The Need for European Surveillance of CDI.

Since the turn of the millennium, the epidemiology of Clostridioides difficile infection (CDI) has continued to challenge. Changes in clinical presentation, severity of disease, descriptions of new risk factors and the occurrence of outbreaks all emphasised the importance of early diagnosis and standardised surveillance systems. However, a lack of consensus on case definitions, clinical guidelines and optimal laboratory diagnostics across Europe has led to the underestimation of CDI and impeded comparison between countries. These inconsistencies have prevented the true burden of disease from being appreciated.Acceptance that a multi-country CDI surveillance program and optimised diagnostic strategies are required has built the foundations for a more robust, unified surveillance. The concerted efforts of the European Centre for Disease Prevention and Control (ECDC) CDI networks led to the development of the European surveillance protocol and an over-arching long-term CDI surveillance strategy for 2014-2020, which has been followed by the development of surveillance systems in at least 20 European countries. However, surveillance activities in individual countries have slowed during the COVID-19 pandemic as resources were diverted to the global health crisis. A renewed and strengthened focus on CDI surveillance and prevention is therefore urgently needed post COVID-19.

Designing a mHealth clinical decision support system for Parkinson's disease: a theoretically grounded user needs approach.

BACKGROUND: Despite the established evidence and theoretical advances explaining human judgments under uncertainty, developments of mobile health (mHealth) Clinical Decision Support Systems (CDSS) have not explicitly applied the psychology of decision making to the study of user needs. We report on a user needs approach to develop a prototype of a mHealth CDSS for Parkinson's disease (PD), which is theoretically grounded in the psychological literature about expert decision making and judgement under uncertainty. METHODS: A suite of user needs studies was conducted in 4 European countries (Greece, Italy, Slovenia, the UK) prior to the development of PD_Manager, a mHealth-based CDSS designed for Parkinson's disease, using wireless technology. Study 1 undertook Hierarchical Task Analysis (HTA) including elicitation of user needs, cognitive demands and perceived risks/benefits (ethical considerations) associated with the proposed CDSS, through structured interviews of prescribing clinicians (N = 47). Study 2 carried out computational modelling of prescribing clinicians' (N = 12) decision strategies based on social judgment theory. Study 3 was a vignette study of prescribing clinicians' (N = 18) willingness to change treatment based on either self-reported symptoms data, devices-generated symptoms data or combinations of both. RESULTS: Study 1 indicated that system development should move away from the traditional silos of 'motor' and 'non-motor' symptom evaluations and suggest that presenting data on symptoms according to goal-based domains would be the most beneficial approach, the most important being patients' overall Quality of Life (QoL). The computational modelling in Study 2 extrapolated different factor combinations when making judgements about different questions. Study 3 indicated that the clinicians were equally likely to change the care plan based on information about the change in the patient's condition from the patient's self-report and the wearable devices. CONCLUSIONS: Based on our approach, we could formulate the following principles of mHealth design: 1) enabling shared decision making between the clinician, patient and the carer; 2) flexibility that accounts for diagnostic and treatment variation among clinicians; 3) monitoring of information integration from multiple sources. Our approach highlighted the central importance of the patient-clinician relationship in clinical decision making and the relevance of theoretical as opposed to algorithm (technology)-based modelling of human judgment.

Prediction model and web-based risk calculator for postoperative ileus after loop ileostomy closure.

BACKGROUND: Postoperative ileus (POI) is a significant complication after loop ileostomy closure given both its frequency and impact on the patient. The purpose of this study was to develop and externally validate a prediction model for POI after loop ileostomy closure. METHODS: The model was developed and validated according to the TRIPOD checklist for prediction model development and validation. The development cohort included consecutive patients who underwent loop ileostomy closure in two teaching hospitals in Montreal, Canada. Candidate variables considered for inclusion in the model were chosen a priori based on subject knowledge. The final prediction model, which modelled the 30-day cumulative incidence of POI using logistic regression, was selected using the highest area under the receiver operating characteristic curve (AUC) criterion. Model calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. The model was then validated externally in an independent cohort of similar patients from the University of British Columbia. RESULTS: The development cohort included 531 patients, in whom the incidence of POI was 16·8 per cent. The final model included five variables: age, ASA fitness grade, underlying pathology/treatment, interval between ileostomy creation and closure, and duration of surgery for ileostomy closure (AUC 0·68, 95 per cent c.i. 0·61 to 0·74). The model demonstrated good calibration (P = 0·142). The validation cohort consisted of 216 patients, and the incidence of POI was 15·7 per cent. On external validation, the model maintained good discrimination (AUC 0·72, 0·63 to 0·81) and calibration (P = 0·538). CONCLUSION: A prediction model was developed for POI after loop ileostomy closure and included five variables. The model maintained good performance on external validation.

ANTECEDENTES: El íleo postoperatorio (postoperative ileus, POI) es una complicación importante tras el cierre de la ileostomía en asa, dada su frecuencia e impacto en el paciente. El propósito de este estudio fue desarrollar y validar externamente un modelo de predicción para el POI después del cierre de la ileostomía en asa. MÉTODOS: El modelo fue desarrollado y validado de acuerdo con la lista de verificación TRIPOD para el desarrollo y validación de un modelo de predicción. La cohorte de desarrollo incluyó pacientes consecutivos en los que se realizó el cierre de la ileostomía en asa en dos hospitales universitarios en Montreal, Canadá. Las variables candidatas consideradas para su inclusión en el modelo se seleccionaron a priori en función del conocimiento del problema. El modelo de predicción final, que modeló la incidencia acumulada a 30 días de POI mediante regresión logística, se seleccionó según el criterio del área más alta bajo la curva operativa del receptor (area under the receiver operating curve, AUC). La calibración del modelo se evaluó utilizando la prueba de bondad de ajuste de Hosmer-Lemeshow. El modelo fue posteriormente validado externamente en una cohorte independiente de pacientes similares de la Universidad de British Columbia. RESULTADOS: La cohorte de desarrollo incluyó a 531 pacientes, y la incidencia de POI fue de 16,7%. El modelo final incluyó cinco variables: edad, clasificación ASA (American Society of Anaesthesiologists), patología inicial y tratamiento, tiempo entre las dos intervenciones quirúrgicas y tiempo operatorio del cierre de ileostomía (AUC = 0,68; i.c. del 95%: 0,61 a 0,74). El modelo demostró buena calibración (P = 0,142). La cohorte de validación consistió en 216 pacientes, y la incidencia de POI fue de 15,7%. En la validación externa, el modelo mantuvo una buena discriminación (AUC = 0,72; i.c. del 95%: 0,63 a 0,81) y calibración (P = 0,538). CONCLUSIÓN: Se ha desarrollado un modelo de predicción de POI después del cierre de la ileostomía en asa que incluía cinco variables. El modelo mantuvo un buen funcionamiento en la validación externa.

The Need for European Surveillance of CDI.

Since the turn of the millennium, the epidemiology of Clostridium difficile infection (CDI) has continued to challenge. Over the last decade there has been a growing awareness that improvements to surveillance are needed. The increasing rate of CDI and emergence of ribotype 027 precipitated the implementation of mandatory national surveillance of CDI in the UK. Changes in clinical presentation, severity of disease, descriptions of new risk factors and the occurrence of outbreaks all emphasised the importance of early diagnosis and surveillance.However a lack of consensus on case definitions, clinical guidelines and optimal laboratory diagnostics across Europe has lead to the underestimation of CDI and impeded comparison between countries. These inconsistencies have prevented the true burden of disease from being appreciated.Acceptance that a multi-country surveillance programme and optimised diagnostic strategies are required not only to detect and control CDI in Europe, but for a better understanding of the epidemiology, has built the foundations for a more robust, unified surveillance. The concerted efforts of the European Centre for Disease Prevention and Control (ECDC) CDI networks, has lead to the development of an over-arching long-term CDI surveillance strategy for 2014-2020. Fulfilment of the ECDC priorities and targets will no doubt be challenging and will require significant investment however the hope is that both a national and Europe-wide picture of CDI will finally be realised.

The good, the bad and the tasty: The many roles of mushrooms.

Fungi are often inconspicuous in nature and this means it is all too easy to overlook their importance. Often referred to as the "Forgotten Kingdom", fungi are key components of life on this planet. The phylum Basidiomycota, considered to contain the most complex and evolutionarily advanced members of this Kingdom, includes some of the most iconic fungal species such as the gilled mushrooms, puffballs and bracket fungi. Basidiomycetes inhabit a wide range of ecological niches, carrying out vital ecosystem roles, particularly in carbon cycling and as symbiotic partners with a range of other organisms. Specifically in the context of human use, the basidiomycetes are a highly valuable food source and are increasingly medicinally important. In this review, seven main categories, or 'roles', for basidiomycetes have been suggested by the authors: as model species, edible species, toxic species, medicinal basidiomycetes, symbionts, decomposers and pathogens, and two species have been chosen as representatives of each category. Although this is in no way an exhaustive discussion of the importance of basidiomycetes, this review aims to give a broad overview of the importance of these organisms, exploring the various ways they can be exploited to the benefit of human society.

Sentinel community Clostridium difficile infection (CDI) surveillance in Scotland, April 2013 to March 2014.

Surveillance of Clostridium difficile infection (CDI) in Scotland does not currently distinguish between CDI cases from hospitals and the community. Therefore, the incidence of CDI in the community is unknown, and the burden of disease and the relationship with the hospital/healthcare setting is not well understood. A one-year sentinel community surveillance programme was initiated in collaboration with five Scottish health boards in 2013 (representing 36% of all CDI cases reported in Scotland). Inclusion criteria were all cases aged ≥15 years with a CDI diagnosis in the community or within 48 h following admission to hospital. CDI cases were categorised according to definitions used by the European Centre for Disease Prevention and Control. 256 CDI cases met the inclusion criteria, of which 158 (62%) were community-associated cases (CA-CDI). This represented 26% of all cases reported during the surveillance period by the participating health boards (n = 614). The overall CA-CDI incidence rate was 9.9 per 100 000 population per year. CA-CDI cases were more likely to be female and younger, compared to hospital acquired cases (HA-CDI). The total proportion of cases that had onset in the community was 27%. Ribotypes 015, 002, 078 and 005 were the most common types isolated from both CA-CDI and HA-CDI cases. There were no statistically significant differences between the proportion of types that were either CA-CDI or HA-CDI. Of the CA-CDI cases, 37% had not received antibiotics in the 12 weeks preceding CDI diagnosis, 4% were resident in care homes, and the case-fatality rate for CA-CDI cases was 5.6% (with a 30-day mortality rate for CA-CDI of 0.44 per 100 000 population per year). This study has shown that a substantial proportion of CDI cases reported in Scotland are community associated and that there are close links between the community and healthcare settings. It is therefore essential to monitor the trends in CDI in the community at a national level. The study also provides evidence for the need to examine the feasibility for development of interventions to reduce the burden in the community in addition to hospitals.

Meals served to hypertensive and cardiac inpatients in Jordan: comparison with WHO and NIH dietary guidelines.

This study aimed to evaluate the compliance of daily meals served to hypertensive and cardiac inpatients in Jordan according to WHO guidelines and the Therapeutic Lifestyle Changes (TLC) and Dietary Approach to Stop Hypertension (DASH) diets plans. Weekly cycle menus from the food service department of major hospitals in Jordan (n = 16) were analysed using ESHA Food Processor software to obtain data about macroand micronutrient contents and food groups represented. The results showed inappropriate amounts of several nutrients in the menus provided, along with a general noncompliance with the DASH, TLC and WHO guidelines. Meals had higher than recommended sodium content coupled with low potassium content. Fatty acid profiles were often outside the recommended ranges. Meals provided to cardiac inpatients in Jordan need to be revised to meet the guidelines specified for the health conditions of these patients.

Antiviral efficacy of entecavir in nucleos(t)ide-naïve patients of Black/African descent with chronic hepatitis B.

This single-arm, open-label, descriptive study assessed the efficacy and safety of entecavir (ETV) in nucleos(t)ide-naïve Black/African American patients with chronic hepatitis B (CHB), a patient population underrepresented in ETV registration trials. Forty patients with HBeAg(+) or HBeAg(-) compensated CHB of self-described Black/African American race received ETV 0.5 mg daily for 52 weeks; 37 patients completed 52 weeks of treatment. At Week 48, 29/40 (72.5%, noncompleter = failure) patients achieved the primary endpoint of HBV DNA <50 IU/mL. Rates for HBeAg loss (11/22; 50%) and HBeAg seroconversion (9/22; 41%) were high, possibly due to the high HBV genotype A prevalence (70%). No patient experienced virological breakthrough. Samples for resistance testing were available in 6/8 patients with HBV DNA >50 IU/mL at Week 48 or last on-treatment visit. No ETV resistance was detected. The safety profile of ETV was consistent with that observed in ETV registration trials. This study shows that in Black/African American patients with CHB, ETV was well tolerated and demonstrated comparable antiviral efficacy to that observed in White and Asian patients in ETV Phase III studies.

Quantitative fitness analysis shows that NMD proteins and many other protein complexes suppress or enhance distinct telomere cap defects.

To better understand telomere biology in budding yeast, we have performed systematic suppressor/enhancer analyses on yeast strains containing a point mutation in the essential telomere capping gene CDC13 (cdc13-1) or containing a null mutation in the DNA damage response and telomere capping gene YKU70 (yku70Δ). We performed Quantitative Fitness Analysis (QFA) on thousands of yeast strains containing mutations affecting telomere-capping proteins in combination with a library of systematic gene deletion mutations. To perform QFA, we typically inoculate 384 separate cultures onto solid agar plates and monitor growth of each culture by photography over time. The data are fitted to a logistic population growth model; and growth parameters, such as maximum growth rate and maximum doubling potential, are deduced. QFA reveals that as many as 5% of systematic gene deletions, affecting numerous functional classes, strongly interact with telomere capping defects. We show that, while Cdc13 and Yku70 perform complementary roles in telomere capping, their genetic interaction profiles differ significantly. At least 19 different classes of functionally or physically related proteins can be identified as interacting with cdc13-1, yku70Δ, or both. Each specific genetic interaction informs the roles of individual gene products in telomere biology. One striking example is with genes of the nonsense-mediated RNA decay (NMD) pathway which, when disabled, suppress the conditional cdc13-1 mutation but enhance the null yku70Δ mutation. We show that the suppressing/enhancing role of the NMD pathway at uncapped telomeres is mediated through the levels of Stn1, an essential telomere capping protein, which interacts with Cdc13 and recruitment of telomerase to telomeres. We show that increased Stn1 levels affect growth of cells with telomere capping defects due to cdc13-1 and yku70Δ. QFA is a sensitive, high-throughput method that will also be useful to understand other aspects of microbial cell biology.

An evaluation of PlayStreets in the South Side neighborhood of Columbus, Ohio.

AIMS: Outdoor play, physical activity, and social cohesion are crucial indicators of community health. PlayStreets, a street play initiative to engage local children and families in outdoor play, physical activity, and social interactions, were implemented in a low-income neighborhood in Columbus, Ohio throughout the summer of 2019. This article aims to describe the implementation of a hospital-sponsored PlayStreets model executed through support from a community health initiative and to assess neighborhood impact through parent and child surveys. METHODS: Approximately 350 children attended the events and 69 surveys were collected. Descriptive statistics were used to analyze survey data. RESULTS: The mean age of children was 7 years, and the majority of children who attended were male. If not for PlayStreets, 55% of caregivers reported that their children would be inside. Event satisfaction levels were high, and 54% of caregivers said that they had more contact with their neighbors because of the events. CONCLUSIONS: Hospital buy-in and community support were crucial to the success of the event. We found that this model can successfully engage the local community while increasing opportunity for childhood outdoor play, physical activity, and neighborhood social interaction.

Sexual health of adults working in pornographic films.

We report the frequency of sexually transmitted infections (STIs) diagnosed in performers in the adult pornographic film industry. Over a 13 month period, 445 STI screens were performed in 115 patients, 56 women and 59 men. All reported unprotected sex during filming. Seventy-five percent (86) had at least one sexual partner outside work, and 90% used condoms inconsistently with them. Women worked exclusively with women (23%), men only (38%) or both genders (39%). Almost all men (97%) worked exclusively heterosexually. Thirty-eight percent (44/115) were diagnosed with 77 STIs, including non-specific urethritis (51), gonorrhoea (10), chlamydia (6) and genital warts (6). Gonorrhoea was found exclusively at the pharynx in three heterosexual men. There were no cases of HIV, syphilis, hepatitis B or hepatitis C. Monthly screening and certification is a working requirement for this population but STIs are common in an industry where unprotected sex is the norm.

Sagittal laxity after posterior cruciate ligament-retaining mobile-bearing total knee arthroplasty.

Posterior cruciate ligament stretching after posterior cruciate ligament-retaining (CR) total knee arthroplasty (TKA) can lead to an increase in sagittal laxity, knee dysfunction, or accelerated damage to the tibial bearing surface. We conducted a prospective study on 74 consecutive mobile-bearing CR TKA to determine if knee laxity changed with time or if knees with large initial laxity experienced greater increases in laxity. Patients were studied with radiographic posterior and anterior drawer examinations at 3 and 23 months. Model-based shape-matching techniques were used to measure TKA kinematics. We found a 1-mm increase in posterior drawer. Knees with large postoperative drawers did not exhibit increased laxity at last follow-up. The use of a mobile-bearing CR TKA did not significantly modify the midterm knee sagittal laxity.

The Sea Empress oil spill (Wales, UK): effects on Common Scoter Melanitta nigra in Carmarthen Bay and status ten years later.

Carmarthen Bay, UK, regularly supports internationally important numbers (>16,000) of non-breeding Common Scoters Melanitta nigra. The spill of 72,000 tonnes of crude oil from the Sea Empress in 1996 affected birds both through direct mortality and likely pollution of key food resources. Numbers were greatly reduced following the spill, whilst changes in the distribution of birds within Carmarthen Bay suggested that potentially sub-optimal foraging zones were used. However, ten years after the incident, numbers of Common Scoter were no different to those recorded immediately before the spill. Compared to some other spills, rapid revival is evident. Numbers increased to pre-spill levels within three winters and distributional changes suggested a concurrent return to previously contaminated feeding areas, implying that the ecosystem had regenerated sufficiently to support its top predator. The importance of prolonged, standardised monitoring of bird numbers and distribution as indicators of ecological recovery from environmental damage is emphasised.

Trends in mortality following Clostridium difficile infection in Scotland, 2010-2016: a retrospective cohort and case-control study.

BACKGROUND: National surveillance of Clostridium difficile infection (CDI) in Scotland enables the monitoring of trends in incidence rates but not mortality. AIM: To assess factors associated with mortality for all CDI cases aged ≥15 years in Scotland between 2010 and 2016. METHODS: All CDI cases aged ≥15 years in Scotland between 2010 and 2016 were linked to hospital admission and mortality datasets. Logistic regression was used to assess factors associated with mortality (30-day all-cause). A case-control study of a hospitalized subset of cases and matched hospitalized controls assessed the impact of CDI on mortality and length of stay. FINDINGS: Thirty-day all-cause mortality decreased over the seven-year period (from 20.5% to 15.6%; P < 0.001), mainly among healthcare-associated CDI (HA-CDI). Increased age, higher Charlson score, HA-CDI, as well as liver, heart and malignancy comorbidities were associated with higher mortality. No association was observed between polymerase chain reaction ribotype and higher mortality, though 015 and 078 were associated with lower mortality. Adjusted odds ratio (OR) for 30-day mortality in hospitalized CDI cases compared to controls was 2.67 (95% confidence interval (CI): 2.42-2.94; P < 0.001). Whereas mortality declined over time in cases and controls, the trend in ORs remained relatively stable. Having CDI increased additional mean length of stay beyond infection by 22.3% (95% CI: 18.0-26.8%; P < 0.001). CONCLUSION: CDI is associated with an almost three-fold increase in 30-day mortality and places an increased burden on hospital resources by increasing mean LOS beyond the infection date by 22.3%. The decreasing CDI mortality trends may be due to overall improvements in mortality among the general and hospital population of Scotland. Therefore, despite large declines in incidence rates, CDI remains a serious healthcare problem.

Risk of infection following semi-invasive ultrasound procedures in Scotland, 2010 to 2016: A retrospective cohort study using linked national datasets.

INTRODUCTION: Outbreak reports indicate a risk of cross-infection following medical procedures using semi-invasive ultrasound probes. This study aimed to evaluate the risk of infection, using microbiological reports and antibiotic prescriptions as proxy measures, associated with semi-invasive ultrasound probe procedures, including transoesophageal echocardiography, transvaginal and transrectal ultrasound. METHODS: Patient records from the Electronic Communication of Surveillance in Scotland and the Prescribing Information System were linked with the Scottish Morbidity Records for cases in Scotland between 2010 and 2016. Three retrospective cohorts were created to include inpatients/day-cases and outpatients in the following specialties: Cardiology, Gynaecology and Urology. Cox regression was used to quantify the association between semi-invasive ultrasound probe procedures and the risk of positive microbiological reports and community antibiotic prescriptions in the 30-day period following the procedure. RESULTS: There was a greater hazard ratio of microbiological reports for patients who had undergone transoesophageal echocardiography (HR: 4.92; 95% CI: 3.17-7.63), transvaginal (HR: 1.41; 95% CI: 1.21-1.64) and transrectal ultrasound (HR: 3.40; 95% CI: 2.90-3.99), compared with unexposed cohort members after adjustment for age, co-morbidities, previous hospital admissions and past care home residence. Similarly, there was a greater hazard ratio of antibiotic prescribing for those who had received transvaginal (HR: 1.26; 95% CI: 1.20-1.32) and transrectal (HR: 1.75; 95% CI: 1.66-1.84) ultrasound, compared with unexposed patients. CONCLUSION: Analysis of linked national datasets demonstrated a greater risk of infection within 30 days of undergoing semi-invasive ultrasound probe procedures, using microbiological reports and antibiotic prescriptions as proxy measures of infection.

Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism.

Alemtuzumab is a humanized IgG1 kappa antibody directed against CD52, a glycosyl-phosphatidylinositol linked cell-membrane protein of unknown function. Herein, we demonstrate that alemtuzumab promotes rapid death of chronic lymphocytic leukemia (CLL) cells in vitro, in a complement and accessory cell free system. Using minimal detergent solubilization of CLL membranes, we found that CD52 colocalizes with ganglioside GM-1, a marker of membrane rafts. Fluorescence microscopy revealed that upon crosslinking CD52 with alemtuzumab+anti-Fc IgG, large patches, and in many cases caps, enriched in CD52 and GM-1 formed upon the CLL cell plasma membrane. Depletion of membrane cholesterol or inhibition of actin polymerization significantly diminished the formation of alemtuzumab-induced caps and reduced alemtuzumab-mediated CLL cell death. We compared alemtuzumab-induced direct cytotoxicity, effector cell-mediated toxicity and complement-mediated cytotoxicity of CLL cells to normal T cells. The direct cytotoxicity and observed capping was significantly greater for CLL cells as compared to normal T cells. Cell-mediated and complement-mediated cytotoxicity did not significantly differ between the two cell types. In summary, our data support the hypothesis that alemtuzumab can initiate CLL cell death by crosslinking CD52-enriched lipid rafts. Furthermore, the differential direct cytotoxic effect suggests that CD52 directed antibodies could possibly be engineered to more specifically target CLL cells.

Delayed repair of the quadriceps using the Mitek anchor system: a case report and review of the literature.

Extensor mechanism disruptions are relatively uncommon knee injuries. Within this group, delayed treatment is an infrequent but difficult clinical situation. Fibrous degeneration, muscle contraction and subsequent hiatus present a challenge to the orthopaedic surgeon. We present an unusual case of a successful delayed repair using the Mitek anchors system (Mitek Products Inc., a division of Ethicon Inc., Westwood, Massachusetts).

Relative mutagenicity of some urinary metabolites of the antitumor drug cyclophosphamide.

Four urinary metabolites of the cytostatic drug cyclophosphamide were tested for mutagenicity in the Ames Salmonella assay: nornitrogen mustard (NM), 4-ketocyclophosphamide, 3-(2-chloroethyl)oxazolidone (OZ), and N,N'-bis(2-chloroethyl)piperazine. All four acted as direct base substitution mutagens although 4-ketocyclophosphamide showed an increase in mutagenicity after metabolic activation with S-9 rat liver fraction. Of the four compounds tested, NM was the strongest mutagen while all the others had weak mutagenic activity, with OZ being the weakest. We observed that, under conditions which facilitate the conversion of NM to OZ (presence of HCO-3 at neutral pH), the former lost both mutagenic and alkylating activities. Our findings, taken together with other reports in the literature, indicate that NM could be a major cause of secondary bladder carcinoma since it is a potent mutagen ad seems to be present in high levels in the urine of cyclophosphamide-treated patients. The fact that it can be detoxified to the weak mutagen OZ in the presence of HCO-3 suggests the possibility that, by increasing the concentration of HCO-3 in the urine of patients, that undesirable side effect of cyclophosphamide treatment can be alleviated.

Occurrence and distribution of brominated flame retardants and perfluoroalkyl substances in Australian landfill leachate and biosolids.

The levels of perfluroalkyl substances (PFASs), polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDDs) were studied in Australian landfill leachate and biosolids. Leachate was collected from 13 landfill sites and biosolids were collected from 16 wastewater treatment plants (WWTPs), across Australia. Perfluorohexanoate (PFHxA) (12-5700ng/L) was the most abundant investigated persistent, bioaccumulative and toxic (PBT) chemical in leachate. With one exception, mean concentrations of PFASs were higher in leachate of operating landfills compared to closed landfills. Polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane isomers (HBCDDs) were detected typically at operating landfills in comparatively lower concentrations than the PFASs. Decabromodiphenyl ether (BDE-209) (<0.4-2300ng/g) and perfluoroctanesulfonate (PFOS) (

Pho4 mediates phosphate acquisition in Candida albicans and is vital for stress resistance and metal homeostasis.

During interactions with its mammalian host, the pathogenic yeast Candida albicans is exposed to a range of stresses such as superoxide radicals and cationic fluxes. Unexpectedly, a nonbiased screen of transcription factor deletion mutants revealed that the phosphate-responsive transcription factor Pho4 is vital for the resistance of C. albicans to these diverse stresses. RNA-Seq analysis indicated that Pho4 does not induce stress-protective genes directly. Instead, we show that loss of Pho4 affects metal cation toxicity, accumulation, and bioavailability. We demonstrate that pho4Δ cells are sensitive to metal and nonmetal cations and that Pho4-mediated polyphosphate synthesis mediates manganese resistance. Significantly, we show that Pho4 is important for mediating copper bioavailability to support the activity of the copper/zinc superoxide dismutase Sod1 and that loss of Sod1 activity contributes to the superoxide sensitivity of pho4Δ cells. Consistent with the key role of fungal stress responses in countering host phagocytic defenses, we also report that C. albicans pho4Δ cells are acutely sensitive to macrophage-mediated killing and display attenuated virulence in animal infection models. The novel connections between phosphate metabolism, metal homeostasis, and superoxide stress resistance presented in this study highlight the importance of metabolic adaptation in promoting C. albicans survival in the host.