Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial.

BACKGROUND: We evaluated the efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in patients living with human immunodeficiency virus (HIV) with cryptosporidiosis. METHODS: We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched individuals living with HIV without cryptosporidiosis. RESULTS: Twenty part A and 10 part B participants completed the study ATP. Almost all part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared with the placebo group. Over the inpatient period, compared with those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit, 3.82), total stool weight decreased by 45.3 g (P = .37), and number of diarrheal episodes increased by 2.32 (P = .87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. One placebo and 3 CFZ participants died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than in part B controls. CONCLUSIONS: Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons living with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy. CLINICAL TRIALS REGISTRATION: NCT03341767.

Long-term efficacy of novel therapies in moderate-to-severe plaque psoriasis: a systematic review and network meta-analysis of PASI response.

BACKGROUND: Patients with moderate-to-severe psoriasis require long-term treatment, yet few trials compare outcomes beyond a short-term induction period. Quantitative comparisons of long-term outcomes in patients with psoriasis are limited. To our knowledge, no network meta-analysis (NMA) of such data has been performed. OBJECTIVE: To compare novel systemic therapies, both biologic and non-biologic, approved for moderate-to-severe psoriasis by conducting a systematic review (SR) and NMA of Psoriasis Area and Severity Index (PASI) outcomes measured at or around 1 year. METHODS: An SR was conducted to identify studies reporting PASI 75, PASI 90 and PASI 100 responses. Feasibility of an NMA on maintenance phase endpoints was assessed and sources of heterogeneity considered. Data appropriate for analysis were modelled using a Bayesian multinomial likelihood model with probit link. Wherever possible, data corresponding to an intention-to-treat approach with non-responder imputation were used. RESULTS: Twenty-four studies reporting outcomes at 40-64 weeks were identified, but heterogeneity in study design allowed synthesis of only 17. Four 52-week randomized controlled trials (RCTs) comprised the primary analysis, which found brodalumab was significantly more efficacious than secukinumab, ustekinumab and etanercept. Secukinumab was also more efficacious than ustekinumab and both outperformed etanercept. In a secondary analysis, evidence from 13 additional studies and 4 further therapies (adalimumab, apremilast, infliximab and ixekizumab) was included by comparing long-term outcomes from active interventions to placebo outcomes extrapolated from induction. Results were consistent with the primary analysis: brodalumab was most effective, followed by ixekizumab and secukinumab, then ustekinumab, infliximab and adalimumab. Etanercept and apremilast had the lowest expected long-term efficacy. Results were similar when studies with low prior exposure to biological therapies were excluded. CONCLUSION: Results suggest that brodalumab is associated with a higher likelihood of sustained PASI response, including complete clearance, at week 52 than comparators. Further long-term active-comparator RCT data are required to better assess relative efficacy across therapies.

Tocilizumab in the treatment of rheumatoid arthritis: a cost-effectiveness analysis in the UK.

BACKGROUND: Since receiving a positive recommendation in England, Wales and Scotland, tocilizumab (TCZ) is one of the options available to clinicians for the treatment of rheumatoid arthritis (RA) patients in the UK. OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of adding TCZ to the current treatment sequence of RA patients from a UK payer's perspective over a patient lifetime horizon. METHODS: An individual sampling model was developed to synthesise all clinical and economic inputs. Two scenarios were explored separately: patients contraindicated to methotrexate (MTX) and those MTX tolerant. For each scenario, the analysis compared three strategies. The standard of care (SoC) strategy included a sequence of the most commonly prescribed biologics; the other two comparator strategies considered the addition of TCZ to SoC at first line and second line. Patient characteristics were representative of UK patients. Treatment efficacy and quality-of-life evidence were synthesised from clinical trials and secondary sources. An analysis of a patient registry informed the model parameters regarding treatment discontinuation. The safety profile of all treatments in a given strategy was based on a network meta-analysis and literature review. Resource utilisation, treatment acquisition, administration, monitoring and adverse event treatment costs were considered. All costs reflect 2012 prices. Uncertainty in model parameters was explored by one-way and probabilistic sensitivity analysis. RESULTS: In the MTX-contraindicated population, if TCZ was added to the SoC in first line, the estimated incremental cost-effectiveness ratio (ICER) was £7,300 per quality-adjusted life-year (QALY) gained; if added in second line, the estimated ICER was £11,400 per QALY. In the MTX-tolerant population, the estimated costs and QALYs of the TCZ strategy were similar to those of the SoC strategy. Sensitivity analysis showed that parameters that affect the treatment cost (such as patient weight) can have a noticeable impact on the overall cost-effectiveness results. The majority of the other sensitivity analyses resulted in modest changes to the ICER. CONCLUSION: For the treatment of RA in MTX-tolerant and contraindicated patients, the addition of TCZ to the SoC was estimated to be a cost-effective strategy.

Spectrally resolved motional Stark effect measurements on ASDEX Upgrade.

A spectrally resolved Motional Stark Effect (MSE) diagnostic has been installed at ASDEX Upgrade. The MSE data have been fitted by a forward model providing access to information about the magnetic field in the plasma interior [R. Reimer, A. Dinklage, J. Geiger et al., Contrib. Plasma Phys. 50, 731-735 (2010)]. The forward model for the beam emission spectra comprises also the fast ion Dα signal [W. W. Heidbrink and G. J. Sadler, Nucl. Fusion 34, 535-615 (1994)] and the smearing on the CCD-chip. The calculated magnetic field data as well as the revealed (dia)magnetic effects are consistent with the results from equilibrium reconstruction solver. Measurements of the direction of the magnetic field are affected by unknown and varying polarization effects in the observation.

Topical therapies for the treatment of localized plaque psoriasis in primary care: a cost-effectiveness analysis.

BACKGROUND: Topical therapies are a mainstay of psoriasis treatment, but they vary substantially in terms of cost. OBJECTIVES: To determine the cost-effectiveness and optimal treatment sequence for psoriasis of the trunk, limbs and scalp. METHODS: Probabilities of response from a network meta-analysis were used to determine the short-term efficacy of topical therapies. Longer-term outcomes, including relapse, were informed by published evidence and clinical opinion. Benefits of treatment were measured as quality-adjusted life years (QALYs). Direct costs included topical agents, primary and secondary care visits and second-line therapies for treatment failures. RESULTS: For the trunk and limbs, initial treatment with a two-compound formulation (TCF) product containing vitamin D and potent corticosteroid provided the most QALYs, followed by separate morning and evening application of vitamin D and potent corticosteroid [two-compound application, TCA (am/pm)], and then twice-daily potent corticosteroids. The use of twice-daily potent corticosteroids was the most cost-effective first-line strategy (incremental cost-effectiveness ratio £ 20,000 per QALY), followed by TCA (am/pm) (£ 22,658 per QALY) and TCF product (£ 179,439 per QALY). For scalp psoriasis, initial treatment with very potent corticosteroids generated the most QALYs, followed by TCF product and then potent corticosteroids. Very potent corticosteroids were the most cost-effective treatment but, if too aggressive, potent corticosteroids were optimal followed by TCF product (£ 219,846 per QALY). The cost-effectiveness of second- and third-line topical agents varied with the assumptions made. CONCLUSIONS: Potent corticosteroids, used alone or in combination with vitamin D, are the most cost-effective treatment for patients with psoriasis of the trunk and limbs. Potent or very potent corticosteroids are the most cost-effective treatment for patients with scalp psoriasis.

Topical therapies for the treatment of plaque psoriasis: systematic review and network meta-analyses.

The majority of people with psoriasis have localized disease, where topical therapy forms the cornerstone of treatment. We set out to summarize evidence on the relative efficacy, safety and tolerability of different topical treatments used in plaque psoriasis. We undertook a systematic review and meta-analyses of randomized trial data of U.K.-licensed topical therapies. The primary outcome was clear or nearly clear status stratified for (i) trunk and limbs; and (ii) scalp. Network meta-analyses allowed ranking of treatment efficacy. In total, 48 studies were available for trunk and limb psoriasis, and 17 for scalp psoriasis (22,028 patients in total); the majority included people with at least moderate severity psoriasis. Strategies containing potent corticosteroids (alone or in combination with a vitamin D analogue) or very potent corticosteroids dominated the treatment hierarchy at both sites (trunk and limbs, scalp); coal tar and retinoids were no better than placebo. No significant differences in achievement of clear or nearly clear status were observed between twice- and once-daily application of the same intervention or between any of the following: combined vitamin D analogue and potent corticosteroid (applied separately or in a single product), very potent corticosteroids, or potent corticosteroids (applied twice daily). Investigator and patient assessment of response differed significantly for some interventions (response rates to very potent corticosteroids: 78% and 39%, respectively). No significant differences were noted for tolerability or steroid atrophy, but data were limited. In conclusion, corticosteroids are highly effective in psoriasis when used continuously for up to 8 weeks and intermittently for up to 52 weeks. Coal tar and retinoids are of limited benefit. There is a lack of long-term efficacy and safety data available on topical interventions used for psoriasis.

Identifying strategies early intervention occupational therapists use to teach caregivers.

This study investigated early intervention occupational therapists' use of strategies to teach caregivers. A sample of 40 videotapes made by early intervention occupational therapists was randomly selected from an archival videotape data set of provider home visits. The sample included 20 videotapes illustrating traditional services and 20 videotapes illustrating therapists providing participation-based services. Videotapes were rated using the Teaching Caregivers Scale, which rates three variables on 30-s intervals: (1) routine, (2) provider role, and (3) strategies used to teach caregivers during early intervention home visits. Regardless of the model of service, explicit teaching strategies were rarely used during home visits.

Treatment of whole blood (WB) and red blood cells (RBC) with S-303 inactivates pathogens and retains in vitro quality of stored RBC.

A pathogen inactivation (PI) process has been developed using the frangible anchor linker effector (FRALE) compound S-303. A series of experiments were performed in whole blood (WB) to measure the level of viral and bacterial inactivation. The results showed that 0.2mM S-303 and 2mM glutathione (GSH) inactivated >6.5 logs of HIV, >5.7 logs of Bluetongue virus, >7.0 logs of Yersinia enterocolitica, 4.2 logs of Serratia marcescens, and 7.5 logs of Staphylococcus epidermidis. Recent development for S-303 is focused on optimization of the PI process for red blood cell concentrates (RBC). A series of studies in RBC showed that 0.2mM S-303 and 20mM GSH inactivated approximately 5 logs or greater of Y. enterocolitica, E. coli, S. marcescens, S. aureus, HIV, bovine viral diarrhoea virus, bluetongue virus and human adenovirus 5. In both applications of the S-303 process, in vitro parameters of RBC function and physiology were retained compared to conventional RBC. Results from these studies indicate that S-303 can be applicable for PI of RBC and WB.

Estimation of organ and effective doses resulting from cone beam CT imaging for radiotherapy treatment planning.

In this study, organ doses were measured for various kilovoltage cone beam CT exposures on the Varian Acuity simulator and an alternative method of dose estimation was also assessed. Organ doses were measured by distributing thermoluminescent dosimeters (TLDs) throughout an anthropomorphic phantom, and effective doses were calculated using International Commission on Radiological Protection (ICRP) 60 and ICRP 103 tissue-weighting factors. The ImPACT CT patient dosimetry calculator was also used to estimate doses for comparison with the TLD results. Effective doses of 15.3 mSv (19.4 mSv), 14.3 mSv (9.7 mSv) and 2.8 mSv (3.2 mSv) were calculated from the TLD measurements and ICRP 60 (ICRP 103) weighting factors for breast, pelvis and head acquisitions, respectively. When a 10 cm pencil ionisation chamber was used to measure the CT dose index, the ImPACT calculator was found to provide an adequate estimation of dose when compared with the TLD results. However, the doses for half-fan exposures were found to be overestimated, with the extent of overestimation depending on the radiosensitive organs irradiated. The organ and effective doses reported provide information for justification and optimisation of cone beam CT procedures, and are compared with doses delivered by other imaging devices. The ImPACT calculator may be used to estimate doses from cone beam CT procedures, if the potential for overestimation is acknowledged.

Relationship between chemical structure and the occupational asthma hazard of low molecular weight organic compounds.

AIMS: To investigate quantitatively, relationships between chemical structure and reported occupational asthma hazard for low molecular weight (LMW) organic compounds; to develop and validate a model linking asthma hazard with chemical substructure; and to generate mechanistic hypotheses that might explain the relationships. METHODS: A learning dataset used 78 LMW chemical asthmagens reported in the literature before 1995, and 301 control compounds with recognised occupational exposures and hazards other than respiratory sensitisation. The chemical structures of the asthmagens and control compounds were characterised by the presence of chemical substructure fragments. Odds ratios were calculated for these fragments to determine which were associated with a likelihood of being reported as an occupational asthmagen. Logistic regression modelling was used to identify the independent contribution of these substructures. A post-1995 set of 21 asthmagens and 77 controls were selected to externally validate the model. RESULTS: Nitrogen or oxygen containing functional groups such as isocyanate, amine, acid anhydride, and carbonyl were associated with an occupational asthma hazard, particularly when the functional group was present twice or more in the same molecule. A logistic regression model using only statistically significant independent variables for occupational asthma hazard correctly assigned 90% of the model development set. The external validation showed a sensitivity of 86% and specificity of 99%. CONCLUSIONS: Although a wide variety of chemical structures are associated with occupational asthma, bifunctional reactivity is strongly associated with occupational asthma hazard across a range of chemical substructures. This suggests that chemical cross-linking is an important molecular mechanism leading to the development of occupational asthma. The logistic regression model is freely available on the internet and may offer a useful but inexpensive adjunct to the prediction of occupational asthma hazard.

Invited review: beta-lactoglobulin: binding properties, structure, and function.

beta-Lactoglobulin (beta-LG) is the major whey protein of ruminant species and is also present in the milks of many, but not all, other species. Its amino-acid sequence and 3-dimensional structure show that it is a lipocalin, a widely diverse family, most of which bind small hydrophobic ligands and thus may act as specific transporters, as does serum retinol binding protein. Bovine beta-LG binds a wide range of ligands, but this may not be the reason for its presence in milk. In reviewing the structure and physicochemical properties of the protein, we present the structures of the ligands cholesterol (at a resolution of 2.0A, R = 0.221; Rfree = 0.295) and vitamin D2 (at a resolution of 2.4A, R = 0.212; Rfree = 0.297) each bound to the central binding cavity of bovine beta-LG at pH 7.3. Neither ligand is fully visible in the electron density maps, and the less well-ordered regions are the polar end groups at the mouth of the binding site. In a separate experiment, a mercury ion was bound to the free Cys121 (at a resolution of 2.2A, R = 0.218; Rfree = 0.288) in a way that transmitted a small structural change through Asp137 via Arg148 to the dimer interface. It is not clear if the known dissociation that arises from the reaction of beta-LG with HgCl2 results from this perturbation. In reviewing the structural studies that reveal the ligand binding sites for long-chain fatty acids, retinoids, and steroids, only the central location, common to all lipocalins so far examined, is occupied under the conditions used. We find that there is no crystallographic evidence of another ligand binding site in our crystals grown in approximately 1.3 M citrate, although low ionic strength studies in solution indicate the possible presence of at least one other low affinity site. The apparent ability of the binding site to accommodate a wide range of ligands may point to a possible physiological function. However, by considering the lipocalin family in general, and the species distribution of beta-LG in particular, some speculation as to the physiological function can be made. beta-Lactoglobulin has been reported as being implicated, inter alia, in hydrophobic ligand transport and uptake, enzyme regulation, and the neonatal acquisition of passive immunity. However, these functions do not appear to be consistent between species. Sequence comparisons among members of the lipocalin family reveal that glycodelin, found in the human endometrium during early pregnancy, is the most closely related to beta-LG. Although the function of glycodelin is also unknown, it appears to have effects on the immune system and/or to be involved in differentiation. It is proposed that beta-LG, over-expressed in the lactating mammary gland of many, but not all, species, is primarily an important source of amino acids for the offspring of those animals that produce it, but that this function arose by gene duplication from the physiologically essential glycodelin. The other functions that have been associated with beta-LG in the neonate are, therefore, fortuitous.

Adaptive, growth-oriented, and positive perceptions of mother-daughter elder caregiving relationships: a path-analytic investigation of predictors.

One hundred twenty-two pairs (n = 244) of filial caregivers (daughters) and care recipients (mothers) were interviewed separately, to investigate the factors underlying positive, growth-oriented caregiving relationships. The outcome variable examined was the type of caregiving pair (positive, negative, mixed, and neutral), as determined by "blind" raters. Based on existing research, factors examined as being significant predictors of this outcome variable were perceived roles (role changes, role relations) and individual-difference characteristics (personality dimensions, fluid intellectual ability). The results of the path model tested support the importance of individual-difference factors in understanding positive mother-daughter elder caregiving relationships.

Crystal structures of bovine beta-lactoglobulin in the orthorhombic space group C222(1). Structural differences between genetic variants A and B and features of the Tanford transition.

The crystal structures of beta-lactoglobulin genetic variants A and B have been determined in the orthorhombic space group C222(1) (lattice Y) by X-ray diffraction at 2.0 A and 1.95 A resolution, respectively. The structural comparison shows that both variants exhibit the open conformation of the EF loop at the pH of crystallization (pH 7.9), in contrast to what has been reported for the same genetic variants at pH 7.1 in the trigonal space group P3221 (lattice Z) [Qin, B.Y., Bewley, M.C., Creamer, L.K., Baker, E.N. & Jameson, G.B. (1999) Protein Sci. 8, 75-83]. Furthermore, it was found that the stereochemical environment of Tyr42 changes significantly with pH variation between pH 7 and pH 8. This may provide a structural explanation for an as yet unexplained feature of the Tanford transition, namely the increase in exposure of a tyrosine residue.

Prognostic factors in severe community-acquired pneumonia in patients without co-morbid illness.

OBJECTIVES: We wished to determine the prognostic factors and the impact of initial empirical antibiotic therapy on the outcome of severe community-acquired pneumonia in patients without underlying co-morbid illness. METHODOLOGY: This is a retrospective record review of consecutive patients with severe community-acquired pneumonia who were divided into those with and without underlying co-morbid illness. RESULTS: There were 182 patients including 112 primary (no co-morbid illness) and 70 secondary (underlying co-morbid illness) pneumonias. The overall mortality was 41.8% and there were no differences in APACHE II score or mortality when comparing cases with primary (37.5%) and secondary infections (48.6%). The mortality was significantly higher in patients with negative microbiology. Univariate analysis identified a number of parameters and various antibiotic regimens, which appeared to be associated with a significantly poorer outcome. On multivariate analysis multilobar pulmonary consolidation, need for mechanical ventilation, inotropes and dialysis were documented to be independent predictors of mortality. Only in their absence could different antibiotic regimens be shown to have an apparent impact on outcome and further analysis suggested that the reason for these differences related predominantly to differences in the severity of the infection. CONCLUSIONS: Markers of disease severity appear to be the most important predictors of outcome in patients with severe community-acquired pneumonia.

The core lipocalin, bovine beta-lactoglobulin.

The lipocalin family became established shortly after the structural similarity was noted between plasma retinol binding protein and the bovine milk protein, beta-lactoglobulin. During the past 60 years, beta-lactoglobulin has been studied by essentially every biochemical technique available and so there is a huge literature upon its properties. Despite all of these studies, no specific biological function has been ascribed definitively to the protein, although several possibilities have been suggested. During the processing of milk on an industrial scale, the unpredictable nature of the process has been put down to the presence of beta-lactoglobulin and certainly the whey protein has been implicated in the initiation of aggregation that leads to the fouling of heat exchangers. This short review of the properties of the protein will concentrate mainly on studies carried out under essentially physiological conditions and will review briefly some of the possible functions for the protein that have been described.

TB PCR in the early diagnosis of tuberculous meningitis: evaluation of the Roche semi-automated COBAS Amplicor MTB test with reference to the manual Amplicor MTB PCR test. .

SETTING: Cecilia Makiwane Hospital, Mdantsane, Eastern Cape, Republic of South Africa. OBJECTIVE: To assess the role of the semi-automated Roche COBAS AMPLICOR(TM)Mycobacterium tuberculosis PCR test in the diagnosis of tuberculous meningitis (TBM). DESIGN: Eighty-three specimens of cerebrospinal fluid (CSF) were collected prospectively from 69 patients with suspected TBM. The COBAS AMPLICOR TB PCR test was compared with the manual AMPLICOR(TM)TB PCR test, clinical and cerebrospinal fluid (CSF) findings, direct ZN smear and radiometric TB culture. RESULTS: CSF from 7/40 (17.5%) patients treated for TBM were positive by TB COBAS AMPLICOR(TM). The sensitivity of the test was not significantly different (p=0.375) from the manual TB AMPLICOR(TM)PCR test. The comparative sensitivities of the TB COBAS AMPLICOR(TM)PCR and the manual AMPLICOR PCR for detecting cases of definite and probable TBM from CSF collected within 9 days of commencing antituberculosis treatment were 40% and 60% respectively. All 29 patients not treated for TBM were negative by COBAS AMPLICOR(TM), giving a specificity of 100%. CONCLUSION: The COBAS AMPLICOR(TM)TB PCR test is a rapid and highly specific diagnostic test for TBM. However, there was a non-significant trend favouring slightly greater sensitivity using the manual AMPLICOR(TM)TB PCR test.