Purpose
The aim of this study was to review the available literature and define clinical practice guidelines for the use of agents for the prevention and treatment of gastrointestinal mucositis.
...Methods
A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible.
Results
A total of 251 clinical studies across 29 interventions were examined. Panel members were able to make one new evidence-based negative recommendation; two new evidence-based suggestions, and one evidence-based change from previous guidelines. Firstly, the panel recommends against the use of misoprostol suppositories for the prevention of acute radiation-induced proctitis. Secondly, the panel suggests probiotic treatment containing
Lactobacillus
spp., may be beneficial for prevention of chemotherapy and radiotherapy-induced diarrhea in patients with malignancies of the pelvic region. Thirdly, the panel suggests the use of hyperbaric oxygen as an effective means in treating radiation-induced proctitis. Finally, new evidence has emerged which is in conflict with our previous guideline surrounding the use of systemic glutamine, meaning that the panel is unable to form a guideline. No guideline was possible for any other agent, due to inadequate and/or conflicting evidence.
Conclusions
This updated review of the literature has allowed new recommendations and suggestions for clinical practice to be reached. This highlights the importance of regular updates.
High cognitive activity possibly reduces the risk of cognitive decline and dementia.
To investigate associations between an individual's need to engage in cognitively stimulating activities (need for ...cognition, NFC) and structural brain damage and cognitive functioning in the Dutch general population with and without existing cognitive impairment.
Cross-sectional data were used from the population-based cohort of the Maastricht Study. NFC was measured using the Need For Cognition Scale. Cognitive functioning was tested in three domains: verbal memory, information processing speed, and executive functioning and attention. Values 1.5 s.d. below the mean were defined as cognitive impairment. Standardised volumes of white matter hyperintensities (WMH), cerebrospinal fluid (CSF) and presence of cerebral small vessel disease (CSVD) were derived from 3T magnetic resonance imaging. Multiple linear and binary logistic regression analyses were used adjusted for demographic, somatic and lifestyle factors.
Participants (
= 4209; mean age 59.06 years, s.d. = 8.58; 50.1% women) with higher NFC scores had higher overall cognition scores (
= 0.21, 95% CI 0.17-0.26,
< 0.001) and lower odds for CSVD (OR = 0.74, 95% CI 0.60-0.91,
= 0.005) and cognitive impairment (OR = 0.60, 95% CI 0.48-0.76,
< 0.001) after adjustment for demographic, somatic and lifestyle factors. The association between NFC score and cognitive functioning was similar for individuals with and without prevalent cognitive impairment. We found no significant association between NFC and WMH or CSF volumes.
A high need to engage in cognitively stimulating activities is associated with better cognitive functioning and less presence of CSVD and cognitive impairment. This suggests that, in middle-aged individuals, motivation to engage in cognitively stimulating activities may be an opportunity to improve brain health.
Activation of the integrated stress response (ISR) by a variety of stresses triggers phosphorylation of the α-subunit of translation initiation factor eIF2. P-eIF2α inhibits eIF2B, the guanine ...nucleotide exchange factor that recycles inactive eIF2•GDP to active eIF2•GTP. eIF2 phosphorylation thereby represses translation. Persistent activation of the ISR has been linked to the development of several neurological disorders, and modulation of the ISR promises new therapeutic strategies. Recently, a small-molecule ISR inhibitor (ISRIB) was identified that rescues translation in the presence of P-eIF2α by facilitating the assembly of more active eIF2B. ISRIB enhances cognitive memory processes and has therapeutic effects in brain-injured mice without displaying overt side effects.While using ISRIB to investigate the ISR in picornavirus-infected cells, we observed that ISRIB rescued translation early in infection when P-eIF2α levels were low, but not late in infection when P-eIF2α levels were high. By treating cells with varying concentrations of poly(I:C) or arsenite to induce the ISR, we provide additional proof that ISRIB is unable to inhibit the ISR when intracellular P-eIF2α concentrations exceed a critical threshold level. Together, our data demonstrate that the effects of pharmacological activation of eIF2B are tuned by P-eIF2α concentration. Thus, ISRIB can mitigate undesirable outcomes of low-level ISR activation that may manifest neurological disease but leaves the cytoprotective effects of acute ISR activation intact. The insensitivity of cells to ISRIB during acute ISR may explain why ISRIB does not cause overt toxic side effects in vivo.
The Spitzer Infrared Nearby Galaxies Survey (SINGS) is carrying out a comprehensive multiwavelength survey on a sample of 75 nearby galaxies. The 1-850 km spectral energy distributions (SEDs) are ...presented using broadband imaging data from Spitzer, 2MASS, ISO, IRAS, and SCUBA. The infrared colors derived from the globally integrated Spitzer data are generally consistent with the previous generation of models that were developed using global data for normal star-forming galaxies, although significant deviations are observed. Spitzer's excellent sensitivity and resolution also allow a detailed investigation of the infrared SEDs for various locations within the three large, nearby galaxies NGC 3031 (M81), NGC 5194 (M51), and NGC 7331. A wide variety of spectral shapes is found within each galaxy, especially for NGC 3031, the closest of the three targets and thus the galaxy for which the smallest spatial scales can be explored. Strong correlations exist between the local star formation rate and the infrared colors f sub(u)(70 km)/f sub(u)(160 km) and f sub(u)(24 km)/f sub(u)(160 km), suggesting that the 24 and 70 km emission are useful tracers of the local star formation activity level. Preliminary evidence indicates that variations in the 24 km emission, and not variations in the emission from polycyclic aromatic hydrocarbons at 8 km, drive the variations in the f sub(u)(8.0 km)/f sub(u)(24 km) colors within NGC 3031, NGC 5194, and NGC 7331. If the galaxy-to-galaxy variations in SEDs seen in our sample are representative of the range present at high redshift, then extrapolations of total infrared luminosities and star formation rates from the observed 24 km flux will be uncertain at the factor of 5 level (total range). The corresponding uncertainties using the redshifted 8.0 km flux (e.g., observed 24 km flux for a z = 2 source) are factors of 10-20. Considerable caution should be used when interpreting such extrapolated infrared luminosities.
INTRODUCTION:Loss to follow-up (LTFU) rates from antiretroviral treatment (ART) programmes in low- and middle-income countries (LMIC) are high, leading to poor treatment outcomes and onward ...transmission of HIV. Knowledge of risk factors is required to address LTFU. In this systematic review, risk factors for LTFU are identified and meta-analyses performed.
METHODS:PubMed, Embase, Psycinfo and Cochrane were searched for studies that report on potential risk factors for LTFU in adults who initiated ART in LMICs. Meta-analysis was performed for risk factors evaluated by at least five studies. Pooled effect estimates and their 95% confidence intervals (95% CI) were calculated using random effect models with inverse variance weights. Risk of bias was assessed and sensitivity analyses performed.
RESULTS:Eighty studies were included describing a total of 1 605 320 patients of which 87.4% from sub-Saharan Africa. The following determinants were significantly associated with an increased risk of LTFU in meta-analysismale sex, older age, being single, unemployment, lower educational status, advanced WHO stage, low weight, worse functional status, poor adherence, nondisclosure, not receiving cotrimoxazole prophylactic therapy when indicated, receiving care at secondary level and more recent year of initiation. No association was seen for CD4 cell count, tuberculosis at baseline, regimen, and geographical setting.
CONCLUSION:There are several sociodemographic, clinical, patient behaviour, treatment-related and system level risk factors for LTFU from ART programs. Knowledge of risk factors should be used to better target retention interventions and develop tools to identify high-risk patients.
Aims
Voriconazole (VCZ) exhibits wide intrapatient pharmacokinetic variability, which is disadvantageous because of its narrow therapeutic range. A considerable part of this variation remains ...unexplainable, despite extensive knowledge of this drug. It is hypothesized that inflammation has an impact on VCZ pharmacokinetics. In the present study, we investigated the correlation between VCZ trough concentrations and various cytokines.
Methods
A prospective single‐centre analysis was performed in adult haematology patients receiving VCZ for possible, probable or proven invasive fungal disease. A linear mixed model was built to explore the contribution of each of the seven pro‐ and anti‐inflammatory cytokines to VCZ trough levels. The Akaike information criterion (AIC) was used to determine the model that fitted the best.
Results
Twenty‐two patients, with a total of 143 combined samples of VCZ trough levels and cytokines, were included. A significant correlation (P < 0.005) was found between VCZ trough concentrations and interleukin (IL) 6, IL‐8 and C‐reactive protein (CRP). IL‐6 showed the lowest AIC, although differences with the other mediators were marginal.
Conclusion
VCZ trough concentrations correlate with IL‐6, IL‐8 and CRP levels but only moderately explain the variability in VCZ pharmacokinetics. Future prospective studies should be undertaken to confirm these findings, and incorporate the data obtained into pharmacokinetic models, to refine the predictive behaviour.
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of ...the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C.
We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis.
The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30-79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation.
The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.
We present 0 15 (1 kpc) resolution ALMA observations of the C ii 157.74 m line and rest-frame 160 m continuum emission in two z ∼ 3 dusty, star-forming galaxies-ALESS 49.1 and ALESS 57.1, combined ...with resolved CO (3-2) observations. In both sources, the C ii surface brightness distribution is dominated by a compact core ≤1 kpc in radius, a factor of 2-3 smaller than the extent of the CO (3-2) emission. In ALESS 49.1, we find an additional extended (8 kpc radius), low surface brightness C ii component. Based on an analysis of mock ALMA observations, the C ii and 160 m continuum surface brightness distributions are inconsistent with a single-Gaussian surface brightness distribution with the same size as the CO (3-2) emission. The C ii rotation curves flatten at 2 kpc radius, suggesting that the kinematics of the central regions are dominated by a baryonic disk. Both galaxies exhibit a strong C ii/far-IR (FIR) deficit on 1 kpc scales, with FIR surface brightness to C ii/FIR slope steeper than in local star-forming galaxies. A comparison of the C ii/CO (3-2) observations with photodissociation region models suggests a strong far-UV (FUV) radiation field (G0 ∼ 104) and high gas density (n(H) ∼ 104-105 cm−3) in the central regions of ALESS 49.1 and ALESS 57.1. The most direct interpretation of the pronounced C ii/FIR deficit is a thermal saturation of the C+ fine-structure levels at temperatures ≥500 K, driven by the strong FUV field.
Standard-of-care antiretroviral treatment (ART) monitoring in low and middle-income countries consists of annual determination of HIV-RNA viral load with confirmatory viral load testing in case of ...viral rebound. We evaluated an intensified monitoring strategy of three-monthly viral load testing with additional drug exposure and drug resistance testing in case of viral rebound.
We performed an open-label randomized controlled trial (RCT) at a rural South African healthcare clinic, enrolling adults already receiving or newly initiating first-line ART. During 96 weeks follow-up, intervention participants received three-monthly viral load testing and sequential point-of-care drug exposure testing and DBS-based drug resistance testing in case of rebound above 1000 copies/ml. Control participants received standard-of-care monitoring according to the WHO guidelines.
Five hundred one participants were included, of whom 416 (83.0%) were randomized at 24 weeks. Four hundred one participants were available for intention-to-treat analysis. Viral rebound occurred in 9.0% (18/199) of intervention participants and in 11.9% (24/202) of controls ( P = 0.445). Time to detection of rebound was 375 days interquartile range (IQR): 348-515 in intervention participants and 360 days IQR: 338-464 in controls hazard ratio: 0.88 (95% confidence interval (95% CI): 0.46-1.66; P = 0.683. Duration of viral rebound was 87 days IQR: 70-110 in intervention participants and 101 days IQR: 78-213 in controls ( P = 0.423). In the control arm, three patients with confirmed failure were switched to second-line ART. In the intervention arm, of three patients with confirmed failure, switch could initially be avoided in two cases.
Three-monthly viral load testing did not significantly reduce the duration of viraemia when compared with standard-of-care annual viral load testing, providing randomized trial evidence in support of annual viral load monitoring.
•Suitable bioelectrochemical application of ceramic clays with varying Fe2O3 content.•5.75% of Fe2O3 and 1100 °C of sintering temperature allow MFCs to reach 1.045 mW.•The Fe2O3 content mitigates the ...effect of porosity features on the MFC power output.•Good stability of the MFCs working during 65 days in continuous mode.
Ceramic materials based on naturally occurring clays are a low cost and environmentally friendly alternative to commercial polymer-based membranes in bioelectrochemical systems. In this work, ceramic membranes containing different amounts of iron oxide (1.06, 2.76 and 5.75 vol.%) and sintered at different temperatures (1100, 1200 and 1300 °C) have been elaborated and tested as separators in urine-fed microbial fuel cells (MFCs). The results reveal that the presence of iron oxide in the ceramic membrane composition increases the structural porosity and reduces the pore size for the three temperatures investigated. On the other hand, it was also observed that the iron content mitigates the negative effect of the high sintering temperature on the power performance of the MFCs. In the case of the ceramic membranes sintered at 1300 °C, power output improved ca. 10-fold when the iron oxide content in the membrane increased from 1.06 up to 5.75 vol.% (30.9 and 286.6 µW, respectively). Amongst the different combinations of iron phase content and sintering temperatures, the maximum power output was obtained by MFCs working with separators containing 5.75 vol. % of iron oxide and sintered at 1100 °C (1.045 mW). Finally, the system was stable for 65 days, which supports the long-term functionality of the different materials assessed.
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