself (Johnson et al. Urea may also be a supply of era of cyanate and isocyanic acid, and these might be at the origin of carbamylation, resulting in structural and practical adjustments of amino acids and proteins (Fluckiger et al. Urea is usually used as a marker of solute retention and removal in dialysed sufferers. Even if dialytic removal from the plasma is analogous, as is the case for different small, water-soluble, non-protein-bound compounds such as creatinine or uric acid (Vanholder et al. Homocysteine and S-adenosylhomocysteine Homocysteine (Hcy), a sulphur-containing amino acid, is produced by the demethylation of dietary methionine.

Additional information:

• Cycloserine

Syndromes

• Chronic unilateral obstructive uropathy
• Heart or lung disorder
• Tibial nerve dysfunction
• Rapid breathing
• Spasms
• The late onset form is seen in infants older than 2 weeks up to 2 months old. It is more common in children who did not receive a vitamin K shot, and in those of Asian descent.

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Customer Reviews

Ramirez, 25 years: Once sufferers are established to be oligo-anuric, the urinary catheter ought to be removed to scale back the danger of infection. A summary of blood stress consequence information from these studies is presented in Table 215.

Thordir, 35 years: The event is usually vital status at discharge or demise by any trigger throughout a predefined period of time. If a enough mass of nephron items are affected, then a recognizable rise in serum creatinine will happen.

Miguel, 54 years: Following cessation of dialysis, demise might happen on the following day or up to a couple of months later depending on different co-morbid issues and the presence of residual kidney function; in one research pattern the common was 8. Plasma renin and exchangeable sodium within the hypertension of continual renal failure.

Jesper, 28 years: The obstruction of the ureter provokes the rise of hydrostatic strain above the stricture. Acute kidney injury is independently associated with mortality in very low birthweight infants: a matched case�control analysis.

Fasim, 60 years: The clearance offered by a dialysis membrane depends upon various membrane characteristics corresponding to floor space, pore size, pore density, and membrane thickness. However, over 10 years 25% of those previously asymptomatic sufferers will develop signs and sufferers < 50 years of age have a higher chance of development to symptoms.

Mamuk, 36 years: On the opposite hand, when nephrocalcinosis could be observed histopathologically, exactly finding the crystal deposits might usually be unimaginable as a outcome of tubular and interstitial deterioration, inflammation, and fibrosis. This protein performs a significant position in major haemostasis forming platelet plugs at websites of vascular injury under high shear stress.