Follow-up of women with cervical adenocarcinoma in situ treated by conization: A single centre clinical experience.

OBJECTIVE: Hysterectomy has been the historical gold standard final step in the treatment algorithm of adenocarcinoma in situ (AIS) recommended by most North American colposcopy guidelines. AIS disproportionately affects young childbearing age women, therefore a fertility sparing treatment option is desirable. Our study examines the impact of conservative treatment of AIS with conization followed by serial surveillance. METHODS: A retrospective chart review was completed of patients treated for AIS from 2006 to 2020. Charts were identified by pathologic diagnosis of AIS on cervical and uterine specimens. Charts were excluded if AIS was not treated with conization, if AIS was not confirmed on initial conization specimen, or if invasive disease was found at initial conization. RESULTS: 121 patient charts were analyzed. Median age of patients at first conization and hysterectomy was 34.8 and 40.9, respectively. First conization was by Cold Knife Cone in 58% of patients, and by Loop Electrosurgical Excisional Procedure in 42% of patients. Median follow-up period in our study was 609 days. 5% of patients had recurrence, with only one patient who recurred as cancer. One case of recurrence had a positive initial conization margin. Median time to recurrence was 700 days. 47% of patients underwent eventual hysterectomy. Residual AIS was found in 23% of hysterectomy specimens. Adenocarcinoma was diagnosed on hysterectomy specimen in four patients. CONCLUSION: Our study demonstrates the oncologic safety of treating AIS with conization and serial surveillance. Routine hysterectomy completed as a part of the AIS treatment algorithm, as in current clinical guidelines, is unnecessary.

Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

Exit strategies: optimising feasible surveillance for detection, elimination, and ongoing prevention of COVID-19 community transmission.

BACKGROUND: Following implementation of strong containment measures, several countries and regions have low detectable community transmission of COVID-19. We developed an efficient, rapid, and scalable surveillance strategy to detect remaining COVID-19 community cases through exhaustive identification of every active transmission chain. We identified measures to enable early detection and effective management of any reintroduction of transmission once containment measures are lifted to ensure strong containment measures do not require reinstatement. METHODS: We compared efficiency and sensitivity to detect community transmission chains through testing of the following: hospital cases; fever, cough and/or ARI testing at community/primary care; and asymptomatic testing; using surveillance evaluation methods and mathematical modelling, varying testing capacities, reproductive number (R) and weekly cumulative incidence of COVID-19 and non-COVID-19 respiratory symptoms using data from Australia. We assessed system requirements to identify all transmission chains and follow up all cases and primary contacts within each chain, per million population. RESULTS: Assuming 20% of cases are asymptomatic and 30% of symptomatic COVID-19 cases present for testing, with R = 2.2, a median of 14 unrecognised community cases (8 infectious) occur when a transmission chain is identified through hospital surveillance versus 7 unrecognised cases (4 infectious) through community-based surveillance. The 7 unrecognised community upstream cases are estimated to generate a further 55-77 primary contacts requiring follow-up. The unrecognised community cases rise to 10 if 50% of cases are asymptomatic. Screening asymptomatic community members cannot exhaustively identify all cases under any of the scenarios assessed. The most important determinant of testing requirements for symptomatic screening is levels of non-COVID-19 respiratory illness. If 4% of the community have respiratory symptoms, and 1% of those with symptoms have COVID-19, exhaustive symptomatic screening requires approximately 11,600 tests/million population using 1/4 pooling, with 98% of cases detected (2% missed), given 99.9% sensitivity. Even with a drop in sensitivity to 70%, pooling was more effective at detecting cases than individual testing under all scenarios examined. CONCLUSIONS: Screening all acute respiratory disease in the community, in combination with exhaustive and meticulous case and contact identification and management, enables appropriate early detection and elimination of COVID-19 community transmission. An important component is identification, testing, and management of all contacts, including upstream contacts (i.e. potential sources of infection for identified cases, and their related transmission chains). Pooling allows increased case detection when testing capacity is limited, even given reduced test sensitivity. Critical to the effectiveness of all aspects of surveillance is appropriate community engagement, messaging to optimise testing uptake and compliance with other measures.

The role of fit-for-purpose assays within tiered testing approaches: A case study evaluating prioritized estrogen-active compounds in an in vitro human uterotrophic assay.

Chemical risk assessment relies on toxicity tests that require significant numbers of animals, time and costs. For the >30,000 chemicals in commerce, the current scale of animal testing is insufficient to address chemical safety concerns as regulatory and product stewardship considerations evolve to require more comprehensive understanding of potential biological effects, conditions of use, and associated exposures. We demonstrate the use of a multi-level new approach methodology (NAMs) strategy for hazard- and risk-based prioritization to reduce animal testing. A Level 1/2 chemical prioritization based on estrogen receptor (ER) activity and metabolic activation using ToxCast data was used to select 112 chemicals for testing in a Level 3 human uterine cell estrogen response assay (IKA assay). The Level 3 data were coupled with quantitative in vitro to in vivo extrapolation (Q-IVIVE) to support bioactivity determination (as a surrogate for hazard) in a tissue-specific context. Assay AC50s and Q-IVIVE were used to estimate human equivalent doses (HEDs), and HEDs were compared to rodent uterotrophic assay in vivo-derived points of departure (PODs). For substances active both in vitro and in vivo, IKA assay-derived HEDs were lower or equivalent to in vivo PODs for 19/23 compounds (83%). Activity exposure relationships were calculated, and the IKA assay was as or more protective of human health than the rodent uterotrophic assay for all IKA-positive compounds. This study demonstrates the utility of biologically relevant fit-for-purpose assays and supports the use of a multi-level strategy for chemical risk assessment.

Potential for children with intellectual disability to engage in cognitive behaviour therapy: the parent perspective.

BACKGROUND: This study aimed to obtain the opinions of parents and carers of children with intellectual disability (ID) as to whether cognitive behaviour therapy (CBT) could be useful for their children. METHODS: A mixed qualitative and quantitative method was employed. Twenty-one carers of children aged 10 to 17 having borderline to moderate intellectual functioning responded to an online questionnaire. Participants were provided with information about CBT and asked to respond to open-ended questions. Quantitative data pertained to questions about their child's ability to identify and describe thoughts, feelings and behaviours. Thematic analysis of responses was conducted using an inductive method of identifying themes from the qualitative data collected. RESULTS: Five themes emerged from the qualitative analysis: Emotional Attunement (i.e. parent's understanding and recognition of their child's emotions), Role of the Therapist (i.e. ways therapists could facilitate the intervention), Role of the Parent (i.e. ways parents could engage in the therapy process), Anticipated Obstacles (i.e. what may get in the way of the therapy) and Suggested Adaptations for Therapy (i.e. how CBT can be adapted to suit the needs of children with ID). Seventy-six per cent agreed that their child would be able to engage in CBT with assistance. CONCLUSIONS: The majority of parents believed that CBT is an intervention that children with ID could engage in, provided the therapy is adapted, and the therapist accommodates their needs.

Provincial Veterinary Services respond to drought in South Africa.

In 2018, Cape Town, South Africa, nearly ran out of water. That this has not yet happened is in large part due to the water-saving efforts of its citizens. It is highly likely that this situation will be repeated in Cape Town and that similar situations will be experienced by major cities in other parts of the world. Efforts to save water should thus continue and the lessons learned in Cape Town should be shared. The functioning of Veterinary Services during a drought is affected in the same way as any business, in terms of running an office, but veterinary professionals face an increased risk of exposure to pathogens, compared to that of many occupations, and of veterinary officials becoming disease vectors. One component of Veterinary Services is veterinary laboratory services. Laboratory procedures rely heavily on water and, without advance planning, a laboratory's function can be severely limited by a restricted water supply. In many cases, innovative water-saving techniques can be used to reduce water use substantially without compromising the quality of the services offered. Here, the authors share their experiences and some lessons learned while working in Veterinary Services in the Western Cape province of South Africa.

En 2018, la ville du Cap en Afrique du Sud a failli manquer d'eau. Si la pénurie totale a pu être évitée, ce fut en grande partie grâce aux efforts déployés par les habitants pour économiser l'eau. Or, il est très probable que cette situation se reproduise au Cap et que des situations analogues surviennent dans nombre de grandes métropoles d'autres régions du monde. C'est pourquoi il convient de poursuivre les efforts d'économie d'eau et de partager avec d'autres les enseignements tirés dans la ville du Cap. L'impact de la sécheresse sur le fonctionnement des Services vétérinaires est similaire à celui de toute organisation en termes de gestion administrative ; en revanche, par rapport à d'autres professionnels, les vétérinaires de terrain sont davantage exposés à des agents pathogènes et au risque de devenir eux-mêmes vecteurs de maladies. Les laboratoires vétérinaires sont l'une des composantes des Services vétérinaires. Les procédures de laboratoire sont amplement tributaires de l'eau ; or, en l'absence d'une planification préalable, les activités d'un laboratoire pourraient être gravement mises à mal par des restrictions de l'approvisionnement en eau. Dans bien des cas, il est possible d'utiliser des techniques innovantes pour économiser l'eau afin d'en diminuer la consommation sans pour autant compromettre la qualité des services rendus. Les auteurs font part de leur expérience et de certains enseignements tirés lorsqu'ils travaillaient dans les Services vétérinaires de la province du Cap-Occidental en Afrique du Sud.

En 2018 faltó poco para que Ciudad del Cabo (Sudáfrica) se quedara sin agua. Si las cosas aún no han llegado a este extremo es, en gran parte, gracias a los esfuerzos de los habitantes por economizar agua. Es muy probable que en el futuro Ciudad del Cabo vuelva a sufrir esta situación y que grandes metrópolis de otras partes del mundo conozcan dificultades parecidas. Por ello hay que perseverar en los esfuerzos de ahorro de agua y se deben compartir las enseñanzas extraídas en Ciudad del Cabo. Durante una sequía, el funcionamiento de los Servicios Veterinarios se ve afectado del mismo modo que cualquier otra actividad, por lo que respecta al trabajo de oficina, pero además los profesionales del ramo, en comparación con los de otros muchos sectores, corren mayor peligro de exposición a patógenos, lo que a su vez entraña el riesgo de que los propios veterinarios ejerzan de vectores de la enfermedad. Uno de los puntales de los Servicios Veterinarios son los laboratorios veterinarios, cuyo quehacer depende en gran medida del uso de agua. Por ello, cuando no se ha planificado con antelación la eventualidad de una penuria de agua, esta puede imponer graves cortapisas a las funciones de laboratorio. En muchos casos es posible emplear innovadoras técnicas de ahorro de agua para reducir sustancialmente las cantidades utilizadas sin menoscabo de la calidad de los servicios dispensados. Los autores comparten su experiencia y algunas de las lecciones que extrajeron de su trabajo en los Servicios Veterinarios de la provincia sudafricana del Cabo Occidental.

Professional and interprofessional identities: a scoping review.

Identity development within the interprofessional field is an emerging area of research. This scoping review aims to establish how professional and interprofessional identities are defined, conceptualized, theorized and measured within the interprofessional literature. Six databases were systematically searched for papers focusing on professional and/or interprofessional identities in interprofessional healthcare and education using a scoping review methodology. A total of 84 papers were included. Most papers discussed professional identity only; the minority discussed both identities. There were three key findings. First, no universal definition of interprofessional identity exists. Second, there is no shared understanding of interprofessional identity and its relationship with professional identity. Third, poor alignment between definitions, conceptualizations, theories and measures of interprofessional identity exists. The absence of a psychometrically robust instrument that specifically measures interprofessional identity and the short-term focus of current interprofessional identity research further limits understanding. Research that critically examines professional and interprofessional identity development should be underpinned by clear definitions, concepts, theories and measures of both identities. High-quality research will allow greater understanding of interprofessional identity development and its impact on interprofessional practice.

Simplified LC/MS assay for the measurement of isolevuglandin protein adducts in plasma and tissue samples.

Isolevuglandins (IsoLGs) are a family of highly reactive 4-ketoaldehydes formed by lipid peroxidation that modify the lysyl residues of cellular proteins. Modification of proteins by IsoLGs have been shown to contribute to disease processes such as the development of hypertension. Accurate quantitation of the extent of protein modification by IsoLGs is essential for understanding the mechanisms whereby these modifications contribute to disease and the efficacy of interventions designed to prevent this modification. The previously described LC/MS assay to quantitate IsoLG protein adducts was extremely labor-intensive and time consuming, and while it offered reasonably low intra-day variation for replicate samples, variation when replicate samples were processed on separate days was significant. These limitations significantly restricted utilization of this approach. We therefore performed a series of studies to optimize the assay. We now report a significantly simplified LC/MS assay for measurement of IsoLG protein adducts with increased sensitivity and lower intra-day and inter-day variability.

Recent drought and tree mortality effects on the avian community in southern Sierra Nevada: a glimpse of the future?

Birds respond rapidly to changes in both habitat and climate conditions and thus are good indicators of the ecological effects of a changing climate, which may include warmer temperatures, changing habitat conditions, and increased frequency and magnitude of extreme events like drought. We investigated how a widespread tree mortality event concurrent with a severe drought influenced the avian community of the Sierra Nevada mountain range in California. We assessed and compared the separate effects of climate stresses and altered habitat conditions on the avian community and used this information to evaluate the changes that are likely to occur in the near future. We built tree mortality maps from freely available Landsat imagery with Google Earth Engine. We analyzed avian point counts from 2010 to 2016 in the southern Sierra Nevada, to model temperature, water deficit, and tree mortality effects on the abundances of 45 bird species, and then used these models to project abundances into the future based on three climate projections. A large portion of the avian community, 47%, had a positive relationship with temperature increase, compared to 20% that responded negatively. More species (36%) declined with drier conditions than increased (29%). More species declined in response to high tree mortality (36%) than increased (9%). A preponderance of species adapted to colder temperatures (higher elevation) had negative responses to high tree mortality and water deficit, but positive responses to increasing temperature. We projected the highest total bird abundances in the future under the warmest climate scenario that we considered, but habitat modification (e.g., tree mortality) and water deficit could offset the positive influence of temperature for many species. As other studies have shown, climate warming may lead to substantial but idiosyncratic effects on wildlife species that could result in community composition shifts. We conclude that future climate conditions may not have a universally negative effect on biodiversity in the Sierra Nevada, but probable vegetation changes and increased likelihood of extreme events such as drought should be incorporated into climate-smart forest and wildlife management decisions.

Maternal hemodynamics, fetal biometry and Doppler indices in pregnancies followed up for suspected fetal growth restriction.

OBJECTIVES: To assess whether, in a cohort of patients with a small-for-gestational-age (SGA) fetus with estimated fetal weight ≤ 10th percentile, maternal hemodynamics, fetal biometry and Doppler indices at presentation can predict the subsequent development of an abnormal fetal Doppler index or delivery of a baby with birth weight < 3rd percentile. METHODS: This was a prospective observational cohort study conducted at a specialist clinic for the management of pregnancies with a SGA fetus at King's College Hospital, London, UK. The study population comprised 86 singleton pregnancies with a SGA fetus, presenting at a median gestational age of 32 (range, 26-35) weeks. We measured maternal cardiac function using a non-invasive transthoracic bioreactance monitor, as well as mean arterial pressure, fetal biometry, and umbilical artery (UA), fetal middle cerebral artery (MCA) and uterine artery (UtA) pulsatility indices (PI), and the deepest vertical pool of amniotic fluid. Z-scores of these variables were calculated based on reported reference ranges and the values were compared between pregnancies with evidence of an abnormal fetal Doppler index at presentation (Group 1), those that had developed an abnormal Doppler index at a subsequent visit (Group 2) and those that did not develop an abnormal Doppler index throughout pregnancy (Group 3). Abnormal fetal Doppler was defined as UA-PI > 95th percentile and/or MCA-PI < 5th percentile. Differences in measured variables at presentation were also compared between pregnancies delivering a baby with birth weight < 3rd percentile and those delivering a baby with birth weight ≥ 3rd percentile. Multivariate logistic regression analysis was used to determine significant predictors of birth weight < 3rd percentile and evolution from normal to abnormal fetal Doppler. RESULTS: In the study population, 14 (16%) cases were in Group 1, 19 (22%) in Group 2 and 53 (62%) in Group 3. Birth weight was < 3rd percentile in 39 (45%) cases and ≥ 3rd percentile in 47 (55%). There was decreased cardiac output and stroke volume and increased peripheral vascular resistance compared with a normal population, and the deviations from normal were most marked in Group 1. Pregnancies with birth weight < 3rd percentile, compared with those with birth weight ≥ 3rd percentile, had greater deviations from normal in fetal biometry, maternal cardiac output, stroke volume, heart rate, peripheral vascular resistance and UtA-PI. Multivariate logistic regression analysis demonstrated that, in the prediction of birth weight < 3rd percentile, maternal hemodynamic profile provided significant improvement to the prediction provided by maternal demographics, fetal biometry, UtA-PI, UA-PI and MCA-PI (difference between areas under receiver-operating characteristics curves, 0.18 (95% CI, 0.06-0.29); P = 0.002). In contrast, there was no significant independent contribution from maternal hemodynamics in the prediction of the subsequent development of abnormal fetal Doppler. CONCLUSIONS: In pregnancies with a SGA fetus, there is decreased maternal cardiac output and stroke volume and increased peripheral vascular resistance, and the deviations from normal are most marked in cases of redistribution in the fetal circulation and reduced amniotic fluid volume. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Using learning flexibly and remembering after a delay: understanding cognitive dysfunction in adults with Down syndrome.

BACKGROUND: Episodic memory deficits are a characteristic of cognitive dysfunction in people with Down syndrome (DS). However, less is known about the processes (i.e. encoding, retention or using learned information flexibly) that underlie these deficits. METHOD: We explored these abilities by administering a relational memory and inference task to participants with DS and mental age-matched controls and testing both immediately and after a 24-h delay. RESULTS: Adults with DS learned paired associates more slowly than controls but showed good recognition at both the immediate and delayed tests. Despite memory for learned pairs, adults with DS were less able to use relational learning flexibly to make inferential judgements than controls. CONCLUSIONS: These results deepen our understanding of the cognitive profile of adults with DS, demonstrating deficits in both encoding new information, and flexibly using such information. These results have important implications for workplace training and intervention programs for people with DS.

Perceived relevance mediates the relationship between professional identity and attitudes towards interprofessional education in first-year university students.

The strength of health science students' identification with their chosen profession is associated with their attitudes towards interprofessional education (IPE). However, little is known about the factors that might mediate this relationship. In this article, we examine the relationships between professional identification, communication and teamwork skills, perceived relevance of IPE, and positive and negative attitudes towards IPE. A sample of 444 first-year university students from 25 health science professions enrolled in a first-year interprofessional program participated in this research by completing a questionnaire. Data were analysed using path analysis. Positive IPE attitudes were more strongly endorsed than negative IPE attitudes. Perceived relevance of IPE to future careers was the strongest predictor of both positive and negative attitudes to IPE, and fully mediated the effect of professional identity. Self-reported communication and teamwork skills were a significant negative predictor of negative attitudes to IPE only, and the effect was not mediated by perceived relevance. These findings indicate that IPE may be particularly challenging for students who do not have confidence in their abilities to communicate and work effectively in teams. Building these skills through alternative communication technologies may decrease negative attitudes. In order to maintain or increase positive attitudes towards IPE in introductory programs that span professions, the curriculum needs to be designed to demonstrate relevance to the future careers of participating students.

Neural plasticity and its initiating conditions in tinnitus.

BACKGROUND AND OBJECTIVE: Deafferentation caused by cochlear pathology (which can be hidden from the audiogram) activates forms of neural plasticity in auditory pathways, generating tinnitus and its associated conditions including hyperacusis. This article discusses tinnitus mechanisms and suggests how these mechanisms may relate to those involved in normal auditory information processing. MATERIALS AND METHODS: Research findings from animal models of tinnitus and from electromagnetic imaging of tinnitus patients are reviewed which pertain to the role of deafferentation and neural plasticity in tinnitus and hyperacusis. RESULTS: Auditory neurons compensate for deafferentation by increasing their input/output functions (gain) at multiple levels of the auditory system. Forms of homeostatic plasticity are believed to be responsible for this neural change, which increases the spontaneous and driven activity of neurons in central auditory structures in animals expressing behavioral evidence of tinnitus. Another tinnitus correlate, increased neural synchrony among the affected neurons, is forged by spike-timing-dependent neural plasticity in auditory pathways. Slow oscillations generated by bursting thalamic neurons verified in tinnitus animals appear to modulate neural plasticity in the cortex, integrating tinnitus neural activity with information in brain regions supporting memory, emotion, and consciousness which exhibit increased metabolic activity in tinnitus patients. DISCUSSION AND CONCLUSION: The latter process may be induced by transient auditory events in normal processing but it persists in tinnitus, driven by phantom signals from the auditory pathway. Several tinnitus therapies attempt to suppress tinnitus through plasticity, but repeated sessions will likely be needed to prevent tinnitus activity from returning owing to deafferentation as its initiating condition.

Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis.

Cognitive dysfunction is a major comorbidity of the epilepsies; however, treatments targeting seizure-associated cognitive dysfunction, particularly deficits in learning and memory are not available. Isoketals and neuroketals, collectively known as gamma-ketoaldehydes are formed via the non-enzymatic, free radical catalyzed oxidation of arachidonic acid and docosahexaenoic acid, respectively. They are attractive candidates for oxidative protein damage and resultant cognitive dysfunction due to their formation within the plasma membrane and their high proclivity to form cytotoxic adducts on protein lysine residues. We tested the hypothesis that gamma-ketoaldehydes mechanistically contribute to seizure-associated memory impairment using a specific gamma-ketoaldehyde scavenger, salicylamine in the kainic acid and pilocarpine rat models of temporal lobe epilepsy. We show that gamma-ketoaldehydes are increased following epileptogenic injury in hippocampus and perirhinal cortex, two brain regions imperative for learning and memory. Treatment with an orally bioavailable, brain permeable scavenger, salicylamine attenuated 1) spatial memory deficits 2) reference memory deficits and 3) neuronal loss and astrogliosis in two mechanistically distinct models of epilepsy without affecting the epileptogenic injury or the development of chronic epilepsy. We have previously demonstrated that reactive oxygen species and the lipid peroxidation biomarkers, F2-isoprostanes are produced following status epilepticus. However, which reactive species specifically mediate oxidative damage to cellular macromolecules remains at large. We provide novel data suggesting that memory impairment occurs via gamma-ketoaldehyde production in two models of epilepsy and that treatment with a gamma-ketoaldehyde scavenger can protect vulnerable neurons. This work suggests a novel target and therapy to treat seizure-induced memory deficits in epilepsy.

Determination of hepatitis B phenotype using biochemical and serological markers.

The aim of this study was to assess the validity of categorization of chronic hepatitis B viral infection into stages or phases based upon measures of disease activity and viral load, assuming these phenotypes will be useful for prognostication and determining the need for antiviral therapy. We assessed the phenotype of hepatitis B of 1,390 adult participants enrolled in the Hepatitis B Research Network Cohort Study, using a computer algorithm. Only 4% were immune tolerant, while 35% had chronic hepatitis B (18% e antigen positive and 17% e antigen negative) while 23% were inactive carriers. Strikingly, 38% of participants did not fit clearly into any one of these groups and were considered indeterminant. The largest subset of indeterminants had elevated serum aminotransferases with low levels of HBV DNA (less than 10,000 iu/mL). Subsequent determination of hepatitis B phenotype on the next available laboratory tests showed that 64% remained indeterminant. These findings call into question the validity of conventional staging of hepatitis B, in large part because of the substantial proportion of patients who do not fit readily into one of the usual stages or phases. Further studies are needed of the indeterminant category of chronic hepatitis B viral infection, including assessments of whether patients in this group are perhaps in transition to another phase or if they are a distinct phenotype with a need to assess liver disease severity and need for antiviral therapy. (ClinicalTrials.gov identifier NCT01263587).

Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study.

BACKGROUND: Intravascular hemolysis is an intrinsic feature of severe malaria pathophysiology but the pathogenic role of cell-free hemoglobin-mediated oxidative stress in severe malaria associated acute kidney injury (AKI) is unknown. METHODS: As part of a prospective observational study, enrolment plasma cell-free hemoglobin (CFH), lipid peroxidation markers (F2-isoprostanes (F2-IsoPs) and isofurans (IsoFs)), red cell deformability, and serum creatinine were quantified in Bangladeshi patients with severe falciparum malaria (n = 107), uncomplicated malaria (n = 80) and sepsis (n = 28). The relationships between these indices and kidney function and clinical outcomes were examined. RESULTS: AKI was diagnosed at enrolment in 58% (62/107) of consecutive patients with severe malaria, defined by an increase in creatinine ≥1.5 times expected baseline. Severe malaria patients with AKI had significantly higher plasma cell-free hemoglobin (geometric mean CFH: 8.8 µM; 95% CI, 6.2-12.3 µM), F2-isoprostane (56.7 pg/ml; 95% CI, 45.3-71.0 pg/ml) and isofuran (109.2 pg/ml; 95% CI, 85.1-140.1 pg/ml) concentrations on enrolment compared to those without AKI (CFH: 5.1 µM; 95% CI, 4.0-6.6 µM; P = 0.018; F2-IsoPs: 27.8 pg/ml; 95% CI, 23.7-32.7 pg/ml; P < 0.001; IsoFs: 41.7 pg/ml; 95% CI, 30.2-57.6 pg/ml; P < 0.001). Cell-free hemoglobin correlated with markers of hemolysis, parasite burden (P. falciparum histidine rich protein 2 (PfHRP2)), and F2-IsoPs. Plasma F2-IsoPs and IsoFs inversely correlated with pH, positively correlated with creatinine, PfHRP2 and fractional excretion of sodium, and were higher in patients later requiring hemodialysis. Plasma F2-IsoP concentrations also inversely correlated with red cell deformability and were higher in fatal cases. Mixed effects modeling including an interaction term for CFH and time showed that F2-IsoPs, IsoFs, PfHRP2, CFH, and red cell rigidity were independently associated with increasing creatinine over 72 h. Multivariable logistic regression showed that admission F2-IsoPs, IsoFs and red cell deformability were associated with the need for subsequent hemodialysis. CONCLUSIONS: Cell-free hemoglobin and lipid peroxidation are associated with acute kidney injury and disease severity in falciparum malaria, suggesting a pathophysiological role in renal tubular injury. Evaluation of adjunctive therapies targeting cell-free hemoglobin-mediated oxidative stress is warranted.

A randomized controlled feasibility trial exploring partnered ballroom dancing for people with Parkinson's disease.

OBJECTIVE: To determine the feasibility of a Dance Centre delivering a programme of mixed dances to people with Parkinson's and identify suitable outcomes for a future definitive trial. DESIGN: A two-group randomized controlled feasibility trial. METHODS: People with Parkinson's were randomized to a control or experimental group (ratio 15:35), alongside usual care. In addition, participants in the experimental group danced with a partner for one hour, twice-a-week for 10 weeks; professional dance teachers led the classes and field-notes were kept. Control-group participants were given dance class vouchers at the end of the study. Blinded assessments of balance, mobility and function were completed in the home. Qualitative interviews were conducted with a subsample to explore the acceptability of dance. RESULTS: A total of 51 people with Parkinson's (25 male) with Hoehn and Yahr scores of 1-3 and mean age of 71 years (range 49-85 years), were recruited to the study. Dance partners were of similar age (mean 68, range 56-91 years). Feasibility findings focused on recruitment (target achieved); retention (five people dropped out of dancing); outcome measures (three measures were considered feasible, changes were recommended). Proposed sample size for a Phase III trial, based on the 6-minute walk test at six months was 220. Participants described dance as extremely enjoyable and the instructors were skilled in instilling confidence and motivation. The main organizational challenges for a future trial were transport and identifying suitable dance partners. CONCLUSION: We have demonstrated the feasibility of conducting the study through a Dance Centre and recommend a Phase III trial.

Assessment of complementary feeding of Canadian infants: effects on microbiome & oxidative stress, a randomized controlled trial.

BACKGROUND: The World Health Organization recommends exclusive breastfeeding until 6 months followed by introduction of iron-rich complementary foods (CFs). The aim of this study was to determine the impact of different iron-rich CFs on infant gut inflammation and microbiota. METHODS: Eighty-seven exclusively breastfed infants were randomly assigned to receive one of the following as their first CF: iron-fortified cereal (Cer), iron-fortified cereal with fruit (Cer + Fr), or meat (M). Urine and stool samples were collected to assess reactive oxygen species (ROS) generation, gut microbiota and inflammation. RESULTS: Fecal iron differed across feeding groups (p < 0.001); levels were highest in the Cer group and lowest in M group. A significant increase of fecal ROS formation (p < 0.002) after the introduction of CFs was observed, but did not differ across feeding groups. Fecal calprotectin increased within all groups after the introduction of CFs (p = 0.004). Gut microbiota richness increased after introduction of M or Cer + Fr. Regardless of feeding group, Coriobacteriaceae were positively correlated with ROS and Staphylococcaceae were negatively correlated with calprotectin. CONCLUSIONS: Choice of first CF may influence gut inflammation and microbiota, potentially due to variations in iron absorption from different foods. Further research is warranted to fully characterize these associations and to establish implications for infant health. This study was registered in the ClinicalTrial.gov registry (Identifier No. NCT01790542 ). TRIAL REGISTRATION: This study was registered in the ClinicalTrial.gov registry under the name "Assessment of Complementary Feeding of Canadian Infants" (Identifier No. NCT01790542 ) February 6, 2013.

The isoprostanes--25 years later.

Isoprostanes (IsoPs) are prostaglandin-like molecules generated independent of the cyclooxygenase (COX) by the free radical-induced peroxidation of arachidonic acid. The first isoprostane species discovered were isomeric to prostaglandin F2α and were thus termed F2-IsoPs. Since the initial discovery of the F2-IsoPs, IsoPs with differing ring structures have been identified as well as IsoPs from different polyunsaturated fatty acids, including eicosapentaenoic acid and docosahexanenoic acid. The discovery of these molecules in vivo in humans has been a major contribution to the field of lipid oxidation and free radical research over the course of the past 25 years. These molecules have been determined to be both biomarkers and mediators of oxidative stress in numerous disease settings. This review focuses on recent developments in the field with an emphasis on clinical research. Special focus is given to the use of IsoPs as biomarkers in obesity, ischemia-reperfusion injury, the central nervous system, cancer, and genetic disorders. Additionally, attention is paid to diet and lifestyle factors that can affect endogenous levels of IsoPs. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance."

Controlled moderate hypovolaemia in healthy volunteers is not associated with the development of oxidative stress assessed by plasma F2-isoprostanes and isofurans.

Hypovolaemia can be associated with substantial morbidity, particularly when it occurs in the setting of trauma and in patients with comorbid diseases. Hypovolaemia and inflammation such as occur in the setting of trauma and surgery, are associated with systemic oxidative stress and free-radical injury. Free-radical injury that results from hypovolaemia-induced organ reperfusion may further augment inflammatory processes. It is unknown exactly what proportion of free-radical injury is associated with isolated hypovolaemia as opposed to the contribution from inflammation from surgery or trauma. In the first human study of its kind, we exposed 8 adult male volunteers to venesection-induced hypovolaemia in progressive aliquots of 5% of total blood volume until 20% had been removed. This blood was subsequently reinfused. Plasma F2-isoprostanes and isofurans, markers of in vivo lipid oxidation, were measured by gas chromatography-mass spectrometry at each 5% aliquot venesected and at each 5% reinfused. Between baseline and maximal blood loss there was a minor fall in haemoglobin concentration from 143.9g/l to 138.8g/l (p=0.004, 95% CI 2.2, 8.0g/L). No significant change from baseline occurred in the concentrations of either plasma F2-isoprostanes or isofurans during venesection (p=0.116 and p=0.152, respectively) or blood reinfusion (p=0.553 and p=0.736, respectively). We can conclude that in healthy adult volunteers, isolated hypovolaemia to 20% total blood volume loss is not associated with detectable systemic oxidative stress. The free-radical injury identified in surgical and trauma patients may represent the effects of tissue damage and inflammation, with an uncertain contribution from tissue ischemia as may occur with hypovolaemia.