Hearing Loss after Discontinuing Secondary Prophylaxis for Cryptococcal Meningitis: Relapse or Immune Reconstitution?

Relapse and immune reconstitution syndrome are difficult to distinguish in HIV-infected patients treated with antiretroviral therapy (ART). We report on a 26-year-old HIV-infected male (CDC C3) with hearing loss on the right side 2 months after discontinuing secondary prophylaxis for cryptococcal meningitis. CD4 cell counts had increased from 32/µl to stable counts > 200/µl for the preceding 6 months on ART but HIV replication was not fully suppressed (7,000 copies/ml). Magnetic resonance imaging identified lesions at the origin of the right cranial nerve VIII. Lumbar puncture revealed monocytic pleocytosis, slightly increased protein, but normal glucose and lactate levels, negative microbiological studies. Fluconazole was restarted and a new ART regimen was started in order to fully suppress HIV replication. Clinical and radiological signs were reversible during follow-up, and secondary prophylaxis was stopped after 6 months without adverse events. We review 26 published cases of cryptococcal infections with immune reconstitution syndrome and highlight the distinguishing feature

Electron Trap Dynamics in Polymer Light-Emitting Diodes

Semiconducting polymers are being studied intensively for optoelectronic device applications, including solution-processed light-emitting diodes (PLEDs). Charge traps in polymers limit the charge transport and thus the PLED efficiency. It is firmly established that electron transport is hindered by the presence of the universal electron trap density, whereas hole trap formation governs the long-term degradation of PLEDs. Here, the response of PLEDs to electrical driving and breaks covering the timescale from microseconds to (a few) hours is studied, thus focusing on electron traps. As reference polymer, a phenyl-substituted poly(para-phenylene vinylene) (PPV) copolymer termed super yellow (SY) is used. Three different traps with depths between approximate to 0.4 and 0.7 eV, and a total trap site density of approximate to 2 x 10(17) cm(-3) are identified. Surprisingly, filling of deep traps takes minutes to hours, at odds with the common notion that charge trapping is complete after a few hundred microseconds. The slow trap filling feature for PLEDs is confirmed using poly(2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylene vinylene (MEH-PPV) and poly(3-hexylthiophene) (P3HT) as active materials. This unusual phenomenon is explained with trap deactivation upon detrapping and slow trap reactivation. The results provide useful insight to pinpoint the chemical nature of the universal electron traps in semiconducting polymers

Factors associated with rifampin resistance in staphylococcal periprosthetic joint infections (PJI): a matched case-control study

Purpose: Rifampin combination therapy plays an important role in the management of staphylococcal periprosthetic joint infection (PJI). However, the emergence of rifampin resistance is a feared complication. We retrospectively analysed predetermined potential risk factors in patients with rifampin-resistant staphylococcal PJI in a multicentre case-control study. Methods: Cases (n=48) were defined as PJI caused by rifampin-resistant staphylococci. Rifampin-susceptible controls (n=48) were matched for microorganism and type of prosthetic joint. Uni- and multivariable conditional logistic regression analyses were performed to estimate odds ratios (OR) with 95% confidence intervals (95% CI). Results: Forty-eight cases (31 men; median age 67years; age range 39-88years) with hip- (n=29), knee- (n=13), elbow- (n=4), shoulder- (n=1) or ankle-PJI (n=1) were enrolled in the study. Staphylococcus aureus and coagulase-negative staphylococci were isolated in ten and 38 episodes, respectively. Most of the cases (n=44, 92%) had a previous PJI, and 93 % (n=41) of these had been treated with rifampin. There was an independent association of emergence of rifampin resistance with male sex (OR 3.6, 95% CI 1.2-11),≥3 previous surgical revisions (OR 4.7, 95% CI 1.6-14.2), PJI treatment with high initial bacterial load (inadequate surgical debridement, <2weeks of intravenous treatment of the combination medication; OR 4.9, 95% CI 1.6-15) and inadequate rifampin therapy (OR 5.4, 95% CI 1.2-25). Conclusions: Based on our results, extensive surgical debridement and adequate antibiotic therapy are needed to prevent the emergence of rifampin resistanc

Dose-response relationship between ambulatory load magnitude and load-induced changes in COMP in young healthy adults

To determine the dose-response relationship between ambulatory load magnitude during a walking stress test and load-induced changes in serum concentration of cartilage oligomeric matrix protein (sCOMP) in healthy subjects.; sCOMP was assessed before and after a 30-min walking stress test performed on three test days by 24 healthy volunteers. In each walking stress test, one of three ambulatory loads was applied in a block randomized crossover design: normal body weight (BW) (100%BW = normal load); reduced BW (80%BW = reduced load); increased BW (120%BW = increased load). Knee kinematics and ground reaction force (GRF) were measured using an inertial sensor gait analysis system and a pressure plate embedded in the treadmill.; Load-induced increases in sCOMP rose with increasing ambulatory load magnitude. Mean sCOMP levels increased immediately after the walking stress test by 26.8 ± 12.8%, 28.0 ± 13.3% and 37.3 ± 18.3% for the reduced, normal or increased load condition, respectively. Lower extremity kinematics did not differ between conditions.; The results of this study provide important evidence of a dose-response relationship between ambulatory load magnitude and load-induced changes in sCOMP. Our data suggests that in normal weight persons sCOMP levels are more sensitive to increased than to reduced load. The experimental framework presented here may form the basis for studying the relevance of the dose-response relationship between ambulatory load magnitude and load-induced changes in biomarkers involved in metabolism of healthy articular cartilage and after injury

Methods to convert continuous outcomes into odds ratios of treatment response and numbers needed to treat: meta-epidemiological study

Background Clinicians find standardized mean differences (SMDs) calculated from continuous outcomes difficult to interpret. Our objective was to determine the performance of methods in converting SMDs or means to odds ratios of treatment response and numbers needed to treat (NNTs) as more intuitive measures of treatment effect. Methods Meta-epidemiological study of large-scale trials (≥100 patients per group) comparing active treatment with placebo, sham or non-intervention control. Trials had to use pain or global symptoms as continuous outcomes and report both the percentage of patients with treatment response and mean pain or symptom scores per group. For each trial, we calculated odds ratios of observed treatment response and NNTs and approximated these estimates from SMDs or means using all five currently available conversion methods by Hasselblad and Hedges (HH), Cox and Snell (CS), Furukawa (FU), Suissa (SU) and Kraemer and Kupfer (KK). We compared observed and approximated values within trials by deriving pooled ratios of odds ratios (RORs) and differences in NNTs. ROR <1 and positive differences in NNTs imply that approximations are more conservative than estimates calculated from observed treatment response. As measures of agreement, we calculated intraclass correlation coefficients. Results A total of 29 trials in 13 654 patients were included. Four out of five methods were suitable (HH, CS, FU, SU), with RORs between 0.92 for SU [95% confidence interval (95% CI), 0.86-0.99] and 0.97 for HH (95% CI, 0.91-1.04) and differences in NNTs between 0.5 (95% CI, −0.1 to −1.6) and 1.3 (95% CI, 0.4-2.1). Intraclass correlation coefficients were ≥0.90 for these four methods, but ≤0.76 for the fifth method by KK (P for differences ≤0.027). Conclusions The methods by HH, CS, FU and SU are suitable to convert summary treatment effects calculated from continuous outcomes into odds ratios of treatment response and NNTs, whereas the method by KK is unsuitabl

Cutibacterium acnes is present in non-herniated human discs; its positivity rate correlates with the patients age

Introduction: The presence of bacteria in the intervertebral discs (IVDs) and their role in disc degeneration is an area of controversy. Numerous studies have detected Cutibacterium acnes and other microbes with 16S DNA Sequencing and microbial cultures. However, those studies fail to determine whether the bacteria are in-vivo disc bacteria or perioperative contamination. Capoor et al. 1 performed confocal scanning laser microscopy for a limited number of herniated IVDs and detected C. acnes biofilms within the human specimens. Our study investigated the presence of Gram-positive bacteria C. acnes and Staphylococcus aureus in non-herniated human IVDs. Furthermore, expression of cellular recognition receptors Toll-like receptor (TLR) 2, TLR4 and NLR family pyrin domain containing 3 (NLRP3) and the pyroptosis marker Gasdermin D were investigated. Methods: Immunohistochemical staining for Gram-positive bacteria, S. aureus, C.acnes TLR2, TLR4, NLRP3 and Gasdermin D was performed on 75 non-herniated human IVD samples. Cell detection and classification was performed using QuPath. Fluorescently labelled S. aureus cells were co-cultured with human NP cells in monolayer across multiplicity of Infection (MOI) range (1:10- 1:100), and analysed by confocal imaging. Furthermore, human nucleus pulposus (NP) cells in monolayer were treated with Lipopolysaccharide (LPS) (5-50μg/ml) and Peptidoglycan (PGN) (5-50 μg/ml) for 48h, and cells in 3D alginate with PGN for up to 72h. Secretome analysis was performed using Luminex for cytokines, chemokines, matrix degrading enzymes and other secreted factors. Statistical analysis was performed using Kruskal-Wallis, Dunn’s multiple comparison test and Pearson correlation. Results Co-culture of S. aureus with NP cells showed internalisation of bacteria. Immunohistochemical staining demonstrated gram positive bacteria was solely detected within cells and not as biofilm within the tissue. The positivity rate of C. acnes ranged between 5-99%. The number of C.acnes positive cells showed a correlation with the age of the patients (r=0.41, p= 0.007). However, it did not correlate with grade of degeneration. The positivity rate of TLR2 ranged between 5-99% and TLR4 from 3-72%. TLR2 and TLR4 showed a strong correlation (r= 0.62, p= 1.5e-006). A significant decrease in TLR2 was observed in females showing a mid-degenerative grade compared to females showing no signs of degeneration. Investigation of the presence and the correlation between NLRP3, GasderminD, S. aureus and the above-mentioned factors is undergoing. Treatment of NP cells with LPS and PGN resulted in an increase of several catabolic cytokines such as IL-1, TNF, IL-6 and IFN-γ alongside increased production of chemokines, neurotrophic and angiogenic factors associated with IVD degeneration. Conclusion This study demonstrated the presence of Gram-positive bacteria such as C. acnes in non-herniated and cadaveric human disc samples. The internalisation of bacteria by human NP cells was demonstrated and aligns with previous publications. Furthermore, this shows a correlation between age and the presence of C. acnes as well as a strong correlation between the two TLRs. Moreover, bacterial cell membrane components triggered a catabolic response in human disc cells. Ongoing interaction studies between bacteria and NP cells will give us insight it to the potential role of bacteria in disc degeneration

Suppression of HBV by Tenofovir in HBV/HIV coinfected patients : a systematic review and meta-analysis

Background: Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent and the one with the lowest risk of resistance appears to be tenofovir (TDF). However there are several questions that remain unanswered regarding the use of TDF, including the proportion of patients that achieves suppression of HBV viral load and over what time, whether suppression is durable and whether prior treatment with other HBV-active drugs such as lamivudine, compromises the efficacy of TDF due to possible selection of resistant HBV strains. Methods: A systematic review and meta-analysis following PRISMA guidelines and using multilevel mixed effects logistic regression, stratified by prior and/or concomitant use of lamivudine and/or emtricitabine. Results: Data was available from 23 studies including 550 HBV/HIV coinfected patients treated with TDF. Follow up was for up to seven years but to ensure sufficient power the data analyses were limited to three years. The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively. No effect of prior or concomitant 3TC/FTC was shown. Virological rebound on TDF treatment was rare. Interpretation: TDF suppresses HBV to undetectable levels in the majority of HBV/HIV coinfected patients with the proportion fully suppressed continuing to increase during continuous treatment. Prior treatment with 3TC/FTC does not compromise efficacy of TDF treatment. The use of combination treatment with 3TC/FTC offers no significant benefit over TDF alone

Interfacial charge transfer in nanoscale polymer transistors

Interfacial charge transfer plays an essential role in establishing the relative alignment of the metal Fermi level and the energy bands of organic semiconductors. While the details remain elusive in many systems, this charge transfer has been inferred in a number of photoemission experiments. We present electronic transport measurements in very short channel ($L < 100$ nm) transistors made from poly(3-hexylthiophene) (P3HT). As channel length is reduced, the evolution of the contact resistance and the zero-gate-voltage conductance are consistent with such charge transfer. Short channel conduction in devices with Pt contacts is greatly enhanced compared to analogous devices with Au contacts, consistent with charge transfer expectations. Alternating current scanning tunneling microscopy (ACSTM) provides further evidence that holes are transferred from Pt into P3HT, while much less charge transfer takes place at the Au/P3HT interface.Comment: 19 preprint pages, 6 figure

Frequency dependent dielectric and mechanical behaviour of elastomers for actuator applications

The low frequency mechanical and dielectric behavior of three different elastomers has been investigated by dynamic mechanical analysis and dielectric spectroscopy, with the aim of accounting for the frequency dependence of the characteristics of the corresponding dielectric elastomer actuators. Satisfactory agreement was obtained between the dynamic response of the actuators and a simple model based on the experimental data for the elastomers, assuming that the relatively large prestrains employed in the actuators to have little influence on the frequency dependence of their effective moduli. It was thus demonstrated that the frequency dependence of the actuator strain is dominated by that of the mechanical response of the elastomer, and that the frequency dependence of the dielectric properties has a relatively minor influence on the actuator performance

Suppression of HBV by Tenofovir in HBV/HIV Coinfected Patients: A Systematic Review and Meta-Analysis

Background:Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent and the one with the lowest risk of resistance appears to be tenofovir (TDF). However there are several questions that remain unanswered regarding the use of TDF, including the proportion of patients that achieves suppression of HBV viral load and over what time, whether suppression is durable and whether prior treatment with other HBV-active drugs such as lamivudine, compromises the efficacy of TDF due to possible selection of resistant HBV strains.Methods:A systematic review and meta-analysis following PRISMA guidelines and using multilevel mixed effects logistic regression, stratified by prior and/or concomitant use of lamivudine and/or emtricitabine.Results:Data was available from 23 studies including 550 HBV/HIV coinfected patients treated with TDF. Follow up was for up to seven years but to ensure sufficient power the data analyses were limited to three years. The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively. No effect of prior or concomitant 3TC/FTC was shown. Virological rebound on TDF treatment was rare.Interpretation:TDF suppresses HBV to undetectable levels in the majority of HBV/HIV coinfected patients with the proportion fully suppressed continuing to increase during continuous treatment. Prior treatment with 3TC/FTC does not compromise efficacy of TDF treatment. The use of combination treatment with 3TC/FTC offers no significant benefit over TDF alone