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Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by loss-of-function of SMN1. SMA is characterized by degeneration of motor neurons in the spinal cord, leading to progressive muscle weakness and atrophy. One of three currently available treatments is onasemnogene abeparvovec, an AAV9-based gene replacement therapy. Despite its effectiveness in improving motor function in SMA patients, its long-term safety profile remains unclear and adverse events such as liver toxicity are common. This may be caused by high vector dose or supraphysiological levels of SMN, driven by its strong, ubiquitous promoter. In this issue of EMBO Molecular Medicine, Xie et al addressed this by replacing the promoter of a benchmark virus—equivalent to onasemnogene abeparvovec—by an endogenous SMN1 promoter. In a common mouse model of SMA, treatment with this 2nd generation vector restored SMN expression close to physiological levels across tissues, resulting in improved safety and efficacy. This approach holds promise for safer and more efficacious AAV gene therapy for SMA and other diseases. E. Groen and M. Zwartkruis discuss improved gene therapy for spinal muscular atrophy as reported by J. Xie and colleagues, in this issue of EMBO Mol Med. [ABSTRACT FROM AUTHOR]

Introduction: Pregnant women are at higher risk of severe illness from coronavirus disease 2019 (COVID‐19) than non‐pregnant women of a similar age. Early in the COVID‐19 pandemic, it was clear that evidenced‐based guidance was needed, and that it would need to be updated rapidly. The National COVID‐19 Clinical Evidence Taskforce provided a resource to guide care for people with COVID‐19, including during pregnancy. Care for pregnant and breastfeeding women and their babies was included as a priority when the Taskforce was set up, with a Pregnancy and Perinatal Care Panel convened to guide clinical practice. Main recommendations: As of May 2022, the Taskforce has made seven specific recommendations on care for pregnant women and those who have recently given birth. This includes supporting usual practices for the mode of birth, umbilical cord clamping, skin‐to‐skin contact, breastfeeding, rooming‐in, and using antenatal corticosteroids and magnesium sulfate as clinically indicated. There are 11 recommendations for COVID‐19‐specific treatments, including conditional recommendations for using remdesivir, tocilizumab and sotrovimab. Finally, there are recommendations not to use several disease‐modifying treatments for the treatment of COVID‐19, including hydroxychloroquine and ivermectin. The recommendations are continually updated to reflect new evidence, and the most up‐to‐date guidance is available online (https://covid19evidence.net.au). Changes in management resulting from the guidelines: The National COVID‐19 Clinical Evidence Taskforce has been a critical component of the infrastructure to support Australian maternity care providers during the COVID‐19 pandemic. The Taskforce has shown that a rapid living guidelines approach is feasible and acceptable. [ABSTRACT FROM AUTHOR]

Objectives: Oral cancer screening can assist in the early detection of oral potentially malignant lesions (OPMLs) and prevention of oral cancers. It can be challenging for clinicians to differentiate OPMLs from benign conditions. Adjunct screening tools such as fluorescence visualisation (FV) and DNA image cytometry (DNA‐ICM) have shown success in identifying OPMLs in high‐risk clinics. For the first time we aimed to assess these technologies in Indian rural settings and evaluate if these tools helped clinicians identify high‐risk lesions during screening. Methods: Dental students and residents screened participants in five screening camps held in villages outside of Hyderabad, India, using extraoral, intraoral, and FV examinations. Lesion and normal tissue brushings were collected for DNA‐ICM analysis and cytology. Results: Of the 1116 participants screened, 184 lesions were observed in 152 participants. Based on white light examination (WLE), 45 lesions were recommended for biopsy. Thirty‐five were completed on site; 25 (71%) were diagnosed with low‐grade dysplasias (17 mild, 8 moderate) and the remaining 10 showed no signs of dysplasia. FV loss was noted in all but one dysplastic lesion and showed a sensitivity of 96% and specificity of 17%. Cytology combined with DNA‐ICM had a sensitivity of 64% and specificity of 86% in detecting dysplasia. Conclusion: DNA‐ICM combined with cytology identified the majority of dysplastic lesions and identified additional lesions, which were not considered high‐risk during WLE and biopsy on site. Efforts to follow‐up with these participants are ongoing. FV identified most high‐risk lesions but added limited value over WLE. [ABSTRACT FROM AUTHOR]

Background and aims: Clinical trials have shown that intensive low‐density lipoprotein cholesterol (LDL‐C) lowering improves cardiovascular outcomes among patients with atherosclerotic cardiovascular disease (ASCVD), but data are limited in real clinical practice, particularly for patients with ASCVD informing different territories. Methods: FRENA was a prospective registry of consecutive outpatients with coronary, cerebrovascular or peripheral artery disease. We compared the incidence of recurrent events in patients with sustained LDL‐C levels <70 mg/dl compared with those with ≥70 mg/dl. Results: As of December 2018, 1182 patients were eligible for this study. Among them, 172 (14.5%) had mean LDL‐C levels ≤70 mg/dl, and 1010 (85.5%) had <70 mg/dl. Their clinical characteristics at baseline were similar. During 5 years of follow‐up, 252 patients (21%) suffered major adverse cardiovascular events (MACE). The incidence rates of MACE were 3.42 events per 100 patient‐years (95% confidence interval [95% CI] 2.17–5.14) in patients with levels <70 mg/dl and 5.57 (95% CI, 4.87–6.34) in those with ≥70 mg/dl; the rate ratio was 0.61 (95% CI, 0.39–0.92), p = 0.019. On multivariable analysis, patients with LDL‐C levels <70 mg/dl were at lower risk for MACE (hazard ratio [HR]: 0.61 [95% CI, 0.39–0.93] p < 0.05). MACE reduction was driven by a decrease in coronary and peripheral events with no significant effect on stroke. Conclusions: Long‐term sustained LDL‐C <70 mg/dl in the clinical practice is associated with reduction in cardiovascular and peripheral vascular events with no apparent effect on stroke. [ABSTRACT FROM AUTHOR]

Objective: To examine the association between county‐level caesarean delivery (CD) rates among women at low risk and morbidity among term newborns. Design: Cross‐sectional study. Setting: Population‐based study of US county‐level birth data from 2015 to 2017. Population: Nulliparous women with term, singleton, vertex‐presenting infants (NTSV) at low risk for morbidity. Methods: The primary exposure was county‐level CD rates. Main outcome measures: The outcome was morbidity among the low‐risk NTSV cohort, categorised as severe (5‐minute Apgar score of ≤3, assisted ventilation for ≥6 hours, severe neurologic injury or seizure, transfer or death) or moderate (5‐minute Apgar score of <7 but >3, administration of antibiotics or assisted ventilation at delivery). We used linear regression models to determine the association between county NTSV CD and neonatal morbidity rates with cluster robust standard errors. Results: The analysis included data from 2 753 522 births in 952 counties from all 48 states. The mean NTSV CD rate was 23.6% (standard deviation 4.8%). The median severe and moderate neonatal morbidity rates were 15.2 (interquartile range, IQR 9.4–23.6) and 52.5 (IQR 33.4–75.7) per 1000 births, respectively. In the unadjusted analysis using the risk‐adjusted exposure and outcome, every percentage point increase in the CD rate of a county was associated with 0.6 (95% CI −0.9, −0.3) and 2.3 fewer (95% CI −3.4, −1.1) cases of severe and moderate neonatal morbidity per 1000 live births. After adjustment for other county factors, the relationships remained significant. These findings were tested in multiple sensitivity analyses. Conclusions: Lower county‐level NTSV CD rates were associated with a small increase in morbidity among term newborns in the USA. Lower county‐level caesarean delivery rates were associated with an increase in morbidity among term newborns in the USA. Lower county‐level caesarean delivery rates were associated with an increase in morbidity among term newborns in the USA. [ABSTRACT FROM AUTHOR]

Objectives: People living with HIV (PLWH) have a high risk of kidney injury. Measurement of serum creatinine, along with proteinuria, is not sensitive to detect early kidney injury. Here, we investigated novel urinary biomarkers of early renal injury in PLWH. Methods: We performed a cross‐sectional study of 166 antiretroviral‐naïve PLWH and 99 HIV‐negative persons who all had an estimated glomerular filtration rate > 90 mL/min/1.73 m2. We compared the levels of seven urinary biomarkers between the two groups using the propensity score matching (PSM) approach and explored the risk factors associated with elevated urinary biomarkers in PLWH. Results: Eighty‐three pairs were successfully matched based on PSM. Compared with the HIV‐negative group, the HIV‐positive group had higher ratios of N‐acetyl‐β‐D‐glucosaminidase (NAG) to urine creatinine (UCr), alpha1‐microglobulin (α1‐M) to UCr, kidney injury marker‐1 (KIM‐1) to UCr, neutrophil gelatinase‐associated lipocalin to UCr, and epidermal growth factor to UCr, whereas the Tamm–Horsfall protein to UCr ratio and the abnormal albumin to UCr ratio were not significantly different. Positive correlations were observed between HIV RNA level and NAG: UCr (rs = 0.32; P < 0.001) and α1‐M:UCr (rs = 0.24; P = 0.002) ratios, and negative correlations were observed between CD4 cell count and NAG:UCr (rs = –0.34; P < 0.001), KIM‐1:UCr (rs = –0.16; P = 0.042) and α1‐M:UCr (rs = –0.36; P < 0.001) ratios. In multivariate linear regression analyses, older age, lower total cholesterol and higher HIV RNA were independently associated with higher NAG:UCr; older age, lower total cholesterol and lower CD4 cell count were independently associated with higher α1‐M:UCr. Conclusions: In comparioson with HIV‐negative participants, PLWH were more likely to have tubular injury. Early antiretroviral treatment might mitigate the development of kidney injury. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to investigate the dynamics of cytomegalovirus (CMV) replication and CMV‐specific immune response recovery after antiretroviral treatment (ART) initiation in patients with advanced HIV infection. Methods: A prospective observational study of patients with HIV infection and CD4 counts of < 100 cells/µL was carried out (September 2015 to July 2018). HIV viral load (VL), CD4 count and CMV VL were determined by quantitative polymerase chain reaction (PCR) at baseline and at 4, 12, 24 and 48 weeks, and CMV‐specific immune response was determined by QuantiFERON‐CMV assay at baseline and 48 weeks. All patients were started on ART but only those with CMV end‐organ disease (EOD) received anti‐CMV treatment. Results: Fifty‐three patients with a median age of 43.6 [interquartile range (IQR) 36.7–52.4] years were included in the study. At baseline, the median CD4 count was 30 cells/µL (IQR 20–60 cells/µL) and the median HIV VL was 462 000 HIV‐1 RNA copies/mL (IQR 186 000–1 300 000 copies/mL). At baseline, 32% patients had detectable CMV viraemia but none had detectable CMV viraemia at 48 weeks. Only one of 53 (1.9%) patients developed EOD during follow‐up. Seven (13.2%) patients were lost to follow‐up and six (11.3%) died; none of the deaths was related to CMV. Similar percentages of patients had a CMV‐specific immune response at baseline (71.7%) and at 48 weeks (70.0%). The magnitude of this response tended to increase over time [median 1.63 (IQR 0.15–5.77) IU/mL at baseline vs. median 2.5 (IQR 0.1–8.325) IU/mL at 48 weeks; P = 0.11]. We did not find any risk factors associated with 48‐week mortality. Conclusions: Although the prevalence of CMV viraemia in patients with advanced HIV infection remains high, achieving a good immunological recovery through ART is enough to suppress CMV viraemia, without an increased risk of CMV EOD. The prevalence of a CMV‐specific immune response was high and endured over time. [ABSTRACT FROM AUTHOR]

Background: The relationship between anticardiolipin (aCL) antibodies and cardiovascular events is uncertain and may vary according to arterial location. Materials and methods: FRENA is an ongoing registry of stable outpatients with symptomatic coronary artery disease (CAD), cerebrovascular disease (CVD) or peripheral artery disease (PAD). The rate of subsequent ischaemic events was cross‐referenced with the presence of aCL antibodies (any isotype, IgG or IgM). Results: As of June 2017, 1387 stable outpatients were recruited. Of these, 120 (8.7%) showed positive levels of aCL antibodies. Over an average follow‐up of 18 months, 250 patients developed subsequent events: 101 myocardial infarction, 57 ischaemic stroke and 92 critical leg events. Patients with positive aCL antibodies had a higher risk of distal artery events (a composite of ischaemic stroke or critical leg events) than patients with undetectable or low levels (rate ratio: 1.66; 95% CI: 1.07‐2.60). However, an association with central coronary events was not found. The multivariate Cox analysis after adjustment for relevant clinical covariates showed that positivity of aCL antibodies is an independent risk factor for distal events (hazard ratio: 1.60; 95% CI: 1.01‐2.55; P <.05). Conclusions: Positivity of aCL antibodies is associated with an increased risk of subsequent distal artery ischaemic events (cerebral or leg arteries) but not coronary artery events. Anticardiolipin antibodies appear to have a different relationship on the localisation of ischaemic events in patients with symptomatic artery disease. [ABSTRACT FROM AUTHOR]

Background: APOE genotype is known as the most important genetic risk factor for developing AD. Understanding the cellular differences between the ApoE isoforms will be crucial for understanding the fundamental pathways that are disrupted in AD and potential pathways that can be therapeutically targeted. Accumulating evidence is suggesting that ApoE isoforms influence the endosomal system, one of the earliest sites affected in AD. However, our understanding of how the isoforms affect the endolysosomal pathway is still limited. We aim to understand how ApoE isoforms affect the endosomal pathway, but also understand the dynamics of the system in the context of ageing and activity. Method: To study cellular changes in neurons we are using primary hippocampal/cortical brain cultures, harvested from ApoE KO mice and targeted replacement mice, expressing human ApoE3 or ApoE4. Neurons in culture have accelerated maturation and with time in culture gradually show signs of age‐like stress. To study ApoE in the context of ageing, mature cultures at 18 days in vitro (DIV18) and more aged cultures at DIV25 were used. To explore how ApoE isoforms adapt to elevated activity DIV18 primary cultures were treated for 48 H with the GABA receptor antagonist bicuculline. Result: Our preliminary data suggests that especially early endosomes are affected in ApoE4 neurons. Interestingly, the appearance of the early endosomes seems to differ depending on both the intracellular localization and time in culture. However, the protein level of the early endosomal marker EEA1 remained unaltered in ApoE4. In addition, preliminary data indicate that ApoE4 has reduced capacity to adjust the endosomal system following 48 hours bicuculline treatment. When studying the trafficking of fluorescently tagged EGF (which has an established endolysosomal route), preliminary results show potential differences between both DIV18 and DIV25 but also between ApoE‐isoforms, suggesting that both time in culture and ApoE isoforms influence endolysosomal trafficking. Conclusion: The endolysosomal pathway is a highly dynamic and important system for all cells, including neurons and is increasingly linked to AD. Our preliminary findings point toward an ApoE isoform effect on endosomal trafficking and that its dynamics might be disrupted by ApoE4. [ABSTRACT FROM AUTHOR]

The practical application of genome‐scale technologies to precision oncology research requires flexible tissue processing strategies that can be used to differentially select both tumour and normal cell populations from formalin‐fixed, paraffin‐embedded tissues. As tumour sequencing scales towards clinical implementation, practical difficulties in scheduling and obtaining fresh tissue biopsies at scale, including blood samples as surrogates for matched 'normal' DNA, have focused attention on the use of formalin‐preserved clinical samples collected routinely for diagnostic purposes. In practice, such samples often contain both tumour and normal cells which, if correctly partitioned, could be used to profile both tumour and normal genomes, thus identifying somatic alterations. Here we report a semi‐automated method for laser microdissecting entire slide‐mounted tissue sections to enrich for cells of interest with sufficient yield for whole genome and transcriptome sequencing. Using this method, we demonstrated enrichment of tumour material from mixed tumour–normal samples by up to 67%. Leveraging new methods that allow for the extraction of high‐quality nucleic acids from small amounts of formalin‐fixed tissues, we further showed that the method was successful in yielding sequence data of sufficient quality for use in BC Cancer's Personalized OncoGenomics (POG) program. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives: National guidelines in Botswana recommend baseline CD4 count measurement and both CD4 and HIV viral load (VL) monitoring post‐antiretroviral therapy (ART) initiation. We evaluated the utility of CD4 count measurement in Botswana in the era of universal ART. Methods: CD4 and VL data were analysed for HIV‐infected adults undergoing CD4 count measurement in 2015–2017 at the Botswana Harvard HIV‐Reference Laboratory. We determined (1) the proportion of individuals with advanced HIV disease (CD4 count < 200 cells/µL) at initial CD4 assessment, (2) the proportion with an initial CD4 count ≥ 200 cells/µL experiencing a subsequent decline in CD4 count to < 200 cells/µL, and (3) the proportion of these immunologically failing individuals who had virological failure. Logistic regression modelling examined factors associated with advanced HIV disease. CD4 count trajectories were assessed using locally weighted scatterplot smoothing (LOWESS) regression. Results: Twenty‐five per cent (3571/14 423) of individuals with an initial CD4 assessment during the study period had advanced HIV disease at baseline. Older age [≥ 35 years; adjusted odds ratio (aOR) 1.9; 95% confidence interval (CI) 1.8–2.1] and male sex were associated with advanced HIV disease. Fifty per cent (7163/14 423) of individuals had at least two CD4 counts during the study period. Of those with an initial CD4 count ≥ 200 cells/µL, 4% (180/5061) experienced a decline in CD4 count to < 200 cells/µL; the majority of CD4 count declines were in virologically suppressed individuals and transient. Conclusions: One‐quarter of HIV‐positive individuals in Botswana still present with advanced HIV disease, highlighting the importance of baseline CD4 count measurement to identify this at‐risk population. Few with a baseline CD4 count ≥ 200 cells/µL experienced a drop below 200 cells/µL, suggesting limited utility for ongoing CD4 monitoring. [ABSTRACT FROM AUTHOR]

Objectives: Understanding the determinants of HIV immune control is important for seeking viable HIV prevention, treatment and curative strategies. The antigen‐specific roles of CD8 T cells in controlling primary HIV infection have been well documented, but their abilities to control the latent HIV reservoir is less well studied. Methods: The scientific literature on this issue was searched on PubMed. Results: Recent reports have demonstrated that CD8 T cells are also involved in the control of viral replication in HIV‐infected individuals receiving antiretroviral therapy (ART). However, based on accumulating evidence, the antiviral role of CD8 T cells in ART patients may not be achieved via an antigen‐specific manner as HIV‐specific CD8 T cells can sense, but not effectively eliminate, cells harbouring intact provirus without first being activated. Our recent study indicated that virtual memory CD8 T cells, a semi‐differentiated component of CD8 T cells, may be involved in the mechanism restraining the HIV DNA reservoir in ART patients. Conclusions: In this review, we summarize recent findings on the role of CD8 T cells in controlling HIV, highlighting differences between conventional antigen‐specific and innate‐like CD8 T cells. A better understanding of the roles of CD8 T cells during HIV infection should benefit the informed design of immune‐based treatment strategies. [ABSTRACT FROM AUTHOR]

Objectives: Elite controllers (ECs), viraemic controllers (VCs), and long‐term nonprogressors (LTNPs) control HIV viral replication or maintain CD4 T‐cell counts without antiretroviral therapy, but may have increased cardiovascular disease (CVD) risk compared to HIV‐uninfected persons. We evaluated subclinical carotid and coronary atherosclerosis and inflammatory biomarker levels among HIV controllers, LTNPs and noncontrollers and HIV‐uninfected individuals in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). Methods: We measured carotid plaque presence and common carotid artery intima‐media thickness (IMT) in 1729 women and 1308 men, and the presence of coronary artery calcium and plaque in a subgroup of men. Associations between HIV control category and carotid and coronary plaque prevalences were assessed by multivariable regression analyses adjusting for demographics and CVD risk factors. Serum inflammatory biomarker concentrations [soluble CD163 (sCD163), soluble CD14 (sCD14), galectin‐3 (Gal‐3), galectin‐3 binding protein (Gal‐3BP) and interleukin (IL)‐6] were measured and associations with HIV control category assessed. Results: We included 135 HIV controllers (30 ECs) and 135 LTNPs in the study. Carotid plaque prevalence and carotid IMT were similar in HIV controllers, LTNPs and HIV‐uninfected individuals. HIV controllers and LTNPs had lower prevalences of carotid plaque compared to viraemic HIV‐infected individuals. The prevalence of coronary atherosclerosis was similar in HIV controllers/LTNPs compared to HIV‐uninfected and viraemic HIV‐infected men. Controllers and LTNPs had higher concentrations of sCD163 and sCD14 compared to HIV‐uninfected persons. Conclusions: Subclinical CVD was similar in HIV controllers, LTNPs and HIV‐uninfected individuals despite elevated levels of some inflammatory biomarkers. Future studies of HIV controllers and LTNPs are needed to characterize the risk of CVD among HIV‐infected persons. [ABSTRACT FROM AUTHOR]

BACKGROUND: Scaling up bioelectrochemical systems for the treatment of wastewater faces challenges. Material costs, low conductivity of wastewater and clogging are issues that need a novel approach. The granular capacitive moving bed reactor can potentially solve these challenges. In this reactor, capacitive activated carbon granules are used as bioanode material. The charge storage capabilities of these capacitive granules allow for the physical separation of the charging and the discharging process and therefore a separation of the wastewater treatment and energy recovery process. RESULTS: This study investigates the performance of the granular capacitive moving bed reactor. In this reactor, activated granules were transported from the bottom to the top of the reactor using a gas lift and settled on top of the granular bed, which moved downwards through the internal discharge cell. This moving granular bed was applied to increase the contact time with the discharge anode to increase the current density. The capacitive moving bed reactor (total volume 7.7 L) produced a maximum current of 23 A m−2 normalized to membrane area (257 A m−3granules). Without granules, the current was only 1.4 A m−2membrane. The activity of the biofilm on the granules increased over time, from 436 up to 1259 A m−3granules. A second experiment produced similar areal current density and increase in activity over time. CONCLUSION: Whereas the produced current density is promising for further scaling up of bioanodes, the main challenges are to improve the discharge of the charged granules and growth of biofilm on the granules under shear stress. © 2019 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

BACKGROUND: The load ratio is a crucial parameter to optimize the current driven recovery of total ammonia nitrogen (TAN) from urine. The load ratio is the ratio between the current density and the TAN loading rate. It is currently not known if the load ratio concept applies to a bioelectrochemical system (BES) because the current density and TAN loading rate cannot be controlled independently. RESULTS: We found a clear increasing trend in TAN removal efficiency with respect to load ratio in the BES for both human and synthetic urine. The maximum TAN removal efficiency was 60.9% at a load ratio of 0.7, corresponding to a TAN transport rate of 119 gN m−2 day−1 at an electrical energy input of 1.9 kWh kgN−1 (synthetic urine). Low load ratios (<1) were obtained, indicating that the current was not enough to transport all the TAN across the membrane. CONCLUSIONS: BES and ES show the same general relationship between TAN removal efficiency and load ratio. Therefore, given a stable current density, the concept of load ratio can also predict the TAN removal efficiency in BES. Higher current densities, and insights into the factors limiting current, are needed to increase the load ratio and therefore the TAN removal efficiency. © 2019 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Summary: The highest rate of human rabies deaths reported in the Americas is in Haiti, and most of these deaths result from rabies virus infections that occur after individuals are bitten by infected dogs and do not receive rabies post‐exposure prophylaxis. One barrier to rabies prevention in Haiti is a lack of knowledge about this disease among healthcare professionals and community members. During the past 4 years, The US Centers for Disease Control and Prevention has collaborated with public health officials and partners to develop, test and refine educational materials aimed at filling this need for rabies education. This report summarizes the use of feedback from knowledge, attitudes and practises surveys; key informant interviews; and focus groups to develop culturally appropriate rabies prevention materials for community members, health officials, clinicians, laboratory professionals, veterinary professionals, government officials and national and local district leaders about ways to prevent rabies. These formative research methods were critically important in ensuring that the materials would be culturally appropriate and would stand the greatest likelihood of motivating Haitians to protect themselves from rabies. Centers for Disease Control and Prevention is using lessons learned in Haiti to develop and test materials in other countries with high rates of canine rabies. [ABSTRACT FROM AUTHOR]

A translational need exists to understand and predict vancomycin-induced kidney toxicity. We describe: (i) a vancomycin high-performance liquid chromatography (HPLC) method for rat plasma and kidney tissue homogenate; (ii) a rat pharmacokinetic (PK) study to demonstrate utility; and (iii) a catheter retention study to enable future preclinical studies. Rat plasma and pup kidney tissue homogenate were analyzed via HPLC for vancomycin concentrations ranging from 3-75 and 15.1-75.5 μg/mL, respectively, using a Kinetex Biphenyl column and gradient elution of water with 0.1% formic acid: acetonitrile (70:30 v/v). Sprague-Dawley rats ( n = 10) receiving 150 mg/kg of vancomycin intraperitoneally had plasma sampled for PK. Finally, a catheter retention study was performed on polyurethane catheters to assess adsorption. Precision was <6.1% for all intra-assay and interassay HPLC measurements, with >96.3% analyte recovery. A two-compartment model fit the data well, facilitating PK exposure estimates. Finally, vancomycin was heterogeneously retained by polyurethane catheters. [ABSTRACT FROM AUTHOR]

Criminal law in dentistry, as shaped and moulded by the prevailing views of society, defines what is or is not socially acceptable. It applies in both personal and professional contexts with the intended consequence of protecting the public from unacceptable conduct and potential imbalances of power. At its centre, a patient's consent plays a pivotal role in transforming unlawful conduct into lawful conduct. This literature review considers the current law and the trend of utilizing criminal law in addition to non-criminal law alternatives of reprimanding clinicians for failure to achieve consent in the course of dental practice. Dentists must appreciate this change and the prosecuting authority's increasing willingness to resort to criminal law. [ABSTRACT FROM AUTHOR]

BACKGROUND Isobutyrate is a platform chemical that is currently produced from a non-renewable fossil-based feedstock. This study aimed at developing a renewable isobutyrate production process by using methanol chain elongation, a novel bioprocess that uses organic waste as primary feedstocks and an undefined reactor microbiome as the catalyst. RESULTS A continuous anaerobic bioreactor experiment was first performed using a synthetic medium containing acetate, butyrate and methanol, all of which are common derivatives from organic residues. Continuous isobutyrate (2.0 g L−1 day−1) and caproate formation (0.2 g L−1 day−1) from methanol, acetate and butyrate were demonstrated. A batch test to synthesise isobutyrate from a real organic waste, i.e. acidified supermarket waste ( ASW), was performed. Up to 6.2 g L−1 isobutyrate was formed which accounted for 63% of all identified products. CONCLUSION In this study, a proof-of-principle for isobutyrate production from organic waste via methanol chain elongation was demonstrated. The continuous accumulation or supply of butyrate, the suppression of methanogenic activity and methanol addition were shown to be of use to provide conditions for isobutyrate formation. © 2016 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND The treatment of source separated urine allows for a more sustainable approach to nutrients recovery in actual wastewater treatment plants. Struvite precipitation from urine yields a slow-release fertilizer (struvite) with a high marketable value for agricultural use. Extensive research on struvite precipitation has been carried out at laboratory scale, but there is still a lack of specific knowledge about the operation and key parameters at larger scale and over the long term. The effectiveness of the struvite reactor was assessed, as well as the quality of the harvested struvite in terms of size and composition. RESULTS The efficiency of recovery of P was maintained at 85-99% for 1 year of continuous operation. Phosphorus was recovered in the form of struvite with purity over 90%. Struvite was harvested as round pellets between 0.3 and 6 mm in diameter, with heavy metals concentration well below the legal limits for fertilizers in The Netherlands. The post-treatment of the reactor effluent yielded almost complete removal (>95%) of calcium and magnesium. A loss of 26 ± 5% of the influent chemical oxygen demand and 16 ± 1% of the NH4+-N occurred during the magnesium ammonium phosphate ( MAP) precipitation and the post-treatment. CONCLUSION This work shows how the treatment of source-separated urine by struvite precipitation in a fluidized bed reactor allows for efficient recovery of phosphorus in the form of a potential fertilizer. © 2016 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

The article focuses on the establishment of the Implementing GeNomics In praTticE (IGNITE) network or Pharmacogenetics Working Group which aim to support the investigation and development of genomic medicine practice models. Topics discussed include the use of pharmacogenetic testing in assisting prescribing decisions, CYP2C19 genotyping for prediction of clopidogrel response, and guide antiplatelet therapy for percutaneous coronary intervention (PCI).

This review aimed to identify childhood and adolescence risk and prognostic factors associated with onset and persistence of persistent abdominal pain and related disability and assess quality of the evidence. While findings suggest a possible role for negative emotional symptoms and parental mental health as risk and prognostic factors for onset and persistence of persistent abdominal pain, the evidence is of poor quality overall and nonexistent when it comes to prognostic factors associated with disability.Conclusion: Further research is needed to increase confidence in existing evidence and to explore new factors. This research will inform prevention. [ABSTRACT FROM AUTHOR]

Objective: To compare bladder sensitivity between patients with pelvic pain and patients who were pain free, undergoing noninvasive, controlled bladder distension via diuresis. We also sought to measure potential mechanisms underlying bladder sensitivity.Design: Prospective observational study.Setting: Community teaching hospital.Population: Reproductive-age women with non-bladder chronic pelvic pain (CPP, n = 23), painful bladder syndrome (PBS, n = 23), and pelvic pain-free controls (n = 42) METHODS: Participants were compared on cystometric capacity, pelvic floor pressure-pain thresholds (PPTs), pelvic muscle function, O'Leary-Sant bladder questionnaire, and psychosocial instruments using Wilcoxon rank-sum tests. Multivariate regression was used to identify factors underlying bladder pain phenotypes.Main Outcome Measures: Pelvic floor pain thresholds; self-reported bladder distension pain.Results: Participants with PBS exhibited higher bladder distension pain than those with CPP, with both groups reporting higher pain levels than controls (P < 0.05). No significant associations were found between bladder distension pain and pelvic muscle structure or pain sensitivity measures; however, bladder distension pain positively correlates with both vaginal PPTs adjacent to the bladder (r = 0.46) and pain with transvaginal bladder palpation (r = 0.56). Pain at maximal distension was less influenced by somatic sensitivity than bladder symptoms (r = 0.35 versus r = 0.59; P < 0.05). Multivariate regression identified three independent components of bladder symptoms in PBS: bladder distension pain, bladder sensation, and somatic symptoms.Conclusions: Diuresis-induced bladder pain differentiates CPP from PBS. Experimental bladder pain is not predicted by pelvic floor sensitivity. Compared with patient-reported outcomes it appears less influenced by psychological factors. Further study is needed to determine whether screening for experimental bladder pain sensitivity could predict future risk of PBS.Tweetable Abstract: Controlled, water ingestion-provoked bladder pain can objectively identify visceral pain sensitivity. [ABSTRACT FROM AUTHOR]

The objective of this study was to model the pharmacokinetics (PKs) of robenacoxib in cats using a nonlinear mixed-effects (NLME) approach, leveraging all available information collected from cats receiving robenacoxib s.c. and/or i.v.: 47 densely sampled laboratory cats and 36 clinical cats sparsely sampled preoperatively. Data from both routes were modeled sequentially using Monolix 4.3.2. Influence of parameter correlations and available covariates (age, gender, bodyweight, and anesthesia) on population parameter estimates were evaluated by using multiple samples from the posterior distribution of the random effects. A bicompartmental disposition model with simultaneous zero and first-order absorption best described robenacoxib PKs in blood. Clearance was 0.502 L/kg/h and the bioavailability was high (78%). The absorption constant point estimate (Ka = 0.68 h−1) was lower than beta (median, 1.08 h−1), unveiling flip-flop kinetics. No dosing adjustment based on available covariates information is advocated. This modeling work constitutes the first application of NLME in a large feline population. [ABSTRACT FROM AUTHOR]

The literature on the pharmacokinetics of vancomycin in patients undergoing extracorporeal membrane oxygenation (ECMO) therapy is sparse. A population pharmacokinetic (PK) model for vancomycin in ECMO patients was developed using a nonlinear mixed effects modeling on the concentration-time profiles of 14 ECMO patients who received intravenous vancomycin. Model selection was based on log-likelihood criterion, goodness of fit plots, and scientific plausibility. Identification of covariates was done using a full covariate model approach. The pharmacokinetics of vancomycin was adequately described with a two-compartment model. Parameters included clearance of 2.83 L/hr, limited central volume of distribution 24.2 L, and low residual variability 0.67%. Findings from the analysis suggest that standard dosing recommendations for vancomycin in non-ECMO patients are adequate to achieve therapeutic trough concentrations in ECMO patients. This further shows that ECMO minimally affects the PK of vancomycin in adults including in higher-weight patients. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the influence of variations in the working angle of the piezoelectric ultrasonic scaler (PUS) on root surfaces. Material and methods: Fifty-five uniradicular bovine teeth were used, of which 25 teeth were used for the analysis of the roughness and root wear, while the remaining 30 teeth were used for the analysis of morphology (MRS) and the attachment of blood components (ABC). The teeth were randomly divided into five groups according to the type of treatment (G1-G5: piezoelectric ultrasonic scaler; G6: manual curette) and to the PUS working angle applied (G1: 0°, G2: 30°, G3: 45°, G4: 60°, G5: 90°). For statistical analysis, the data describing the MRS and ABC were analysed by the Kruskal-Wallis and Dunn's tests, and the data describing the roughness and tooth wear were analysed by ANOVA and Tukey's tests at the significance level of 5%. Results: Manual curette (MC) promoted a smoother root surface than the application of the PUS. The PUS used at the angles of 30°and 45°resulted in a high level of ABC that was comparable to that obtained by MC. Additionally, the group in which the PUS was applied at an angle of 45°exhibited less tooth wear than the other groups. Conclusions: Changes in the working angle of the PUS influenced the characteristics of root surfaces after instrumentation. [ABSTRACT FROM AUTHOR]

Nitrogen fertilizer management is vital to corn (Zea mays L.) production from financial and environmental perspectives. Poultry litter as a nutrient source in this cropping system is generally surface broadcast, potentially causing volatilization of NH3. Recently a new application method was developed allowing subsurface banding of poultry litter with minimal soil surface disturbance. However, there are limited data with this application method on corn production. In this study, we used farm-scale plots (7.6 by 91.2 m) to evaluate the response of notill corn growth and post-harvest soil nutrient concentrations from subsurface poultry litter application. All treatments were applied pre-plant at a rate of 168 kg N ha-1 and included (i) a standard commercial fertilizer surface broadcast, (ii) poultry litter surface applied, and (iii) poultry litter applied in subsurface bands placed 30 cm apart and 8-cm deep below the soil surface. Results showed that poultry litter subsurface banded plots resulted in corn grain and above ground biomass yields similar to plots treated with commercial fertilizer. In 2011, corn grain yield of 11.35 Mg ha-1 produced by the subsurface banded poultry litter treatment was significantly higher when compared to surface applied poultry litter that yielded 10.10 Mg ha-1. Poultry litter application method did not have a significant effect on post-harvest soil pH, total C, total N, NH4+-N, NO3--N, P, and K concentrations. Results from this study suggest that subsurface banding of poultry litter can be utilized as an alternate application method in no-till corn without detrimental impacts on productivity. [ABSTRACT FROM AUTHOR]

The low bioavailability of the anti-migraine drug sumatriptan is partially caused by first-pass hepatic metabolism. In this study, we analyzed the impact of the hepatic organic cation transporter OCT1 on sumatriptan cellular uptake, and of OCT1 polymorphisms on sumatriptan pharmacokinetics. OCT1 transported sumatriptan with high capacity and sumatriptan uptake into human hepatocytes was strongly inhibited by the OCT1 inhibitor MPP+. Sumatriptan uptake was not affected by the Met420del polymorphism, but was strongly reduced by Arg61Cys and Gly401Ser, and completely abolished by Gly465Arg and Cys88Arg. Plasma concentrations in humans with two deficient OCT1 alleles were 215% of those with fully active OCT1 ( P = 0.0003). OCT1 also transported naratriptan, rizatriptan, and zolmitriptan, suggesting a possible impact of OCT1 polymorphisms on the pharmacokinetics of other triptans as well. In conclusion, OCT1 is a high-capacity transporter of sumatriptan and polymorphisms causing OCT1 deficiency have similar effects on sumatriptan pharmacokinetics as those observed in subjects with liver impairment. [ABSTRACT FROM AUTHOR]

Objectives The World Health Organization ( WHO) recommends screening HIV-infected people for cryptococcal antigens to identify cryptococcosis, a major cause of AIDS-related deaths. As the burden of cryptococcosis is unknown in South Africa's Kwa Zulu- Natal province, we assessed the cryptococcal antigenuria prevalence among newly diagnosed HIV-infected adults there. Methods We conducted a cross-sectional study of newly diagnosed HIV-infected adults who received voluntary HIV testing in an out-patient clinic. Participants provided a urine specimen in a sterile container, and we performed testing with a WHO-endorsed rapid cryptococcal antigen lateral flow assay ( Immy Inc., Norman, OK, USA) per the manufacturer's specifications. We assessed cryptococcal antigenuria prevalence among participants with CD4 counts < 200 cells/μL, and stratified results by CD4 count categories. Results Among 432 participants, the mean (± standard deviation) age was 36.1 ± 9.9 years and 172 (40%) were female. The overall estimated prevalence of cryptococcal antigenuria was 9.0% [95% confidence interval ( CI) 6.5-12.1%]. CD4 counts were available for 319 participants (74%); the median CD4 count was 75 cells/μL [interquartile range ( IQR) 34-129 cells/μL]. Participants with a negative cryptococcal antigenuria screening test had a median CD4 count of 79 cells/μL ( IQR 36-129 cells/μL), while participants with a positive cryptococcal test had a median CD4 count of 41 cells/μL ( IQR 10-112 cells/μL). The estimated prevalence of cryptococcal antigenuria among participants with CD4 counts < 50 cells/μL was 12.5% (95% CI 7.0-20.1%), which was significantly higher than that among participants with CD4 counts of 50-200 cells/μL (4.8%; 95% CI 2.3-8.7%). Conclusions Nearly 1 in 10 newly diagnosed HIV-infected adults with CD4 counts < 200 cells/μL in Kwa Zulu-Natal had evidence of cryptococcal antigenuria. Point-of-care CD4 count testing and cryptococcal antigen screening may rapidly identify cryptococcosis at the time of HIV diagnosis. [ABSTRACT FROM AUTHOR]

Contents Pregnancy-associated glycoproteins ( PAG) are secreted by the binucleate giant cells of the ruminant placenta and enter maternal circulation at the time of placental attachment. The IDEXX Milk Pregnancy Test ( IDEXX, Westbrook, ME) detects a subset of PAG in milk. Although designed as a management tool for dairy cows, there is potential for using the milk PAG test in beef cows. Our objective was to compare the performance of the milk PAG ELISA with a gold standard method for pregnancy diagnosis and determine the agreement between milk and serum PAG analysis in lactating beef cows. Angus and Angus-crossed cows (n = 332) from two Michigan beef herds were enrolled in this study. Cows were subjected either to timed artificial insemination followed by exposure to a bull or exclusively exposed to a bull. The bulls and cows were separated 30 days prior to examination. Serum and milk samples were collected and submitted within 24 h of collection to a commercial laboratory for PAG analysis using the IDEXX Milk Pregnancy Assay (milk) and the IDEXX Bovine Pregnancy Assay (serum). Concurrently with milk and serum collection, each cow was examined transrectally by palpation or ultrasonography. When compared to transrectal examination, the performance (and 95% confidence intervals) of the milk PAG ELISA was sensitivity of 99.7% (99.0-100.0%) and specificity of 80.8% (65.6-95.9%). The lower specificity is likely due to the low prevalence (9.9%) of open cows (n = 30) in the herds examined. Of the 332 cows examined, 1.8% (n = 6) were classified as rechecks using the milk PAG ELISA. Results of the milk and serum PAG ELISA were in high agreement (kappa coefficient = 0.91). The milk PAG ELISA was accurate in predicting pregnancy status using milk collected from beef cattle between days 37 and 125 post-insemination and may be useful for aiding management decisions in beef herds. [ABSTRACT FROM AUTHOR]

Societal change through an increase in knowledge and accessibility of education as well as a push for autonomy has con-tributed to a shift in the balance of power from clinician to patient (especially in the last 20 years). This drive for personal autonomy has seen a shift from medical paternalism, a consequence of ignorance, to personal autonomy, a continuously evolving by-product of 17th century liberalism as expressed and facilitated by access of information. Consequently, patient-centred care has become the new standard for health care involving a two-way communication process of shared information and informed decision-making. At its centre is the patient's right to accept or decline treatment recommended by a clinician, be it detrimental or beneficial. Clinicians must recognize and appreciate this shift to patient-centred care and its legal ramifications. [ABSTRACT FROM AUTHOR]

Objectives The risks and benefits of initiating antiretroviral treatment ( ART) at high CD4 cell counts have not been reliably quantified. The Strategic Timing of AntiRetroviral Treatment ( START) study is a randomized international clinical trial that compares immediate with deferred initiation of ART for HIV-positive individuals with CD4 cell counts above 500 cells/μL. We describe the demographics, HIV-specific characteristics and medical history of this cohort. Methods Data collected at baseline include demographics, HIV-specific laboratory values, prior medical diagnoses and concomitant medications. Baseline characteristics were compared by geographical region, gender and age. Results START enrolled 4685 HIV-positive participants from 215 sites in 35 countries. The median age is 36 years [interquartile range ( IQR) 29-44 years], 27% are female, and 45% self-identify as white, 30% as black, 14% as Latino/Hispanic, 8% as Asian and 3% as other. The route of HIV acquisition is reported as men who have sex with men in 55% of participants, heterosexual sex in 38%, injecting drug use in 1% and other/unknown in 5%. Median time since HIV diagnosis is 1.0 year ( IQR 0.4-3.0 years) and the median CD4 cell count and HIV RNA values at study entry are 651 cells/μL ( IQR 584-765 cells/μL) and 12 754 HIV RNA copies/mL ( IQR 3014-43 607 copies/mL), respectively. Conclusions START has enrolled a diverse group of ART-naïve individuals with high CD4 cell counts who are comparable to the HIV-positive population from the regions in which they were enrolled. The information collected with this robust study design will provide a database with which to evaluate the risks and benefits of early ART use for many important outcomes. [ABSTRACT FROM AUTHOR]

Brain tumor diagnosis has an extremely poor prognosis, due in part to the blood-brain barrier (BBB) that prevents both early diagnosis and effective drug delivery. The infiltrative nature of primary brain tumors and the presence of micro-metastases lead to tumor cells that reside behind an intact BBB. Recent genomic technologies have identified many genetic mutations present in glioma and other central nervous system (CNS) tumors, and this information has been instrumental in guiding the development of molecularly targeted therapies. However, the majority of these agents are unable to penetrate an intact BBB, leading to one mechanism by which the invasive brain tumor cells effectively escape treatment. The diagnosis and treatment of a brain tumor remains a serious challenge and new therapeutic agents that either penetrate the BBB or disrupt mechanisms that limit brain penetration, such as endothelial efflux transporters or tight junctions, are required in order to improve patient outcomes in this devastating disease. [ABSTRACT FROM AUTHOR]

Objective This study aimed to provide an indication of the prevalence and severity of anthelmintic resistance (AR) in the Australian sheep industry by compiling the results of faecal worm egg count reduction tests (FECRTs). Methods Government and private parasitology laboratories, pharmaceutical companies and veterinarians known to have conducted FECRTs were asked to provide results that conformed to Australian and New Zealand standard diagnostic procedures. Results Data were available from a total of 390 tests, with larval differentiation conducted in 222 cases. Pooled results from all states for the macrocyclic lactone (ML) class showed a lower prevalence of AR against combined species for moxidectin (54%) compared with abamectin (77%) and ivermectin (87%). Analysis by state revealed higher levels of ML-resistant Teladorsagia sp. in Tasmania and Western Australia than in other states and ML-resistant Haemonchus sp. was more frequently detected in New South Wales. Conclusion This compilation of results of FECRTs conducted by Australian parasitology laboratories in 2009-12 showed widespread AR of the common sheep nematodes ( Teladorsagia, Trichostrongylus and Haemonchus) to all broad-spectrum anthelmintics, with the exception of monepantel, whether used singly or in combination. [ABSTRACT FROM AUTHOR]

Objective To demonstrate the protection of Merino sheep from flystrike by Lucilia cuprina with cyromazine or dicyclanil in an implant study and in the field. Methods In the implant study, sheep were treated with cyromazine or dicyclanil and implanted with 1st-stage larvae from a newly isolated field strain of L. cuprina ( CYR-LS) or a reference strain ( DZR50), then assessed over 3 days and compared with the implants on untreated control sheep. In the field study, weaner lambs were treated with cyromazine or dicyclanil and monitored weekly for flystrike over 18 weeks of grazing on the same farm from which the L. cuprina were isolated. Results Implant study: cyromazine (6%) provided effective protection against CYR-LS and DZR50 L. cuprina for a minimum of 13 and 10 weeks, respectively. Dicyclanil (5%) provided at least 18 weeks' protection against both strains. Field study: only 1 of 386 lambs in the cyromazine-treated group was struck in the first 14 weeks of the trial. No strikes occurred in the 198 sheep treated with dicyclanil (5%). Rainfall, temperature and flytrap data indicated consistent fly pressure during the study. Conclusions Based on the results of these studies, there was no evidence of reduced susceptibility to cyromazine or dicyclanil and the periods of protection of sheep against L. cuprina were unaffected and consistent with the registered label claims. [ABSTRACT FROM AUTHOR]

Contents This short communication reports the impact of endometrial biopsies, uterine flushings and follicular fluid aspiration procedures at day 6 post artificial insemination ( AI) on pregnancy rates. In Experiment 1, cows were timed AI ( TAI) and assigned to the following treatment groups: control (n = 37), uterine flushing (n = 35) and endometrial biopsy (n = 38). On day 30 post AI, pregnancy rates were 40.5%, 33% and 28.5%, respectively (p > 0.1). Pregnancy rate on day 60 was lower (p < 0.004) in flushed cows than in the controls. In Experiment 2, oestrus was detected and cows were assigned to flushing (n = 32) or biopsy (n = 33) treatments 6 days after AI, which resulted in pregnancy rates of 31% and 36%, respectively (p > 0.1). In Experiment 3, cows were, 6 days after TAI, randomly assigned to the following treatments: control (n = 84) or aspiration of the largest follicle (n = 73). Pregnancy rates on day 30 post AI were 63.5% for the control group and 53% for the aspirated group (p > 0.1). In conclusion, uterine flushing and endometrial biopsy negatively affect pregnancy rates, but neither procedure can be considered to be incompatible with pregnancy maintenance. Follicular aspiration during pregnancy does not interact with pregnancy success. The amount and quality of samples obtained are compatible with the use of cellular and molecular analysis of uterine variables from cows that failed or succeeded on maintaining pregnancy. [ABSTRACT FROM AUTHOR]

Objective This 1-month longitudinal study assessed whether the oral status and the oral-health-related quality of life ( OHRQoL) of children changed after four sessions of an educational preventive programme. Study population and methods Fifty Brazilian students (11-12 year old) were examined for signs and symptoms of gingivitis using the Community Periodontal Index and two questions about gingival bleeding. The OHRQoL was measured using the Brazilian Portuguese version of the Child Oral Impacts on Daily Performances (Child- OIDP). Higher scores indicated worse OHRQoL. The results were analysed using the Shapiro-Wilk, Chi-square, Wilcoxon signed-rank and Mann-Whitney tests. The magnitude of the mean change was calculated using the effect size. Results Twenty-four percentage of children had more than six sites with bleeding at follow-up compared with 58% at baseline. There was a significant decline in the intensity and extension of impacts at follow-up. A significant improvement in the clinical status and oral hygiene was observed for both transitional categories. There was a significant decline in the Child- OIDP scores of those reporting 'much improved'. A significant improvement in the global ratings of oral health was observed at follow-up. Conclusions In the studied sample, an improvement occurred with respect to the severity of disease, intensity and extension of impacts and global ratings of oral health after 1-month follow-up. These results suggest that improving the global transition in health by enhancing coping and management skills while inducing slight changes in the clinical status and the specific aspects of health compromised by the disease is possible. [ABSTRACT FROM AUTHOR]

Nitrogen is one of the most important and costly nutrient inputs for crop production. Farmers are looking for better management practice to enhance production and reduce environmental impact. A 3-yr field study was established to examine corn (Zea mays L.) grain yield and nutrient uptake resulting from application of 168 kg N ha-1 as urea (U), urea-ammonium nitrate (UAN), ammonium nitrate (NH4NO3), poultry litter (PL), and similar rate of commercially available enhanced-efficiency nitrogen fertilizers (EENF) as follow: polymer-coated urea (ESN), SuperU, UAN + AgrotainPlus, and PL + AgrotainPlus in a no-till corn production. Treatments were replicated four times in a completely randomized block design from 2009 to 2011. Aboveground plant biomass was harvested at physiological maturity each year to determine dry matter and nutrient uptake. Soil samples were taken three times per year to evaluate the status of the selected nutrients in soil. There was a significant increase in corn aboveground dry matter and grain yield with application of 168 kg N ha-1 compared with control treatment. There was no significant difference in corn grain yield or dry matter among the N sources. However, averaged across all N sources, corn grain yield (10.1 Mg ha-1) in 2009 was greater than grain yield (7.5 Mg ha-1) in 2010 and 2011, mainly due to higher rainfall and better distribution in 2009. Addition of AgrotainPlus to UAN and PL did not influence corn grain yield. Additional research is needed to evaluate EENFs under different climatic conditions and different management practices. [ABSTRACT FROM AUTHOR]

Studies suggest that patients carrying a BRCA variant of uncertain significance ( VUS) may have lingering confusion concerning results interpretation. Counseling for uninformative BRCA-negative ( UN) results is thought to be more straightforward, despite the fact that both results lead to similar methods of empiric cancer risk counseling. This study compared surgical choices and perceptions between 71 patients with VUS results and 714 patients with UN results. All patients underwent genetic counseling because of a personal or family history of breast or ovarian cancer between 1997 and 2010, and completed a 2-year follow-up survey. Risk-reducing mastectomy rates in both groups were 7% (p = 1.00) and risk-reducing oophorectomy rates were 5% and 3%, respectively (p = 0.42). The VUS group reported less cancer distress reduction than the UN group (23.0% vs 35.8%, respectively, p = 0.043). Over 90% of both groups found the counseling process helpful. Overall, the study suggests that VUS results disclosed in genetic counseling did not cause excessive surgery or exaggerated cancer distress, though patients with a VUS found counseling somewhat less informative or reassuring. Future research on communication of VUS results, including pre-and post-test counseling, is essential for full realization of the potential for genomic medicine. [ABSTRACT FROM AUTHOR]

Whole exome sequencing and chromosomal microarrays are two powerful technologies that have transformed the ability of researchers to search for potentially causal variants in human disease. This study combines these tools to search for causal variants in a patient found to have maternal uniparental isodisomy of chromosome 2. This subject has a complex phenotype including skeletal and renal dysplasia, immune deficiencies, growth failure, retinal degeneration and ovarian insufficiency. Eighteen non-synonymous, rare homozygous variants were identified on chromosome 2. Additionally, five genes with compound heterozygous mutations were detected on other chromosomes that could lead to a disease phenotype independent of the uniparental disomy found in this case. Several candidate genes with potential connection to the phenotype are described but none are definitively proven to be causal. This study highlights the potential for detection of a large number of candidate genes using whole exome sequencing complicating interpretation in both the research and clinical settings. Forums must be created for publication and sharing of detailed phenotypic and genotypic reports to facilitate further biological discoveries and clinical counseling. [ABSTRACT FROM AUTHOR]

Contents The objectives of this study were to assess the efficiency of polarized light microscopy ( PLM) in detecting microtubule-polymerized protein in in vitro-matured bovine oocytes; to examine its effects on oocyte developmental competence; and to assess the meiotic spindle of in vitro-matured oocytes after vitrification/warming and further assessment of oocyte developmental competence. In the first experiment, the presence of microtubule-polymerized protein ( MPP) was confirmed as a positive PLM signal detected in 99.1% of analysed oocytes (n = 115), which strongly correlated ( r = 1; p < 0.0001) with the presence of MPP as confirmed by immunostaining. In the second experiment, oocytes (n = 651) were exposed or not (controls) to PLM for 10 min and then fertilized and cultured in vitro. Oocytes exposed to PLM did not significantly differ from controls with regard to cleavage, total blastocyst and expanded blastocyst rates and cell numbers. In the third experiment, meiotic spindles were detected in 145 of 182 oocytes (79.6%) following vitrification and warming. Interestingly, after parthenogenetic activation and in vitro culture, oocytes that displayed a positive PLM signal PLM(+) differed significantly from PLM(−) in cleavage and Day 8 blastocyst rates. These results suggest that polarized light microscopy is an efficient system to detect microtubule-polymerized protein in in vitro-matured bovine oocytes and does not exert detrimental effects on bovine oocyte developmental competence. Moreover, PLM could be used as a tool to assess post-warming viability in vitrified bovine oocytes. [ABSTRACT FROM AUTHOR]

Contents This work analyses the effects of a high hydrostatic pressure (HHP) treatment on in vitro survival of in vitro produced (IVP) bovine embryos vitrified with the Cryologic Vitrification Method (CVM). Consequences on embryo quality in terms of cell proliferation and differentiation, and levels of embryonic Heat Shock Protein 70 (Hsp-70) were also examined. Day 7 and 8 bovine in vitro-produced blastocysts were submitted to an HHP treatment (60 MPa, at 32°C for 1 h) and allowed to recover for 1 or 2 h in culture medium. The HHP treatment did not improve blastocyst survival rates after vitrification/warming. Survival (24 h post-warming) and hatching (48 h post-warming) rates were 79.3 ± 4.9 and 51.8 ± 4.2 vs 73.9 ± 4.2 and 44.7 ± 4.1 for untreated controls and HHP-treated embryos, respectively. Total cell numbers measured in fresh embryos were reduced after 1 h at 32°C, with or without HHP treatment, indicating that cell proliferation was stopped as a result of stress. Vitrified HHP-treated embryos that hatched at 48 h after warming showed increased cell numbers in their ICM compared with untreated controls (50.2 ± 3.1 vs 38.8 ± 2.7), indicating higher embryo quality. Treatment of blastocysts with HHP did not alter the level of the Hsp-70 protein. In our conditions, HHP treatment did not affect the cryoresistance of these embryos. However, combination of HHP treatment and vitrification in fibreplugs resulted in an increase in the ICM cell number of hatched embryos 48 h post-warming. [ABSTRACT FROM AUTHOR]

Background: Plasma exchange (PEX) treatment for patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has risk for major complications.Study Design and Methods: Data for PEX-related complications have been prospectively collected on all patients enrolled in the Oklahoma TTP-HUS Registry, 1996 to 2011. PEX-related complications have been defined as major or minor and as central venous catheter related or plasma related.Results: During 15 years, 1996 to 2011, 72 (24%) of 302 consecutive patients had major PEX-related complications. Analysis of five consecutive 3-year cohorts demonstrated that there has been a significant trend for decreasing frequency of all PEX-related major complications (p = 0.014) and central venous catheter-related major complications (p = 0.021) but not for the less common plasma-related major complications (p = 0.380). ADAMTS13 activity was measured in 288 (95%) of the 302 patients. Analysis of the 66 patients with ADAMTS13 activity of less than 10% demonstrated a significant trend for decreasing frequency of PEX-related major complications (p = 0.036); the trend for the 222 patients with ADAMTS13 activity of at least 10% was not significant (p = 0.118). The decreased frequency of PEX-related major complications among patients with ADAMTS13 activity of less than 10% may be related to a significant trend for decreasing duration of PEX treatment (p = 0.040) and decreasing frequency of requirement for more than one central venous catheter (p = 0.044). The decreased duration of PEX treatment may be related to increased use of adjunctive treatments: corticosteroids (p < 0.001) and rituximab (p < 0.001).Conclusions: The frequency of PEX-related major complications has decreased from 1996 to 2011, possibly related to increased use of corticosteroids and rituximab and the decreased duration of PEX required to achieve remission. [ABSTRACT FROM AUTHOR]