When Azoles Cannot Be Used: The Clinical Effectiveness of Intermittent Liposomal Amphotericin Prophylaxis in Hematology Patients.

BACKGROUND: Patients unable to take azoles are a neglected group lacking a standardized approach to antifungal prophylaxis. We evaluated the effectiveness and safety of intermittent liposomal amphotericin B (L-AMB) prophylaxis in a heterogenous group of hematology patients. METHODS: A retrospective cohort of all hematology patients who received a course of intravenous L-AMB, defined as 1 mg/kg thrice weekly from July 1, 2013 to June 30, 2018, were identified from pharmacy records. Outcomes included breakthrough-invasive fungal disease (BIFD), reasons for premature discontinuation, and acute kidney injury. RESULTS: There were 198 patients who received 273 courses of L-AMB prophylaxis. Using a conservative definition, the BIFD rate was 9.6% (n = 19 of 198) occurring either during L-AMB prophylaxis or up to 7 days from cessation in patients who received a course. Probable/proven BIFD occurred in 13 patients (6.6%, 13 of 198), including molds in 54% (n = 7) and non-albicans Candidemia in 46% (n = 6). Cumulative incidence of BIFD was highest in patients with acute myeloid leukemia (6.8%) followed by acute lymphoblastic leukemia (2.7%) and allogeneic stem cell transplantation (2.5%). The most common indication for L-AMB was chemotherapy, or anticancer drug-azole interactions (75% of courses) dominated by vincristine, or acute myeloid leukemia clinical trials, followed by gut absorption concerns (13%) and liver function abnormalities (8.8%). Acute kidney injury, using a modified international definition, complicated 27% of courses but was not clinically significant, accounting for only 3.3% (9 of 273) of discontinuations. CONCLUSIONS: Our findings demonstrate a high rate of BIFD among patients receiving L-AMB prophylaxis. Pragmatic trials will help researchers find the optimal regimen of L-AMB prophylaxis for the many clinical scenarios in which azoles are unsuitable, especially as targeted anticancer drugs increase in use.

Improvement in Hidradenitis Suppurativa and quality of life in patients treated with adalimumab: Real-world results from the HARMONY Study.

BACKGROUND: Hidradenitis suppurativa (HS), a chronic, recurrent, debilitating skin disease, is characterized by painful, inflammatory, subcutaneous lesions of the axilla, inguinal and anogenital regions. Overall prevalence of HS is ˜1%, and the impact of disease on patient quality of life (QoL) and healthcare resource utilization (HRU) is high. OBJECTIVES: To estimate the real-world effectiveness of adalimumab (Humira®) treatment in patients with moderate-to-severe HS on disease severity, pain, QoL, work productivity and HRU. METHODS: HARMONY (Effectiveness of Adalimumab in Moderate to Severe HidrAdenitis SuppuRativa Patients - a Multi-cOuNtry studY in Real Life Setting) is a multicentre, postmarketing observational study in adult patients with moderate-to-severe HS. Disease severity and QoL parameters were evaluated using validated measures at 12-week intervals over 52 weeks of treatment. The primary endpoint was the proportion of patients achieving a Hidradenitis Suppurativa Clinical Response (HiSCR: ≥50% reduction in abscess and inflammatory nodule count, with no increase in abscess and draining fistula counts relative to baseline) at 12 weeks. Secondary endpoints were HiSCR at 24, 36 and 52 weeks and changes in QoL parameters and work productivity assessments. Analyses were conducted using as-observed data. RESULTS: The proportion of patients reaching the primary HiSCR endpoint was 70.2% (n = 132/188 enrolled) and remained ≥70% until study completion. There were statistically significant (P < 0.0001) reductions in worst and average skin pain. All of the QoL measures evaluated improved significantly (P < 0.0001) by 12 weeks of adalimumab treatment, as did work productivity assessments (P < 0.05), and there was a ˜50% decrease in HRU between baseline and week 52. Adalimumab was well tolerated. CONCLUSIONS: In this real-world setting, adalimumab treatment of moderate-to-severe HS resulted in decreased disease severity and improvements in QoL and productivity. Response to adalimumab was rapid (within 12 weeks) and sustained (52 weeks). No unexpected safety signals were reported.

Mental health and caregiving experiences of family carers supporting people with psychosis.

AIMS: Family carers supporting an individual with psychosis often experience poorer mental health, however, little is known about specific risk factors among these carers. We investigated the associations between demographic, caregiving characteristics and mental health outcomes in family carers supporting an individual with psychosis and compared carers' outcomes with general population norms. METHODS: We analysed baseline data from the COPe-support randomised controlled trial of online psychoeducation and peer support for adult carers supporting an individual with psychosis between 2018 and 2020. We collected carers' demographic and health outcome data, including wellbeing using Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS as primary outcome), quality of life using EQ-5D-5L and caregiving experience assessed with Experience of Caregiving Inventory. We tested associations between carers' demographic and caregiving characteristics for each outcome in turn and meta-analysed carers' WEMWBS and EQ-5D-5L with Health Survey England (HSE) general population data from 2016 and 2017, respectively. RESULTS: The 407 carers of people with psychosis had a mean WEMWBS score of 42.2 (s.d. 9.21) and their overall weighted pooled WEMWBS score was 7.3 (95% confidence interval (CI) -8.6 to -6.0, p < 0.01) lower than the HSE general population sample, indicating carers have poorer mental wellbeing by more than double the minimum clinically important difference of 3 points on WEMWBS. Among all caring relationships, partners had poorer wellbeing compared to parents with lower WEMWBS score (-6.8, -16.9 to 3.3, p = 0.03). Single carers had significantly poorer wellbeing (-3.6, -5.6 to -1.5, p < 0.01) and a more negative caregiving experience than those who were cohabiting. Spending more than 35 h per week caregiving increased carers' negative experience significantly (p = 0.01). CONCLUSION: Carers of people with psychosis have poorer mental health than non-carers. Partners, lone carers and those spending more than 35 h per week on caring were found to be most at risk of poor mental health. Based on the results, we advocate that the details of carers for individuals with psychosis should be added to the existing carers or severe mental illness registers at all general practitioner surgeries and for their wellbeing screened routinely. Future large-scale prospective studies are needed to develop a predictive model to determine risk factors, hence to aid early identification of carers' support needs. Such understandings are also useful to inform tailored intervention development.

Photopatch testing-- a retrospective review using the 1 day and 2 day irradiation protocols.

Photopatch testing is indicated in the investigation of patients with eczematous eruptions, affecting mainly light-exposed sites and in those who give a history of worsening of their condition with sun exposure. 3 different protocols are described by the British Photodermatology Group (Br J Dermatol 1997:136:371-376), 1 of which includes irradiation of allergens 1 day after application and 2 using irradiation of allergens 2 days after application. There is no evidence for superiority of any of these protocols. We reviewed the records of all patients who underwent photopatch testing in Leeds over a 50-month period, who had had the allergens applied in triplicate with 1 set irradiated after 1 day occlusion and another after 2 days. The control was occluded for 2 days. Readings were performed at 2 days and 4 days. 15 of 74 patients photopatch tested during this period had 49 positive results between them. 43 of these were felt to be of current relevance to their clinical problem. 34 of the positive results were indicative of photoallergy. Additional photoallergic reactions were detected following 2 days occlusion and irradiation compared with 1 day occlusion (16 versus 5). In conclusion, our case series suggests that 2 days occlusion before irradiation of allergens is more sensitive at detecting photoallergy.

Vanadium(V) complexes of alpha-hydroxycarboxylic acids in aqueous solution.

51V NMR and IR spectroscopic studies of the complexes formed between vanadate and the alpha-hydroxylic acid ligands, (S)-2-hydroxypropanoic acid (L-(+)-lactic acid), 2-hydroxy-2-methylpropanoic acid, and 2-ethyl-2-hydroxybutanoic acid were carried out for aqueous 1 M ionic strength (NaCl) solutions. Three major products in V to L stoichiometries of 1:1, 2:2, and 3:2 were identified from vanadate and ligand concentration studies, while a pH variation study allowed charge states to be determined. At pH 7.06, the formation constants for the predominant reactions were (26 +/- 1) M (-1), (V + L <= => VL); (6.8 +/- 0.4) x 10(3) M(-1), (2VL <= => V(2)L(2)); and (3.5 +/- 0.3) x 10(3) M(-1), (V(2)L(2) + V <= => V(3)L(2)). Dissolution studies of various crystalline products were carried out for aqueous, nonaqueous, and mixed solvent systems. These studies combined with information available from X-ray structural studies provided a basis for the assignment of solution state structures. Pentacoordinate vanadium in a trigonal-bipyramidal geometry was proposed for the both the 1:1 and 2:2 complexes when in aqueous solution. Observed changes in (51)V chemical shift patterns were consistent with a cis fusion in octahedral coordination for the central vanadium of the 3:2 complex, while the remaining vanadiums retained a pentacoordinate geometry.

Gold-gold interactions as crystal engineering design elements in heterobimetallic coordination polymers.

A series of coordination polymers containing Cu(II) and [Au(CN)(2)](-) units has been prepared. Most of their structures incorporate attractive gold-gold interactions, thus illustrating that such "aurophilic" interactions can be powerful tools for increasing structural dimensionality in supramolecular systems. [Cu(tren)Au(CN)(2)][Au(CN)(2)] (1, tren = tris(2-ethylamino)amine) forms a cation/anion pair, which is weakly linked by hydrogen bonds but not by aurophilic interactions. [Cu(en)(2)Au(CN)(2)][Au(CN)(2)] (2-Au, en = ethylenediamine) is a 2-D system composed of a chain of [Au(CN)(2)](-) anions and another chain of [(en)(2)Cu-NCAuCN](+) cations; short Au-Au bonds of 3.1405(2) A connect the anions. This bond is shorter than that observed in the analogous silver(I) structure, 2-Ag. The average M-C bond lengths of 1.984(8) A in 2-Au are significantly shorter than those found in 2-Ag, suggesting that Au(I) is smaller than Ag(I). Cu(dien)[Au(CN)(2)](2) (3, dien = diethylenetriamine) forms a 1-D chain of tetranuclear [Au(CN)(2)](-) units that are bound to [Cu(dien)] centers. Aurophilic interactions of ca. 3.35 A hold the tetramer together. Cu(tmeda)[Au(CN)(2)](2) (4, tmeda = N,N,N',N'-tetramethylethylenediamine) forms a 3-D network by virtue of aurophilic interactions of 3.3450(10) and 3.5378(8) A. Altering the Cu:Au stoichiometry yields Cu(tmeda)[Au(CN)(2)](1.5)(ClO(4))(0.5) (5), which has an unusual 2-D rhombohedral layer structure (space group R32). Complex 5 is composed of three mutually interpenetrating Cu[Au(CN)(2)](1.5) networks which are interconnected by aurophilic interactions of 3.4018(7) and 3.5949(8) A. Weak antiferromagnetic coupling is observed in 2 and 5.

Conformational preferences in glycosylamines. implications for the exo-anomeric effect.

The conformational preferences about the C-N bond in N-(4-methoxyphenyl)-2,3,4,6-tetra-O-acetyl-alpha (1) and beta-D-glucopyranosylamine (2), in the solid state and in solution, have been investigated. The crystal structure of the axially substituted alpha anomer (1) indicates a conformational preference about the C-1-N bond in which nN-->sigma*C-O exo-anomeric interactions may be expressed, although this conformational preference is not displayed in solution. The solution conformation relieves steric interactions that result from expression of the exo-anomeric effect in the solid-state conformation. The conformational preference in the equatorially substituted beta anomer (2) both in solution and in the solid state is similar and permits expression of nN-->sigma*C-O exo-anomeric interactions. The structural data for 1 and 2 indicate significant differences in O-5-C-1-N-1 bond angles but insignificant differences in each of the O-5-C-1 or C-1-N-1 bond lengths. The J(C-1-H-1 coupling constants in 1 and 2 indicate a greater coupling constant for the alpha anomer that is consistent with a dominant nO-->sigma*C-H orbital interaction in the beta anomer that weakens the C-1-H-1 bond.

Significant frequencies of T cells with indirect anti-donor specificity in heart graft recipients with chronic rejection.

BACKGROUND: The purpose of this study was to determine whether T cells with indirect allospecificity could be detected in heart transplant recipients with chronic rejection. METHOD AND RESULTS: Human T-cell clones were used to determine the most effective way to deliver major histocompatibility complex alloantigens for indirect presentation. Seven allograft recipients with evidence of progressive, chronic rejection were selected. Four heart graft recipients with no evidence of chronic rejection were used as controls. Peripheral blood T cells and antigen-presenting cells from the recipients were cultured with frozen/thawed stored donor cells or major histocompatibility complex class I-derived synthetic peptides in limiting dilution cultures and then compared with controls using tetanus toxoid and frozen/thawed third-party cells with no human leukocyte antigens in common with the donor. In 5 of 7 patients analyzed who had chronic rejection, elevated frequencies of T cells with indirect, anti-donor specificity (iHTLf) were detected. No such elevated iHTLf were detected in recipients without chronic rejection. DISCUSSION: iHTLf can be obtained from human transplant recipients, which supports the contention that the indirect pathway is involved in chronic transplant rejection.