Background Atopic dermatitis (AD) is the most common inflammatory skin disorder and an important cause of morbidity in young children in the U.K. Such disability produces significant economic burden reflected in direct medical costs associated with health service utilization, direct family care costs such as transport costs, indirect costs associated with loss of productivity of carers, and intangible costs associated with the psychological effects of the disease. Objectives In order to evaluate this economic burden we conducted a cross‐sectional survey of children aged 1–5 years in the Nottingham area in 1995–96. Methods We sent a postal questionnaire to parents of all children aged 1–5 years with questions to identify those with AD; a second questionnaire was sent to parents of identified children regarding costs and utilization of medical services. Intangible costs were not evaluated. Results The 12‐month period prevalence of AD according to a dermatologist's diagnosis in 1761 children was 16·5% (95% confidence interval 14·7–18·2%). Total mean disease costs were estimated to be £79·59 per child over the 12‐month period of the study. The most significant costs were due to costs to the state for National Health Service (NHS) consultations (£28·62 mean annual cost) and prescriptions (£22·03). Consultations with general practitioners accounted for the significant bulk of consultation costs, with only 6% of children being seen in secondary care (17 of 290). Most prescribing costs (76%) were due to emollients and bath preparations. Family care costs (£28·94 mean annual cost) accounted for 36% of total disease costs and were associated with changes to the home environment, purchase of over‐the‐counter medicines, transport costs, visits to homoeopaths and salary loss. Conclusions The results signify that AD is an important cause of economic burden both to the NHS and to the families of affected children. Using population census data and the results in this study, we estimated that the annual U.K. cost of AD in children aged 1–5 years in 1995–96 was £47 million.
Twenty‐four patients with psoriasis completed a double‐blind trial of benoxaprofen for their cutaneous lesions. Six out of thirteen on the active drug showed very marked improvement. It is believed that benoxaprofen acts by interfering with the migration of polymorphs into the skin through inhibition of leukotriene B4 synthesis.
Evaluation of the clinical impact of a pharmacist led-penicillin allergy assessment initiative to enhance antibiotic selection is reported.A retrospective analysis was conducted on patients with a self-reported penicillin allergy (SRPA) at a 529-bed community teaching hospital and compared clinical response rate before and after implementation of a penicillin allergy assessment initiative, consisting of pharmacy staff education and pocket card development. Patients admitted with SRPA who received antibiotics with gram-negative coverage for at least 48 hours were included. The primary outcome was the clinical response rate of penicillin-allergic patients determined preimplementation and postimplementation of the initiative and was based upon improvement in signs and symptoms of infection. Secondary outcomes included antibiotics used, antibiotic durations, length of stay, survival rate, antibiotic discontinuation rate, and Clostridium difficile infection rate.A total of 280 patients were reviewed. Clinical response rate improved after implementation of the initiative (p = 0.047). There were significant differences in the type of antibiotics prescribed between the preimplementation group and the postimplementation group: increased cephalosporin use (p < 0.001), decreased aztreonam use (p = 0.017), and lower fluoroquinolone use (p = 0.008). Median length of stay (p = 0.943), in-hospital mortality rate (p = 0.173), and C. difficile infection rate (p = 0.426) were similar before and after implementation of the initiative.After implementation of an initiative to encourage the use of cephalosporins rather than aztreonam in patients with SRPA, the rate of clinical response and cephalosporin use increased and rates of exposure to aztreonam and fluoroquinolones decreased.
No other drug has a name that evokes such emotions as that of thalidomide. Its infamous and unexpected teratogenicity has, more than any other single factor, been responsible for the current stringent regulations concerning drug development and use. Thalidomide was first synthesized in 1954 and marketed as a hypnotic in 1956. It rapidly became popular because it was effective and lacked acute toxicity, but it was withdrawn from general use throughout the world between late 1961 and early 1962, having been linked with irreversible neuropathy and limb deformities in the children of mothers who had taken the drug during the first trimester of pregnancy. Initially thalidomide appeared to be the ideal hypnotic with negligible acute toxicity. The early animal work was encouraging, clinical trials were favourable and neither the animal nor the clinical studies uncovered the risks which were subsequently to become only too clear. The story of the disaster is fully described by Mellin.1 The frequency of phocomelia in Germany rose from four cases in 1958 to eight in 1959, 70 in 1960 and 222 in 1961, paralleling the increased use of thalidomide before the link was recognised. Even small doses can be devastating and anecdotal reports of 50 mg daily for 1 week starting 7 days after the last menstrual period and 100 mg taken for 3 nights followed by 50 mg for 2 nights during the second week have been recorded as causing deformities. Phocomelia is more common in the upper limbs. In 65–75% of cases only the arms are affected; in 10–25% both upper and lower limbs are involved and in 2–5% only the legs are deformed. The embryotoxic effects of thalidomide vary between species. Thalidomide is teratogenic in humans, monkey, rabbit, rat, mouse, and chicken but not in the hamster;2 despite the fact that it does cross the placental barrier. The critical period for embryopathy occurs in the period between 20 and 40 days of gestation. The exact risk is not known. The intact phthalimide or phthalimidine groups appear to be responsible for the teratogenic activity but the mechanism has not been conclusively demonstrated. Hypothetical bases for thalidomide's teratogenicity include vitamin or amino acid antagonism, acylation of biogenic amines, interaction with various enzymes or nucleic acids, interference with energy metabolism, and interference with hydroxyproline biosynthesis.3 The possibilities have been reviewed by Stephens.4 Thalidomide is also known to cause an axonal neuropathy that predominantly affects sensory nerves although there is some evidence to suggest more widespread effects on the nervous system.5 The clinical symptoms reported and reviewed by Gunzler6 include hypo- and hyper-aesthesia, impaired temperature sensitivity and impaired autonomic function. Reports of motor disturbances are rare. It has been claimed that symptoms may occur some time after thalidomide has been stopped. They may resolve slowly but usually persist. The most useful objective measurement of thalidomide-induced peripheral neuropathy is decreased sensory nerve action potential amplitude as measured in the sural and median nerves.7 Conflicting estimates of the incidence of thalidomide-induced neurological disturbances have been given ranging from less than 1% to 50%. It may be related to the total dose but this is far from clear with cases having been reported with cumulative doses of 15 g whereas other patients have been treated continuously for years without overt problems. It has been suggested that the risk of neuropathy is unpredictable and cannot be correlated to the total dose of thalidomide.8 Symptoms in the original 13 patients developed 2–18 months after starting regular medication on 50–400 mg nightly.5 It is recommended that sensory nerve conduction studies are performed, using standard techniques and surface electrodes at regular intervals throughout therapy, which will permit an early detection of reduced amplitudes before symptoms occur. Thalidomide has two distinct pharmacological actions: a potent depressant effect on the CNS, and a less clearly understood immunomodulatory effect in inflammatory disease. The efficacy of thalidomide as a hypnotic and sedative was the reason for its introduction and popularity in the 1950s. These effects are probably a result of the glutarimide moiety substituted in the 3 position with a nonspecific space-filling group. This configuration exists in a number of sedative and hypnotic drugs such as glutethimide.3 Interest in thalidomide has been rekindled by its effect in type II reactions in leprosy and its potent anti-inflammatory and immunomodulatory properties in a number of different diseases. Most of the reports on the efficacy of thalidomide in all of its indications, none of which are licensed in this country, are anecdotal and most of the information has been acquired by uncontrolled clinical observations over the past 30 years. There is nevertheless ample clinical evidence that thalidomide has anti-inflammatory properties in certain specific diseases such as erythema nodosum leprosum (ENL) reactions, severe aphthous stomatitis, Behçet's disease and graft-vs.-host disease (GVHD), but it remains open to question how these are effected and whether they are the result of a single activity. Attention has recently focused on the ability of thalidomide to selectively inhibit the inflammatory cytokine tissue necrosis factor (TNF-α). This is achieved by accelerating the degradation of mRNA encoding the protein. Serum levels of TNF-α are elevated in ENL9 and lowered with thalidomide therapy.10In vitro, thalidomide in concentrations up to 1 µg mL−1 has been reported to inhibit TNF-α production by 40% in peripheral blood mononuclear cells.11 The number of publications on thalidomide is rising, with over 1000 in the last decade but its increasing popularity should not make us complacent about its use and its potential to cause harm. In this issue Chave et al. look at the way thalidomide is being used in Wales, a small (2·93 million) but clearly defined population served by 19 dermatologists.12 They draw attention to the wide variation between the United Kingdom and the United States in the requirements before thalidomide is prescribed. In the U.K., there are voluntary guidelines and recommendations whereas in the U.S. registration of patients is mandatory and their supervision arduous. They also draw attention to the haphazard and potentially dangerous way in which thalidomide is sometimes being used. The purpose of any guidelines or regulations is to ensure that a drug is used safely and effectively. There have been several attempts to have thalidomide prohibited worldwide and there are still some who are understandably bitter about the damage it caused and would wish, even now, to have it banned. Conversely, there are patients whose lives have been transformed by its use. It is essential that those who do prescribe it do so responsibly and are fully conversant with all the precautions surrounding its use in order to minimise the risks of any further disasters that could result in the loss of an invaluable drug.
A multicentre, randomized, double-blind, controlled crossover clinical trial was conducted on 33 patients with severe refractory atopic dermatitis, to determine the effects of cyclosporin (5 mg/kg/day) on their health-related quality of life. Treatments were administered for 8-week periods. One group (n = 16) received placebo followed by cyclosporin, and the other (n = 17) received cyclosporin and then placebo. Health-related quality of life was assessed at 0, 8 and 16 weeks using a general measure, the United Kingdom Sickness Impact Profile (UKSIP), an eczema-specific measure, the Eczema Disability Index (EDI), and a global 5-point rating scale of overall health (very good to very poor). In addition, clinical assessments (i.e. extent and activity of disease) were made by the investigators. UKSIP and EDI scores indicated significant improvement in quality of life (P < 0.05-P < 0.01) of patients with atopic dermatitis after treatment with cyclosporin. Although no patient required withdrawal from the study, 20 patients receiving cyclosporin reported adverse events, compared with eight taking placebo. There was a close correlation (P < 0.05-P < 0.01) between the UKSIP and EDI scores. In contrast, there was either no correlation, or only a very poor correlation, between the quality of life parameters and clinical measures of extent and activity of eczema. When cyclosporin was stopped, relapse was rapid, but the mean scores for disease activity and extent of disease were less than their baseline values (i.e. an improvement of greater than 25% was maintained in 11 patients at week 4).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract Purpose Colonization of methicillin-resistant Staphylococcus aureus (MRSA) can be detected via nasal screens. Evidence indicates that negative MRSA nasal screens may be used to de-escalate anti-MRSA antibiotics in pulmonary infections. In the ICU, universal decolonization with intranasal mupirocin is implemented to reduce MRSA infection risk. This study aimed to determine whether mupirocin administration affects the reliability of MRSA PCR nasal screens. Methods This retrospective study divided subjects based on timing of intranasal mupirocin administration—before and after MRSA screen. Subjects with confirmed pulmonary infection that received vancomycin, blood/respiratory cultures, and had MRSA PCR screen collected were included. Subjects with concurrent infection requiring vancomycin or MRSA infection in prior 30 days were excluded. Primary outcome of this non-inferiority study was the negative predictive value (NPV) of the screen. Secondary outcomes included the positive predictive value (PPV), sensitivity, and specificity of the screen and duration of vancomycin. Results Ultimately, 125 subjects were included in each group. The NPV in the group receiving mupirocin before screen was 95.2%, whereas the NPV in the group receiving mupirocin after screen was 99%. The difference between groups was -3.8% (90% CI -7.8%-0.2%; p=0.31), which failed to meet non-inferiority criteria. The secondary outcomes of PPV, sensitivity and specificity of the screen were similar in both groups. The duration of vancomycin was significantly longer in subjects receiving mupirocin before screen (3 days vs. 2 days; p<0.05). Conclusion Intranasal mupirocin prior to the screen may reduce NPV in pulmonary infections. Approach de-escalation of vancomycin based on screen results with caution.
Significant practice variation exists when selecting between hydrocortisone and vasopressin as second line agents in patients with septic shock in need of escalating doses of norepinephrine. The goal of this study was to assess differences in clinical outcomes between these two agents.Multicenter, retrospective, observational study.Ten Ascension Health hospitals.Adult patients with presumed septic shock receiving norepinephrine prior to study drug initiation between December 2015 and August 2021.Vasopressin (0.03-0.04 units/min) or hydrocortisone (200-300 mg/day).A total of 768 patients were included with a median (interquartile range) SOFA score of 10 (8-13), norepinephrine dose of 0.3 mcg/kg/min (0.1-0.5 mcg/kg/min), and lactate of 3.8 mmol/L (2.4-7.0 mmol/L) at initiation of the study drug. A significant difference in 28-day mortality was noted favoring hydrocortisone as an adjunct to norepinephrine after controlling for potential confounding factors (OR 0.46 [95% CI, 0.32-0.66]); similar results were seen following propensity score matching. Compared to vasopressin, hydrocortisone initiation was also associated with a higher rate of hemodynamic responsiveness (91.9% vs. 68.2%, p < 0.01), improved resolution of shock (68.8% vs. 31.5%, p < 0.01), and reduced recurrence of shock within 72 h (8.7% vs. 20.7%, p < 0.01).Addition of hydrocortisone to norepinephrine was associated with a lower 28-day mortality in patients with septic shock, compared to the addition of vasopressin.
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