Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT)

Anaerobic ammonium oxidation in the old trickling filters at Daspoort Wastewater Treatment Works

The century-old trickling filters at the Daspoort Wastewater Treatment Works in Pretoria (Gauteng, South Africa) are known for their remarkable removal of nitrogen from municipal wastewater. Our study was conducted to identify the microbiological processes responsible for this phenomenon and to establish whether anammox bacteria may be involved. An aerobic and anaerobic bench top reactor, both inoculated with biofilm-covered stones from one of the filters, were spiked with ammonia-nitrogen  (NH4+-N) and nitrite-nitrogen (NO2.-N). These reactors were subsequently monitored by conducting stoichiometric analyses of chemical oxygen demand (COD), NH4+-N, NO2.-N, and nitrate-nitrogen (NO3.-N). In the aerobic reactor, the COD concentration decreased over the 56 h batch reaction period and nitrification was revealed by a decrease in NH4+-N and NO2.-N concentrations. However, the NO3.-N concentration showed no  notable decrease. In contrast, in the anaerobic reactor the concentrations of COD, NH4+-N, NO2¡¥-N, NO3¡¥-N, as well as total nitrogen decreased during the batch reaction period. The decrease of both the NH4+-N and NO2.-N concentrations, the latter to zero under anaerobic conditions,   suggested that, in addition to heterotrophic denitrification, anaerobic ammonium oxidation (anammox) may also occur in the trickling filter biofilm. This was highlighted by the observation that ammonium removal in the anaerobic reactor stopped as soon as the nitrite concentration  became zero. The ratio of nitrite:ammonium removal was 1.33 on  average, which conforms to anammox behaviour. Gene sequence analysis was used to test for the possible presence of anammox bacteria in the  trickling filter biofilm. Genomic DNA was extracted from trickling filter  humus sludge and the polymerase chain reaction (PCR) was used to  amplify taxonomically informative 16S rRNA gene sequences, using  primers specific for selected anammox species. Subsequent sequence analysis, including using the online Basic Local Alignment Search Tool (BLAST), and constructing a phylogenic tree using a heuristic search  strategy for Maximum Parsimony analysis, confirmed the presence of an anammox bacterium closely related to Candidatus ¡®Brocadia  anammoxidans¡¯ and Candidatus ¡®Brocadia fulgida¡¯ on the biofilm-covered stones of the Daspoort trickling filters.Keywords: Daspoort, trickling filter, anammox, nitrification, denitrification, stoichiometric analyses, polymerase chain reactio

Motivations for contralateral prophylactic mastectomy as a function of socioeconomic status

BACKGROUND: Despite no demonstrated survival advantage for women at average risk of breast cancer, rates of contralateral prophylactic mastectomy (CPM) continue to increase. Research reveals women with higher socioeconomic status (SES) are more likely to select CPM. This study examines how indicators of SES, age, and disease severity affect CPM motivations. METHODS: Patients (N = 113) who underwent CPM at four Indiana University affiliated hospitals completed telephone interviews in 2013. Participants answered questions about 11 CPM motivations and provided demographic information. Responses to motivation items were factor analyzed, resulting in 4 motivational factors: reducing long-term risk, symmetry, avoiding future medical visits, and avoiding treatments. RESULTS: Across demographic differences, reducing long-term risk was the strongest CPM motivation. Lower income predicted stronger motivation to reduce long-term risk and avoid treatment. Older participants were more motivated to avoid treatment; younger and more-educated patients were more concerned about symmetry. Greater severity of diagnosis predicted avoiding treatments. CONCLUSIONS: Reducing long-term risk is the primary motivation across groups, but there are also notable differences as a function of age, education, income, and disease severity. To stop the trend of increasing CPM, physicians must tailor patient counseling to address motivations that are consistent across patient populations and those that vary between populations

Social Network, Surgeon, and Media Influence on the Decision to Undergo Contralateral Prophylactic Mastectomy

OBJECTIVES: The rate of contralateral prophylactic mastectomy (CPM) has risen sharply in the past decade. The current study was designed to examine social network, surgeon, and media influence on patients' CPM decision-making, examining not only who influenced the decision, and to what extent, but also the type of influence exerted. METHODS: Patients (N=113) who underwent CPM at 4 Indiana University-affiliated hospitals between 2008 and 2012 completed structured telephone interviews in 2013. Questions addressed the involvement and influence of the social network (family, friends, and nonsurgeon health professionals), surgeon, and media on the CPM decision. RESULTS: Spouses, children, family, friends, and health professionals were reported as exerting a meaningful degree of influence on patients' decisions, largely in ways that were positive or neutral toward CPM. Most surgeons were regarded as providing options rather than encouraging or discouraging CPM. Media influence was present, but limited. CONCLUSIONS: Patients who choose CPM do so with influence and support from members of their social networks. Reversing the increasing choice of CPM will require educating these influential others, which can be accomplished by encouraging patients to include them in clinical consultations, and by providing patients with educational materials that can be shared with their social networks. Surgeons need to be perceived as having an opinion, specifically that CPM should be reserved for those patients for whom it is medically indicated

The effect of the COVID-19 lockdown on mental health care use in South Africa: an interrupted time-series analysis.

AIMS The coronavirus disease 2019 (COVID-19) pandemic and ensuing restrictions have negatively affected the mental health and well-being of the general population, and there is increasing evidence suggesting that lockdowns have led to a disruption of health services. In March 2020, South Africa introduced a lockdown in response to the COVID-19 pandemic, entailing the suspension of all non-essential activities and a complete ban of tobacco and alcohol sales. We studied the effect of the lockdown on mental health care utilisation rates in private-sector care in South Africa. METHODS We conducted an interrupted time-series analysis using insurance claims from 1 January 2017 to 1 June 2020 of beneficiaries 18 years or older from a large private sector medical insurance scheme. We calculated weekly outpatient consultation and hospital admission rates for organic mental disorders, substance use disorders, serious mental disorders, depression, anxiety, other mental disorders, any mental disorder and alcohol withdrawal syndrome. We calculated adjusted odds ratios (OR) for the effect of the lockdown on weekly outpatient consultation and hospital admission rates and the weekly change in rates during the lockdown until 1 June 2020. RESULTS 710 367 persons were followed up for a median of 153 weeks. Hospital admission rates (OR 0.38; 95% confidence interval (CI) 0.33-0.44) and outpatient consultation rates (OR 0.74; 95% CI 0.63-0.87) for any mental disorder decreased substantially after the introduction of the lockdown and did not recover to pre-lockdown levels by 1 June 2020. Health care utilisation rates for alcohol withdrawal syndrome doubled after the introduction of the lockdown, but the statistical uncertainty around the estimates was large (OR 2.24; 95% CI 0.69-7.24). CONCLUSIONS Mental health care utilisation rates for inpatient and outpatient services decreased substantially after the introduction of the lockdown. Hospital admissions and outpatient consultations for alcohol withdrawal syndrome increased after the introduction of the lockdown, but statistical uncertainty precludes strong conclusions about a potential unintended effect of the alcohol sales ban. Governments should integrate strategies for ensuring access and continuity of essential mental health services during lockdowns in pandemic preparedness planning

The effects of periodontal therapy on serum antibody (IgG) levels to plaque microorganisms *

The influence of periodontal therapy on serum antibody titers to selected periodontal disease-associated microorganisms was assessed in 23 patients having chronic inflammatory periodontal disease (CIPD), The immunoglobulin G (IgG) titers were dÉtÉrmined by the micro ELISA technique in serum samples obtained prior to treatment; following a hygienic phase which included scaling, root planing, and oral hygiene instruction; following surgical treatment; and one year and two years following hygienic phase (maintenance phase). Considerable individual variability existed in the magnitude of immune response to specific bacterial preparations. Significant reductions in the mean antibody titers were seen to A. viscosus. S. sanguis. F. nucleatum, S, spuligena, B. gingivalis. B. interme-dius. B. melaninogeniem, T. vincentii , and T denticola by the end of the second year of maintenance. There was no consistent response to Capnucytophaga. When individual patient responses were examined. 6 of the 23 were found to have elevated titers to at least one of the microorganisms in the interval between pretreatment and the end of the hygienic phase; however, in all but one case, the titers at the end of the second year of maintenance were below pretreatment levels. Antibody levels to bacteria such as S. sanguis were modified during therapy. This would indicate that immune responses to microbes not generally considered to be “periodontal pathogens” may be modified by adjuvant activity associated with subgingival plaque or changes in the environment of the sulcus and that subsequent changes in titer do not necessarily reflect a role of that microorganism in the disease process.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75110/1/j.1600-051X.1988.tb02127.x.pd

Extracellular traps released by antimicrobial TH17 cells contribute to host defense.

peer reviewedTH17 cell subpopulations have been defined that contribute to inflammation and homeostasis, yet the characteristics of TH17 cells that contribute to host defense against infection are not clear. To elucidate the antimicrobial machinery of the TH17 subset, we studied the response to Cutibacterium acnes, a skin commensal that is resistant to IL-26, the only known TH17 secreted protein with direct antimicrobial activity. We generated C. acnes-specific antimicrobial TH17 clones (AMTH17) with varying antimicrobial activity against C. acnes, which we correlated by RNA-seq to the expression of transcripts encoding proteins that contribute to antimicrobial activity. Additionally, we validated that AMTH17-mediated killing of C. acnes as well as bacterial pathogens, was dependent on the secretion of granulysin, granzyme B, perforin and histone H2B. We found that AMTH17s can release fibrous structures composed of DNA decorated with the histone H2B that entangle C. acnes that we call T cell extracellular traps (TETs). Within acne lesions, H2B and IL-17 colocalized in CD4+ T cells, in proximity to TETs in the extracellular space composed of DNA decorated with H2B. This study identifies a functionally distinct subpopulation of TH17 cells with an ability to form TETs containing secreted antimicrobial proteins that capture and kill bacteria

Third party consultation: a method for the study and resolution of conflict

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66597/2/10.1177_002200277201600105.pd