Local Anaesthesia for Enzymatic Debridement of Cutaneous Burns: A Prospective Analysis of 27 Cases.

Enzymatic debridement (ED) is increasingly used for cutaneous burns. Compared with surgical debridement, ED has better preservation of viable dermis, less blood loss and autografting, however ED is painful. Current recommendations suggest local anaesthesia (LA) is useful for minor burns, but the evidence base is minimal. In our centre, we routinely use LA with good analgesic effect. This study was a single-centre, prospective analysis conducted at the Queen Victoria Hospital (UK). Patients had at least superficial partial thickness burns and received subcutaneous LA prior to ED during a 1-year period (October 2019-September 2020). Pain was assessed using a numeric scale of 1-10, recorded before, during and after the procedure. In total, 27 patients were included (n=17 males) with a median age of 47 (18-88 years). The mean total burn surface area was 1.5% (0.3-5.0). Treated sites included head and neck (1), trunk (5), upper limb (9) and lower limb (16). The most used LAwas bupivacaine 0.25% (n=25), followed by lidocaine 1% (n=2). Some required additional oral analgesia (n=8) or a regional blockade (n=2). Average pain score during debridement was 1.9 We have found LA effective, with favourable pain scores in comparison to previous studies with oral analgesia or regional blockade. LA is quick and easy to perform, as opposed to nerve blocks, which require trained personnel with ultrasound guidance. LA is a useful analgesic for patients with minor cutaneous burns undergoing ED. In some cases, it is sufficient without additional oral analgesia or regional blockade.

Le débridement enzymatique (DE) des brûlures est de plus en plus utilisé, ayant l'avantage d'être moins hémorragique et plus respectueux des tissus sains que la chirurgie, au prix d'une douleur plus importante. Les recommandations actuelles suggèrent l'utilisation de l'anesthésie locale (AL) sur les petites zones, avec un niveau de preuve minime. Dans notre centre, nous utilisons régulièrement l'AL, avec un bon effet analgésique. Cette étude a été conduite dans le CTB de l'hôpital Queen Vicoria (Royaume Uni). Durant 1 année (octobre 2019- septembre 2020), les patients devant bénéficier d'un DE recevaient préalablement une AL par infiltration. La douleur a été évaluée par échelle numérique (0 à 10) avant, pendant et après la procédure. Nous avons étudié 27 patients dont 17 hommes, d'âge médian 47 ans (18 à 88), brûlés en moyenne sur 1,5% (0,3 à 5), sur le cou (1), le tronc (5), le membre supérieur (9) et le membre supérieur (16). La bupivacaïne 0,25% a été la plus utilisée (25 fois), la lidocaïne 1% l'étant anecdotiquement (2 fois). Une analgésie complémentaire a été 10 fois nécessaire : orale 8 fois, régionale 2 fois. La douleur procédurale était cotée à 1,9 en moyenne. Nous estimons que l'AL est efficace, avec des scores de douleur favorables comparativement aux analgésies orale ou régionale. À la différence des analgésies régionales qui nécessitent un personnel entraîné et un écho- guidage, l'AL est facile et rapide. Elle peut être suffisante à elle seule pour le DE de brûlures minimes.

Visible laser emission from a praseodymium-doped fluorozirconate guided-wave chip.

We report visible continuous-wave laser emission at 636 nm from a praseodymium-doped fluorozirconate glass guided-wave chip laser. This ultra-fast laser inscribed gain chip is demonstrated to be a compact and integrated laser module. The laser module, pumped by 442 nm GaN laser diodes, generates >8 mW lasing output with a beam quality of Mxy2∼1.15×1.1(±0.1). To the best of our knowledge, this is the first visible laser emission from a glass-based waveguide chip laser.

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.

Holmium-doped 2.1 µm waveguide chip laser with an output power > 1 W.

We demonstrate the increasing applicability of compact ultra-fast laser inscribed glass guided-wave lasers and report the highest-power glass waveguide laser with over 1.1 W of output power in monolithic operation in the short-infrared near 2070 nm achieved (51% incident slope efficiency). The holmium doped ZBLAN chip laser is in-band pumped by a 1945 nm thulium fiber laser. When operated in an extended-cavity configuration, over 1 W of output power is realized in a linearly polarized beam. Broad and continuous tunability of the extended-cavity laser is demonstrated from 2004 nm to 2099 nm. Considering its excellent beam quality of M² = 1.08, this laser shows potential as a flexible master oscillator for single frequency and mode-locking applications.

Widely tunable short-infrared thulium and holmium doped fluorozirconate waveguide chip lasers.

We report widely tunable (≈ 260 nm) Tm(3+) and Ho(3+) doped fluorozirconate (ZBLAN) glass waveguide extended cavity lasers with close to diffraction limited beam quality (M(2) ≈ 1.3). The waveguides are based on ultrafast laser inscribed depressed claddings. A Ti:sapphire laser pumped Tm(3+)-doped chip laser continuously tunes from 1725 nm to 1975 nm, and a Tm(3+)-sensitized Tm(3+):Ho(3+) chip laser displays tuning across both ions evidenced by a red enhanced tuning range of 1810 to 2053 nm. We also demonstrate a compact 790 nm diode laser pumped Tm(3+)-doped chip laser which tunes from 1750 nm to 1998 nm at a 14% incident slope efficiency, and a beam quality of M(2) ≈ 1.2 for a large mode-area waveguide with 70 µm core diameter.

Superior sensitivity and decreased time to detection with the Bactec Peds Plus/F system compared to the BacT/Alert Pediatric FAN blood culture system.

Here, we compare the sensitivities and times to detection (TTD) of BacT/Alert Pediatric FAN (PF) and Bactec Peds Plus blood culture bottles. Test bottles were inoculated with 2 ml of banked whole blood, 1-ml aliquots of antibiotic suspension, and organisms diluted to simulate a bacteremia level of 10 to 100 CFU/ml. The control bottles were inoculated with 3 ml of banked blood and organism suspensions only. The organism-drug combinations were Staphylococcus epidermidis and vancomycin, methicillin-resistant Staphylococcus aureus and vancomycin, Streptococcus pneumoniae, vancomycin, and ceftriaxone, Streptococcus agalactiae, ampicillin, and cefotaxime, Escherichia coli, cefotaxime, and cefepime, Pseudomonas aeruginosa, piperacillin-tazobactam, cefepime, and gentamicin, Neisseria meningitidis and ceftriaxone, and Haemophilus influenzae and ceftriaxone. The control and test bottle combinations were tested in duplicate. The bottles were incubated for 5 days; 32 control and 104 test bottles were incubated. Overall, the bacterial recovery rates for the PF and Peds Plus bottles were 37% and 62%, 94% and 100% in the controls, 19% and 50% in the test bottles, and 33% and 92% in the bottles with vancomycin, respectively. No bacteria were recovered from the bottles with S. pneumoniae, S. agalactiae, E. coli, N. meningitidis, or H. influenzae in combination with cefotaxime or ceftriaxone. The Peds Plus system detected P. aeruginosa in bottles with cefepime and piperacillin-tazobactam, but the PF system recovered bacteria only in bottles with trough levels of piperacillin-tazobactam. The mean TTD were shorter in the Peds Plus system controls (14.2 versus 18.0 h; P = 0.001) and the test bottles (14.3 versus 17.8 h; P = 0.008) than in the PF bottles. Overall, we demonstrated superior sensitivity, TTD, and antibiotic neutralization in the Bactec Peds Plus system compared to those in the Pediatric FAN system.

Versatile large-mode-area femtosecond laser-written Tm:ZBLAN glass chip lasers.

We report performance characteristics of a thulium doped ZBLAN waveguide laser that supports the largest fundamental modes reported in a rare-earth doped planar waveguide laser (to the best of our knowledge). The high mode quality of waveguides up to 45 um diameter (~1075 µm(2) mode-field area) is validated by a measured beam quality of M(2)~1.1 ± 0.1. Benefits of these large mode-areas are demonstrated by achieving 1.9 kW peak-power output Q-switched pulses. The 1.89 µm free-running cw laser produces 205 mW and achieves a 67% internal slope efficiency corresponding to a quantum efficiency of 161%. The 9 mm long planar chip developed for concept demonstration is rapidly fabricated by single-step optical processing, contains 15 depressed-cladding waveguides, and can operate in semi-monolithic or external cavity laser configurations.

2.1 µm waveguide laser fabricated by femtosecond laser direct-writing in Ho3+, Tm3+:ZBLAN glass.

We report the first Ho3+ doped waveguide laser, which was realized by femtosecond direct-writing of a depressed cladding structure into ZBLAN glass. Tm3+ sensitizing allows the 9 mm long Ho3+ gain medium to be conveniently pumped at 790 nm, achieving an optical-to-optical slope efficiency of 20% and a threshold of 20 mW. The potentially widely tunable laser produces up to 76 mW at 2052 nm and also operates at shorter wavelengths near 1880 nm and 1978 nm for certain cavity configurations.

Fifty percent internal slope efficiency femtosecond direct-written Tm³âº:ZBLAN waveguide laser.

We report a 790 nm pumped, Tm³âº doped ZBLAN glass buried waveguide laser that produces 47 mW at 1880 nm, with a 50% internal slope efficiency and an M² of 1.7. The waveguide cladding is defined by two overlapping rings created by femtosecond direct-writing of the glass, which results in the formation of a tubular depressed-index-cladding structure, and the laser resonator is defined by external dielectric mirrors. This is, to the best of our knowledge, the most efficient laser created in a glass host via femtosecond waveguide writing.

Modulation of gamma oscillations by endogenous adenosine through A1 and A2A receptors in the mouse hippocampus.

Adenosine serves as a homeostatic factor, regulating hippocampal activity through A(1) receptor-mediated inhibition. Gamma frequency oscillations, associated with cognitive functions, emerge from increased network activity. Here we test the hypothesis that hippocampal gamma oscillations are modulated by ambient adenosine levels. In mouse hippocampal slices exogenous adenosine suppressed the power of both kainate-induced gamma oscillations and spontaneous gamma oscillations, observed in a subset of slices in normal aCSF. Kainate-induced gamma oscillation power was suppressed by the A(1) receptor agonist PIA and potentiated by the A(1) receptor antagonist 8-CPT to three times matched control values with an EC(50) of 1.1microM. 8-CPT also potentiated spontaneous gamma oscillation power to five times control values. The A(2A) receptor agonist CGS21680 potentiated kainate-induced gamma power to two times control values (EC(50) 0.3nM), but this effect was halved in the presence of 8-CPT. The A(2A) receptor antagonist ZM241385 suppressed kainate-induced gamma power. The non-selective adenosine receptor antagonist caffeine induced gamma oscillations in slices in control aCSF and potentiated both kainate-induced gamma and spontaneous gamma oscillations to three times control values (EC(50) 28muM). Decreasing endogenous adenosine levels with adenosine deaminase increased gamma oscillations. Increasing endogenous adenosine levels with the adenosine kinase inhibitor 5-iodotubericidin suppressed gamma oscillations. Partial hypoxia-induced suppression of gamma oscillations could be prevented by 8-CPT. These observations indicate that gamma oscillation strength is powerfully modulated by ambient levels of adenosine through A(1) receptors, opposed by A(2A) receptors. Increased gamma oscillation strength is likely to contribute to the beneficial cognitive effects of caffeine.

Factor inhibiting hypoxia-inducible factor (FIH) and other asparaginyl hydroxylases.

FIH (Factor inhibiting hypoxia-inducible factor), an asparaginyl beta-hydroxylase belonging to the super-family of 2-oxoglutarate and Fe(II)-dependent dioxygenases, catalyses hydroxylation of Asn-803 of hypoxia-inducible factor, a transcription factor that regulates the mammalian hypoxic response. Only one other asparaginyl beta-hydroxylase, which catalyses hydroxylation of both aspartyl and asparaginyl residues in EGF (epidermal growth factor)-like domains, has been characterized. In the light of recent crystal structures of FIH, we compare FIH with the EGFH (EGF beta-hydroxylase) and putative asparagine/asparaginyl hydroxylases. Sequence analyses imply that EGFH does not contain the HXD/E iron-binding motif characteristic of most of the 2-oxoglutarate oxygenases.

Tolerance of nitrosurea-based multiagent chemotherapy regime for low-grade pediatric gliomas.

The aim of this study was to compare tolerance of a nitrosurea-based regime with 'standard' therapy of vincristine (VCR) and carboplatin for low-grade gliomas. Ten children with low-grade gliomas received second line therapy consisting of thioguanine, procarbazine, CCNU and vincristine (TPCV). Two groups were identified, i.e. patients who had either experienced significant toxicity with carboplatin (reaction group) or had re-growth of their tumor (re-growth group) following first line therapy. Patients were evaluated for toxicity. Data was available on nine patients. Patients in the reaction group completed a mean of 3 cycles of TPCV (range 2-4). One patient stopped after 2 cycles of TPCV due to tumor progression and died 3 months later and one remained on therapy at the time of analysis. Patients in the re-growth group received a mean of 5.5 cycles of TPCV (range 4-8). Treatment was discontinued in one patient after 4 cycles due to hematological toxicity, one experienced tumor progression after 4 cycles and one stopped after 6 cycles because of neurological toxicity. There was no difference in the incidence of grade 3/4 neutropenia or thrombocytopenia, transfusion requirements or delays in chemotherapy between TPCV and VCR/carboplatin in either group. There were no serious infections or toxic deaths. Seven of nine patients had stable disease at a mean of 13 months of follow up. TPCV therapy is a well-tolerated regime with comparable bone marrow toxicity to VCR/carboplatin. Significant disease stabilization was observed with TPCV and hence this regime may be used as second line therapy.

Calcium supplement and bone medication use in a US Medicare health maintenance organization.

This study was conducted to determine the prevalence of the use of calcium supplements and of prescription medications to prevent or treat osteoporosis in men and women in a large New England Medicare Health Maintenance Organization (HMO). A two-page diet, medication use and medical history questionnaire was sent to a random sample of 9000 out of 82 985 members and 2932 (32.6%) responded. Over 97% of the participants were Caucasian and 64.7% were female. The mean ages of the men and women were 74.4+/-5.8 and 74.6+/-6.2 years, respectively. Sixty-nine percent of the men and 59% of the women consumed two or fewer servings of dairy foods per day. Calcium supplement use was more prevalent among the women than the men (66.8% vs 24.9%, p<0.001). Men and women with higher dairy food intakes were more likely to take calcium supplements than were those with lower dairy intakes. Prescription bone medications (including bisphosphonates, raloxifene and calcitonin) were used currently by 17.5% of the women and 2.3% of the men ( p<0.001). An additional 16.2% of the women currently took estrogen. Among the women, bone medication use did not change with age but estrogen use declined with increasing age. Among women age 80+ years, 15.6% used bone medications and 4.9% took estrogen. According to a national survey, more than half the US Caucasian female population over age 80 years has bone density low enough to warrant treatment under current guidelines. Based on the results of this survey, many elderly men and women may benefit from increased utilization of calcium supplements and bone-active medications.

Leucocyte versus erythrocyte thioguanine nucleotide concentrations in children taking thiopurines for acute lymphoblastic leukaemia.

PURPOSE: The aim of this study was to compare leucocyte and erythrocyte thioguanine nucleotide (TGN) cytotoxic metabolite concentrations in children with lymphoblastic leukaemia taking mercaptopurine (MP) or thioguanine (TG) as part of their long-term remission maintenance chemotherapy. METHODS: Ten consecutive children treated on the MRC ALL97 protocol were studied. Six were randomized to TG and four to MP. Leucocyte and erythrocyte thiopurine nucleotide metabolites were measured after the children had been titrated to the standard thiopurine protocol dose, or higher. RESULTS: Children taking TG accumulated significantly higher erythrocyte TGN concentrations than those taking MP (median difference 1171 pmol/8 x 10(8) erythrocytes, 95% CI 766 to 2169, P<0.02), but there was no significant difference in the concentration range of leucocyte TGNs generated from TG or MP. In those children taking TG, median TGN concentrations were 5142 pmol/8 x 10(8) leucocytes and 1472 pmol/8 x 10(8) erythrocytes (3.5-fold difference, median difference 3390 pmol/8 x 10(8) cells, 95% CI 1559 to 7695, P=0.005), compared to 5422 pmol/8 x 10(8) leucocytes and 261 pmol/8 x 10(8) erythrocytes (20-fold difference, median difference 5054 pmol/8 x 10(8) cells, 95% CI 2281 to 6328, P=0.03) in those taking MP. CONCLUSIONS: Despite the accumulation of significantly higher erythrocyte TGN concentrations for TG compared with MP, the accumulation of leucocyte TGNs in children taking TG was similar to the range of leucocyte TGNs in children taking MP. Therefore, when correlating intracellular TGNs to clinical effect, the range of erythrocyte TGN metabolites will be higher for those children taking TG than in those taking MP.

Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy.

We conducted a case study of human immunodeficiency virus (HIV)-negative patients with cryptococcosis at 15 United States medical centers from 1990 through 1996 to understand the demographics, therapeutic approach, and factors associated with poor prognosis in this population. Of 306 patients with cryptococcosis, there were 109 with pulmonary involvement, 157 with central nervous system (CNS) involvement, and 40 with involvement at other sites. Seventy-nine percent had a significant underlying condition. Patients with pulmonary disease were usually treated initially with fluconazole (63%); patients with CNS disease generally received amphotericin B (92%). Fluconazole was administered to approximately two-thirds of patients with CNS disease for consolidation therapy. Therapy was successful for 74% of patients. Significant predictors of mortality in multivariate analysis included age > or =60 years, hematologic malignancy, and organ failure. Overall mortality was 30%, and mortality attributable to cryptococcosis was 12%. Cryptococcosis continues to be an important infection in HIV-negative patients and is associated with substantial overall and cause-specific mortality.

6-Thioguanine in children with acute lymphoblastic leukaemia: influence of food on parent drug pharmacokinetics and 6-thioguanine nucleotide concentrations.

AIMS: Since relatively little is known about the pharmacokinetics of 6-thioguanine (6TG) in children receiving 6-thioguanine for maintenance therapy of acute lymphoblastic leukaemia (ALL), we studied plasma drug concentrations under standardized conditions and investigated the effect of food on parent drug pharmacokinetics and the accumulation of the active metabolites 6-thioguanine nucleotides (6-TGNs) in red cells. METHODS: Single oral doses of 40 mg of 6-TG were administered both in the fasting and fed state to children with ALL. Pharmacokinetic sampling was performed up to 6 h post dose. Daily oral doses of 40 mg m(-2) of 6-TG were administered both fasting and after food over two 4 week periods. Twice weekly samples were taken for metabolite concentrations. The study design was cross-over with each child receiving dosing in either fasted or after food over a 4 week period in each phase. RESULTS: Eleven patients were studied. A wide interindividual variation in Cmax (median 313 pmol ml(-1), range 51-737) and AUC (median 586 pmol ml(-1) h, range 156-1306) was observed in the fasted state. Concomitant food administration resulted in a significant reduction in Cmax (median 71 vs 313 pmol ml(-1), P = 0.006, CI from 36 to 426), AUC (median 200 vs 586 pmol ml(-1) h, P = 0.006, 95% CI from 109 to 692), and time to reach Cmax (median 1.5 vs 3 h, P = 0.013, 95% CI from 0.74 to 2.73). There was no difference in the steady state concentration of red cell 6-TGNs observed after a 4 week period of 6-TG administered fasting or after food. CONCLUSIONS: Children with ALL demonstrate significant interindividual variation in 6-TG pharmacokinetics. Although there would appear to be a reduction in parent drug Cmax and AUC with food there was no difference in 6-TGN concentrations after 4 weeks of 6-TG. Taking the drug on an empty stomach may not be necessary.

Multicenter case-control study of risk factors for histoplasmosis in human immunodeficiency virus-infected persons.

We conducted a multicenter case-control study to identify risk factors for histoplasmosis among persons with acquired immunodeficiency syndrome (AIDS) and to evaluate predictors of a poor outcome (defined as death or admission to the intensive care unit). Patients with histoplasmosis were each matched by age, sex, and CD4 lymphocyte count to 3 controls. From 1996 through 1999, 92 case patients and 252 controls were enrolled. Of the case patients, 81 (89%) were men, 50 (55%) were black, 78 (85%) had a CD4 lymphocyte count of <100 cells/microL, 80 (87%) were hospitalized, and 11 (12%) died. Multivariable analysis found that receipt of antiretroviral therapy and of triazole drugs were independently associated with a decreased risk of histoplasmosis. Chronic medical conditions and a history of infections with herpes simplex virus were associated with poor outcome. Triazoles should be considered for chemoprophylaxis for persons with AIDS, especially those who take part in high-risk activities that involve frequent exposure to soil, who have CD4 lymphocyte counts of <100 cells/microL, and who live in areas where histoplasmosis is endemic.

A quality measurement framework for managed care organizations.

This article presents a framework for a quality measurement system and its corresponding principles for quality improvement within a managed care environment. The quality measurement system comprises four modes: quality assessment, comparison, improvement, and system evaluation. If these modes are to be effective, the measurement system must incorporate the following five principles: (a) maintain and continually improve the data systems, (b) develop and utilize sound methodology and valid indicators, (c) build a competent measurement team, (d) develop effective strategies for implementation, and (e) protect member confidentiality. This model is helpful in the ongoing development and testing of new measurement systems.

Use of capecitabine as first-line therapy in patients with metastatic breast cancer relapsing after high-dose chemotherapy and autologous stem cell support.

High-dose chemotherapy with autologous stem cell support (HDC-ASCS) can produce high complete remission rates in patients with metastatic breast cancer (MBC). However, the majority of those so treated will relapse within 3 years. The ability of such patients to tolerate further myelosuppressive chemotherapy may be limited and the best therapy is undefined. In this retrospective study we assessed the role of capecitabine as initial therapy after relapse. Ten patients (median age = 47 years; oestrogen receptor-positive, n = 4; visceral disease, n = 6; prior anthracycline, n = 8, prior taxanes, n = 10), whose disease progressed at a median of 246 days (range 69-480) after HDC-ASCS and who were treated with capecitabine (2500 mg/m2 per day for 2 weeks of a 3-week cycle) as initial therapy for relapse, were assessed retrospectively for response and toxicity. They received a median of eight cycles (range 4-24) of capecitabine. The toxicities encountered while receiving capecitabine were: hand-foot syndrome (grade 1, n = 3; grade 2, n = 4; grade 3, n = 1); diarrhoea (grade 1, n = 1; grade 2, n = 3); nausea (n = 2) and fatigue (n = 5). Haematological toxicity was seen in only one patient. No patient required hospitalization for toxicity. Three achieved a complete remission, four a partial remission and three disease stabilization. After a median follow-up of 183 days from commencing capecitabine (range 97-540), all patients were alive and five were in remission. Five progressed after remissions that lasted between 63 and 252 days. Oral capecitabine is an active and well-tolerated agent when used alone as first-line therapy in patients who have relapsed after HDC-ASCS for MBC.