Absolute risk reduction in total mortality with implantable cardioverter defibrillators: analysis of primary and secondary prevention trial data to aid risk/benefit analysis.
Absolute risk reduction (ARR) and number needed to treat (NNT) are considered by many to be the most appropriate figures to use for the informed consent process, yet the results of published implantable cardioverter defibrillators (ICD) trials are frequently presented as relative risk reduction or odds ratio. The period over which risk reduction is calculated also varies between trials, making comparison difficult. Published ICD trials used to formulate national and international guidelines were examined for 1, 2, and 3 year total mortality in ICD and medically treated patients. The number of patients enrolled and at risk at these time points were also sought. Where the raw data were not included in the original text, estimates were taken from published Kaplan-Meier graphs. Eight primary prevention (PP) trials, three secondary prevention (SP) trials, and one SP meta-analyses were included. For PP, ARR at 3-year follow-up ranged from 0 (no benefit) to 24.6% (NNT = 4). For SP, ARR at 3-year follow up ranged from 3.7% (NNT = 27) to 11.3% (NNT = 9). Absolute risk reduction increased with follow-up in PP trials, whereas there was considerable variation in SP trials. Overall, very few trial patients received 3-year follow-up, giving wide confidence intervals (CIs). Absolute risk reduction from ICD trials varies significantly depending upon trial entry criteria, subgroup characteristics, and duration of follow-up. The relatively small number of patients followed for 2 or more years leads to wide CIs. Despite these limitations, the standardized ARR and NNT data presented may give a more individualized estimate of risk/benefit that could potentially aid an informed consent process.


Effects of moderate drinking during pregnancy on placental gene expression.
Many children adversely affected by maternal drinking during pregnancy cannot be identified early in life using current diagnostic criteria for fetal alcohol spectrum disorder (FASD). We conducted a preliminary investigation to determine whether ethanol-induced alterations in placental gene expression may have some utility as a diagnostic indicator of maternal drinking during pregnancy and as a prognostic indicator of risk for adverse neurobehavioral outcomes in affected offspring. Pregnant Long-Evans rats voluntarily consumed either a 0 or 5% ethanol solution 4 h each day throughout gestation. Ethanol consumption produced a mean maternal daily intermittent peak serum ethanol concentration of 84 mg/dL. Placentas were harvested on gestational day 20 for gene expression studies. Microarray analysis of more than 28,000 genes revealed that the expression of 304 known genes was altered twofold or greater in placenta from ethanol-consuming dams compared with controls. About 76% of these genes were repressed in ethanol-exposed placentas. Gene expression changes involved proteins associated with central nervous system development; organ morphogenesis; immunological responses; endocrine function; ion homeostasis; and skeletal, cardiovascular, and cartilage development. To date, quantitative real-time polymerase chain reaction analysis has confirmed significant alterations in gene expression for 22 genes, including genes encoding for three calcium binding proteins, two matrix metalloproteinases, the cannabinoid 1, galanin 2 and toll-like receptor 4, iodothyronine deiodinase 2, 11-β hydroxysteroid dehydrogenase 2, placental growth factor, transforming growth factor alpha, gremlin 1, and epithelial growth factor (EGF)-containing extracellular matrix protein. These results suggest that the expression of a sufficiently large number of placental mRNAs is altered after moderate drinking during pregnancy to warrant more detailed investigation of the placenta as a biomarker system for maternal drinking during pregnancy and as an early indicator of FASD. Furthermore, these results provide new insights into novel mechanisms on how ethanol may directly or indirectly mediate its teratogenic effects through alterations in placental function during pregnancy.


Identification at the crime scene: The sooner, the better? The interpretation of rapid identification information by CSIs at the crime scene.
New technologies will allow Crime Scene Investigators (CSIs) in the near future to analyse traces at the crime scene and receive identification information while still conducting the investigation. These developments could have considerable effects on the way an investigation is conducted. CSIs may start reasoning based on possible database-matches which could influence scenario formation (i.e. the construction of narratives that explain the observed traces) during very early phases of the investigation. The goal of this study is to gain more insight into the influence of the rapid identification information on the reconstruction of the crime and the evaluation of traces by addressing two questions, namely 1) is scenario formation influenced from the moment that ID information is provided and 2) do database matches influence the evaluation of traces and the reconstruction of the crime. We asked 48 CSIs from England to investigate a potential murder crime scene on a computer. Our findings show that the interpretation of the crime scene by CSIs is affected by the moment identification information is provided. This information has a higher influence on scenario formation when provided after an initial scenario has been formed. Also, CSIs seem to attach great value to traces that produce matches with databases and hence yield a name of a known person. Similar traces that did not provide matches were considered less important. We question whether this kind of selective attention is desirable as it may cause ignorance of other relevant information at the crime scene.


The Arabidopsis RGA gene encodes a transcriptional regulator repressing the gibberellin signal transduction pathway.
The recessive rga mutation is able to partially suppress phenotypic defects of the Arabidopsis gibberellin (GA) biosynthetic mutant ga1-3. Defects in stem elongation, flowering time, and leaf abaxial trichome initiation are suppressed by rga. This indicates that RGA is a negative regulator of the GA signal transduction pathway. We have identified 10 additional alleles of rga from a fast-neutron mutagenized ga1-3 population and used them to isolate the RGA gene by genomic subtraction. Our data suggest that RGA may be functioning as a transcriptional regulator. RGA was found to be a member of the VHIID regulatory family, which includes the radial root organizing gene SCARECROW and another GA signal transduction repressor, GAI. RGA and GAI proteins share a high degree of homology, but their N termini are more divergent. The presence of several structural features, including homopolymeric serine and threonine residues, a putative nuclear localization signal, leucine heptad repeats, and an LXXLL motif, indicates that the RGA protein may be a transcriptional regulator that represses the GA response. In support of the putative nuclear localization signal, we demonstrated that a transiently expressed green fluorescent protein-RGA fusion protein is localized to the nucleus in onion epidermal cells. Because the rga mutation abolished the high level of expression of the GA biosynthetic gene GA4 in the ga1-3 mutant background, we conclude that RGA may also play a role in controlling GA biosynthesis.


Utility of the Neuropsychological Assessment Battery in detecting cognitive impairment after unilateral stroke.
This study evaluated the clinical utility of the Neuropsychological Assessment Battery (NAB) in a stroke sample by examining the NAB's ability to differentiate a chronic stroke group with radiologically confirmed unilateral damage (n = 42) and a demographically matched healthy control (HC) group (n = 36). The stroke group performed more poorly than the control group across NAB Total score and all five Domain scores. Receiver operator curves (ROC) were derived and area under the curve (AUC) showed moderate diagnostic effectiveness (AUC .70 to .90) for NAB Total score, all five Domain scores, a motor composite, and a Global Deficit Score (GDS) that has been shown to closely approximate clinical ratings of neuropsychological impairment. The NAB Total, GDS, and motor composite had comparable clinical utility, whereas the Attention and Executive domain scores demonstrated better classification utility compared with the Memory domain. Because 90.5% of our stroke sample had middle cerebral artery territory strokes, the comparison of motor and cognitive classification utility may be biased. However, follow-up analyses showed that the NAB accounted for additional variance even when motor composite was included in the model. Sensitivity, specificity, and odds ratios at various clinical cutoffs are provided. These results suggest that the NAB is a useful clinical tool for detection of cognitive deficits in individuals with chronic unilateral stroke, although lenient clinical cutoffs appear warranted to maximize sensitivity.


Cholinergic modulation of Pavlovian fear conditioning in rats: differential effects of intrahippocampal infusion of mecamylamine and methyllycaconitine.
The cholinergic system has consistently been implicated in Pavlovian fear conditioning. Considerable work has been done to localize specific nicotinic receptor subtypes in the hippocampus and determine their functional importance; however, the specific function of many of these subtypes has yet to be determined. An alpha7 nicotinic antagonist methyllycaconitine (MLA) (35 microg), and a broad spectrum non-alpha7 nicotinic antagonist mecamylamine (35 microg) was injected directly into the dorsal hippocampus or overlying cortex either 15 min pre-, 1 min post-, or 6h post-fear conditioning. One week after conditioning, retention of contextual and cue (tone) conditioning were assessed. A significant impairment in retention of contextual fear was observed when mecamylamine was injected 15 min pre- and 1 min post-conditioning. No significant impairment was observed when mecamylamine was injected 6h post-conditioning. Likewise, a significant impairment in retention of contextual fear was observed when MLA was injected 1 min post-conditioning; however, in contrast, MLA did not show any significant impairments when injected 15 min pre-conditioning, but did show a significant impairment when injected 6h post-conditioning. There were no significant impairments observed when either drug was injected into overlying cortex. No significant impairments were observed in cue conditioning for either drug. In general, specific temporal dynamics involved in nicotinic receptor function were found relative to time of receptor dysfunction. The results indicate that the greatest deficits in long-term retention (1 week) of contextual fear are produced by central infusion of MLA minutes to hours post-conditioning or mecamylamine within minutes of conditioning.


Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial.
Studies conducted by the Eastern Cooperative Oncology Group (ECOG) indicate both paclitaxel and carboplatin are associated with an improvement in 1-year survival in patients with stage IV non-small-cell lung cancer (NSCLC). Based on these findings, a phase II trial of these agents in combination was conducted in patients with advanced NSCLC. Eligibility included previously untreated stage IIIB or IV NSCLC patients with a good performance status (PS). Paclitaxel (135 or 175 mg/m2) was administered by 24-hour infusion on day 1, followed by a 1-hour infusion of carboplatin on day 2 (300 mg/m2 or dosed to an area under the concentration-time curve [AUC] of 6 mg/mL.min). Treatment was repeated every 28 days for a total of six cycles. Hematopoietic growth factors were not routinely used. Among 51 eligible patients, there were no complete and 14 partial responses, for an overall response rate of 27% (95% confidence interval [CI], 17% to 41%). The median progression-free survival time was 23.8 weeks (range, 12.1 to 73.9) and median survival time, 38 weeks. The survival rate at 1 year was 32%. Grade 3 or 4 granulocytopenia and thrombocytopenia were observed in 47% and 3%, respectively, of the 184 treatment cycles administered. The most common nonhematologic toxicities included nausea and emesis, neuropathy, and arthralgia/myalgia. Paclitaxel plus carboplatin is a moderately active regimen in patients with advanced NSCLC and warrants comparison with existing cisplatin-based regimens in a prospective randomized trial. The toxicities of this regimen are well tolerated in patients with a good PS.


Members of the public in the USA, UK, Canada and Australia expressing genetic exceptionalism say they are more willing to donate genomic data.
Public acceptance is critical for sharing of genomic data at scale. This paper examines how acceptance of data sharing pertains to the perceived similarities and differences between DNA and other forms of personal data. It explores the perceptions of representative publics from the USA, Canada, the UK and Australia (n = 8967) towards the donation of DNA and health data. Fifty-two percent of this public held 'exceptionalist' views about genetics (i.e., believed DNA is different or 'special' compared to other types of medical information). This group was more likely to be familiar with or have had personal experience with genomics and to perceive DNA information as having personal as well as clinical and scientific value. Those with personal experience with genetics and genetic exceptionalist views were nearly six times more likely to be willing to donate their anonymous DNA and medical information for research than other respondents. Perceived harms from re-identification did not appear to dissuade publics from being willing to participate in research. The interplay between exceptionalist views about genetics and the personal, scientific and clinical value attributed to data would be a valuable focus for future research.


No evidence for genome editing in mouse zygotes and HEK293T human cell line using the DNA-guided Natronobacterium gregoryi Argonaute (NgAgo).
A recently published research article reported that the extreme halophile archaebacterium Natronobacterium gregoryi Argonaute enzyme (NgAgo) could cleave the cellular DNA under physiological temperature conditions in cell line and be implemented as an alternative to CRISPR/Cas9 genome editing technology. We assessed this claim in mouse zygotes for four loci (Sptb, Tet-1, Tet-2 and Tet-3) and in the human HEK293T cell line for the EMX1 locus. Over 100 zygotes were microinjected with nls-NgAgo-GK plasmid provided from Addgene and various concentrations of 5'-phosphorylated guide DNA (gDNA) from 2.5 ng/μl to 50 ng/μl and cultured to blastocyst stage of development. The presence of indels was verified using T7 endonuclease 1 assay (T7E1) and Sanger sequencing. We reported no evidence of successful editing of the mouse genome. We then assessed the lack of editing efficiency in HEK293T cell line for the EMX1 endogenous locus by monitoring the NgAgo protein expression level and the editing efficiency by T7E1 assay and Sanger sequencing. We reported that the NgAgo protein was expressed from 8 hours to a maximum expression at 48 hours post-transfection, confirming the efficient delivery of the plasmid and the gDNA but no evidence of successful editing of EMX1 target in all transfected samples. Together our findings indicate that we failed to edit using NgAgo.


[Analysis on adulthood weight change in adults in China].
Objective: To understand the characteristics of adulthood weight change through the analysis on data from China Kadoorie Biobank (CKB) Study of 0.5 million adults from ten areas in China. Methods: An electronic questionnaire was used to collect the information about the body weight at age 25 years, social-demographic characteristics and lifestyle of the study subjects and their body weight were measured. After excluding the adults with self-reported histories of coronary heart disease, stroke, cancer or diabetes and those who had no data of body weight at age 25 years and those aged outside of 35-70 years, a total of 360 903 adults were included in the analysis. Adulthood weight change were defined as difference value between current body weight and body weight at age 25 years. Results: The mean adulthood weight change of the participants was 4.9 kg. The adults living in urban area showed more body weight increase compared with those living in rural area, so did the adults in northern area compared with those in southern area. Among the ten areas in China, Qingdao reported the highest adulthood weight increase (9.3 kg), and Gansu reported the lowest adulthood weight increase (1.5 kg). Older adults had higher BMI at early adulthood (25 years old), but the adults aged 45-50 years had the highest adulthood body weight increase. Adults with higher educational level, higher household income level, but lower physical activity level had more body weight increase, while current smokers, farmers and workers had less body weight increase. BMI at age 25 years was negatively associated with adulthood body weight change, but current BMI was positively associated with adulthood body weight change (P<0.001). Conclusion: Adulthood body weight change varied greatly among population with different demographic characteristics and lifestyle and in ten areas in China.


Oxygen extraction fraction mapping at 3 Tesla using an artificial neural network: A feasibility study.
The oxygen extraction fraction (OEF) is an important biomarker for tissue-viability. MRI enables noninvasive estimation of the OEF based on the blood-oxygenation-level-dependent (BOLD) effect. Quantitative OEF-mapping is commonly applied using least-squares regression (LSR) to an analytical tissue model. However, the LSR method has not yet become clinically established due to the necessity for long acquisition times. Artificial neural networks (ANNs) recently have received increasing interest for robust curve-fitting and might pose an alternative to the conventional LSR method for reduced acquisition times. This study presents in vivo OEF mapping results using the conventional LSR and the proposed ANN method. In vivo data of five healthy volunteers and one patient with a primary brain tumor were acquired at 3T using a gradient-echo sampled spin-echo (GESSE) sequence. The ANN was trained with simulated BOLD data. In healthy subjects, the mean OEF was 36 ± 2% (LSR) and 40 ± 1% (ANN). The OEF variance within subjects was reduced from 8% to 6% using the ANN method. In the patient, both methods revealed a distinct OEF hotspot in the tumor area, whereas ANN showed less apparent artifacts in surrounding tissue. In clinical scan times, the ANN analysis enables OEF mapping with reduced variance, which could facilitate its integration into clinical protocols. Magn Reson Med 79:890-899, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Bone loss and muscle atrophy in spinal cord injury: epidemiology, fracture prediction, and rehabilitation strategies.
Individuals with spinal cord injury (SCI) often experience bone loss and muscle atrophy. Muscle atrophy can result in reduced metabolic rate and increase the risk of metabolic disorders. Sublesional osteoporosis predisposes individuals with SCI to an increased risk of low-trauma fracture. Fractures in people with SCI have been reported during transfers from bed to chair, and while being turned in bed. The bone loss and muscle atrophy that occur after SCI are substantial and may be influenced by factors such as completeness of injury or time postinjury. A number of interventions, including standing, electrically stimulated cycling or resistance training, and walking exercises have been explored with the aim of reducing bone loss and/or increasing bone mass and muscle mass in individuals with SCI. Exercise with electrical stimulation appears to increase muscle mass and/or prevent atrophy, but studies investigating its effect on bone are conflicting. Several methodological limitations in exercise studies with individuals with SCI to date limit our ability to confirm the utility of exercise for improving skeletal status. The impact of standing or walking exercises on muscle and bone has not been well established. Future research should carefully consider the study design, skeletal measurement sites, and the measurement techniques used in order to facilitate sound conclusions.


Client language as a mediator of motivational interviewing efficacy: where is the evidence?
Identifying in-session indicators of client outcomes is important in determining the mechanisms of psychotherapeutic treatments, including Motivational Interviewing (MI). The current studies sought to determine if clinician behavior influences client speech, and the extent to which client speech predicted treatment outcome in clients receiving treatment for substance abuse. Study 1 examined 38 sessions from 5 sites in Project MATCH. Sessions were coded using the Sequential Code for Process Exchanges (SCOPE) behavioral coding system. Transition probabilities and inter-rater reliability were calculated. Study 2 examined 45 sessions from the New Mexico site in Project MATCH. Sessions were coded using the MISC 1.0 behavioral coding system. Distal outcome measures were calculated for proportion of days abstinent (PDA) and drinks per drinking day (DDD). Hierarchical multiple regression and hierarchical logistic regression were used to characterize the relationship between client speech and outcome. In Study 1, inter-rater reliability estimates indicate that coders reliably distinguished between the categories within the SCOPE. Behaviors consistent with MI (MICO) were significantly likely to be followed by client Change Talk (CT) and behaviors inconsistent with MI (MIIN) were significantly likely to be followed by Counterchange Talk (CCT). There was also a significant negative transition probability between MICO and CCT. In Study 2, CT was found to account for significant portions of outcome variability beyond that attributable to baseline measures of problem severity. Client speech during early therapy sessions appears to be a powerful predictor of substance abuse outcome. The pattern of therapist behaviors and subsequent client language found in this data supports the intervention test in the causal chain we have described for motivational interviewing. These studies provide preliminary support for a causal chain between therapist behaviors, subsequent client speech, and drinking outcomes within motivational interviewing sessions. The results of both studies provide further support to the proposition that client speech impacts the likelihood of behavioral change, and that the occurrence of such speech is influenced by the therapist.


Tdrd3 is a novel stress granule-associated protein interacting with the Fragile-X syndrome protein FMRP.
Tudor domains are widespread among proteins involved in RNA metabolism, but only in a few cases their cellular function has been analyzed in detail. Here, we report on the characterization of the ubiquitously expressed Tudor domain containing protein Tdrd3. Apart from its Tudor domain, we show that Tdrd3 possesses an oligosaccharide/nucleotide binding fold (OB-fold) and an ubiquitin associated domain capable of binding tetra-ubiquitin. A set of biochemical experiments revealed an interaction of Tdrd3 with FMRP, the product of the gene affected in Fragile X syndrome, and its autosomal homologs FXR1 and FXR2. FMRP has been implicated in the translational regulation of target mRNAs and shown to be a component of stress granules (SG). We demonstrate that overexpression of Tdrd3 in cells induces the formation of SGs and as a result leads to its co-localization with endogenous FMRP in these structures. Interestingly, the disease-associated FMRP missense mutation I304N identified in a Fragile X patient severely impairs the interaction with Tdrd3 in biochemical experiments. We propose a contribution of Tdrd3 to FMRP-mediated translational repression and suggest that the loss of the FMRP-Tdrd3 interaction caused by the I304N mutation might contribute to the pathogenesis of Fragile X syndrome.


Responsive crosslinked polymer nanogels for imaging and therapeutics delivery.
Water-soluble, nano-sized crosslinked polymer networks, or nanogels, are delivery vehicles, which have highly interesting properties for therapeutic delivery and imaging. Nanogels may also possess responsive properties, depending on the employed polymers, allowing controlled release of therapeutics or image contrast generation upon exposure to physical or (bio)chemical cues. In this review, polymer nanogels are explored for application in imaging as well as for controlled drug and gene delivery. Moreover, nanogels are explored as responsive biomaterials and future applications are highlighted.


Dreaming is not enough. Audiovisual methodologies, social inclusion, and new forms of youth biopolitical resistance.
The eleventh Sustainable Development Goal, "make cities and human settlements inclusive, safe, resilient and sustainable," can only be truly answered when there are no individuals in our societies who feel forgotten by the various social institutions. Not in Education, Employment, or Training [NEET] are among those most affected by this social invisibility. Nevertheless, these young people are not alienated or lost. Far from it. Instead, some of them found in the arts registered in the community-music, dance, photography and graffiti-a possibility to resist the various social stigmas attached on them. This was the view on which we conducted our artistic and social intervention, based on the innovative "arts-based research" methodology and "youth-led participatory research," called "The Neighborhood is Ours II!," with young NEETs in the socially underprivileged Cerco neighborhood of Porto in Portugal in 2022. We propose a theoretical-empirical approach around a visual/narrative sociology-namely using digital cinema-which will be based on a short film about the life narrative of a young NEET, who has used artistic practices to establish himself in the city of Porto as a cultural mediator. Thus-through these processes of co-creation of knowledge (cine-making)- we aim to demonstrate how the use of the arts can be a key tool in promoting social inclusion and reducing/minimizing feelings of insecurity, but also act as a means of resistance to the daily adversities experienced by marginalized young people and, of course, demonstrate the ways in which the use of artistic practices plays a pivotal role in the development of sustainable and alternative professional, social futures and citizenship.


Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP study of 576 patients.
Despite the widespread use of antiemetics, nausea continues to be reported by over 70% of patients receiving chemotherapy. In this double blind, multicenter trial, we randomly assigned 744 cancer patients to four arms: 1) placebo, 2) 0.5 g ginger, 3) 1.0 g ginger, or 4) 1.5 g ginger. Nausea occurrence and severity were assessed at a baseline cycle and the two following cycles during which patients were taking their assigned study medication. All patients received a 5-HT(3) receptor antagonist antiemetic on Day 1 of all cycles. Patients took three capsules of ginger (250 mg) or placebo twice daily for 6 days starting 3 days before the first day of chemotherapy. Patients reported the severity of nausea on a 7-point rating scale ("1" = "Not at all Nauseated" and "7" = "Extremely Nauseated") for Days 1-4 of each cycle. The primary outcomes were to determine the dose and efficacy of ginger at reducing the severity of chemotherapy-induced nausea on Day 1 of chemotherapy. A total of 576 patients were included in final analysis (91% female, mean age = 53). Mixed model analyses demonstrated that all doses of ginger significantly reduced acute nausea severity compared to placebo on Day 1 of chemotherapy (p = 0.003). The largest reduction in nausea intensity occurred with 0.5 g and 1.0 g of ginger (p = 0.017 and p = 0.036, respectively). Anticipatory nausea was a key factor in acute chemotherapy-induced nausea (p < 0.0001). Ginger supplementation at a daily dose of 0.5 g-1.0 g significantly aids in reduction of the severity of acute chemotherapy-induced nausea in adult cancer patients.


Cannabis and cannabinoids in cancer pain management.
An increasing number of patients are turning to cannabis and cannabinoids for management of their palliative and nonpalliative cancer pain and other cancer-related symptoms. Canadians have a legal framework for access to medical cannabis, which provides a unique perspective in a setting lacking robust clinical evidence. This review seeks to delineate the role of cannabis and cannabinoids in cancer pain management and offers insight into the Canadian practice. A cohort study using nabiximols on advanced cancer pain in patients already optimized on opioids, over 3 weeks, demonstrated improved average pain score. A large observational study of cancer patients using cannabis over 6 months demonstrated a decreased number of patients with severe pain and decreased opioid use, whereas the number of patients reporting good quality of life increased. Good preclinical animal data and a large body of observational evidence point to the potential efficacy of cannabinoids for cancer pain management. However, there are relatively weak data pointing to clinical efficacy from clinical trial data to date. In Canada, the burgeoning cannabis industry has driven the population to embrace a medicine before clinical evidence. There remains a need for high-quality randomized controlled trials to properly assess the effectiveness and safety of medical cannabis, compared with placebo and standard treatments for cancer-related symptoms.


LI-RADS and transplantation for hepatocellular carcinoma.
Patients with hepatocellular carcinoma (HCC) may be eligible for liver transplantation. Liver transplant candidates with HCC compete for the same deceased donor organs as those without HCC. These scarce organs must be allocated fairly and justly to those who will benefit most. Unlike most other cancers, HCC is often diagnosed noninvasively by imaging without biopsy confirmation. Therefore, radiologists play an important role in diagnosing definite HCC (i.e., LR-5 category) that counts toward staging and determination of liver transplant eligibility. This review explains the conversion of LI-RADS observation categories to organ procurement and transplantation network classes, illustrates the radiologic T-staging systems, reviews selection criteria for liver transplant eligibility, and discusses prioritization of liver transplant candidates with HCC. In addition, this review summarizes imaging requirements, including contrast agents accepted, minimum specifications for dynamic CT or MRI of the liver, and modalities accepted for assessment of extrahepatic spread or metastatic disease in liver transplant candidates with HCC.


Imaging interferometric microscopy.
We introduce and demonstrate a new microscopy concept: imaging interferometric microscopy (IIM), which is related to holography, synthetic-aperture imaging, and off-axis-dark-field illumination techniques. IIM is a wavelength-division multiplex approach to image formation that combines multiple images covering different spatial-frequency regions to form a composite image with a resolution much greater than that permitted by the same optical system using conventional techniques. This new type of microscopy involves both off-axis coherent illumination and reinjection of appropriate zero-order reference beams. Images demonstrate high resolution, comparable with that of a high-numerical-aperture (NA) objective, while they retain the long working distance, the large depth of field, and the large field of view of a low-NA objective. A Fourier-optics model of IIM is in good agreement with the experiment.


Regression of U-87 MG human glioblastomas in nude mice after treatment with a cytotoxic somatostatin analog AN-238.
Receptors for somatostatin (SST) found on brain tumors could be used for targeting of chemotherapeutic agents. This study was conducted to investigate the effects of targeted cytotoxic SST analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201), a potent derivative of doxorubicin (DOX) linked to somatostatin analogue RC-121, on the growth of SST receptor-positive U-87 MG human glioblastomas. Nude mice bearing U-87 MG xenografts received i.v. saline or equimolar doses of AN-238 or AN-201 (150 nmol/kg). Experiments also included groups that were administered RC-121 prior to the injection of AN-238, and groups injected with AN-162, a cytotoxic SST analogue similar to AN-238 but containing DOX instead of AN-201. Tumor volume, weight, and burden were determined. The effect of AN-238 and AN-201 on the survival time of nude mice bearing orthotopically implanted U-87 MG tumors was also evaluated. The binding of AN-238 to U-87 MG tumors was determined by radioreceptor assay and SST receptor (SSTR) subtype by reverse transcription-PCR. Nineteen days after a single administration of AN-238 the growth of U-87 MG tumors in nude mice was significantly inhibited (P = 0.00168), whereas two injections of AN-238 produced the regression of tumors (P = 0.0046). AN-201 was toxic and ineffective at the same dose. The antitumor effect on AN-238 could be blocked by pretreatment of the tumor-bearing mice with RC-121. The mean survival time of nude mice inoculated orthotopically with U-87 MG cells into the brain was significantly prolonged by treatment with AN-238 (P = 0.0099). AN-162 failed to inhibit significantly the growth of U-87 MG xenografts. High affinity binding sites for SST and mRNA for SST-2 receptor subtype were detected in U-87 MG tumors. Cytotoxic SST analogue AN-238 can be targeted to SST receptors on U-87 MG human glioblastomas to produce powerful inhibition of growth.


Pain channelopathies.
Pain remains a major clinical challenge, severely afflicting around 6% of the population at any one time. Channelopathies that underlie monogenic human pain syndromes are of great clinical relevance, as cell surface ion channels are tractable drug targets. The recent discovery that loss-of-function mutations in the sodium channel Nav1.7 underlie a recessive pain-free state in otherwise normal people is particularly significant. Deletion of channel-encoding genes in mice has also provided insights into mammalian pain mechanisms. Ion channels expressed by immune system cells (e.g. P2X7) have been shown to play a pivotal role in changing pain thresholds, whilst channels involved in sensory transduction (e.g. TRPV1), the regulation of neuronal excitability (potassium channels), action potential propagation (sodium channels) and neurotransmitter release (calcium channels) have all been shown to be potentially selective analgesic drug targets in some animal pain models. Migraine and visceral pain have also been associated with voltage-gated ion channel mutations. Insights into such channelopathies thus provide us with a number of potential targets to control pain.


Comparison of the reproductive ecology of two sympatric blacktip sharks (Carcharhinus limbatus and Carcharhinus tilstoni) off north-eastern Australia with species identification inferred from vertebral counts.
Precaudal vertebral counts were used to distinguish between 237 morphologically similar Carcharhinus limbatus and Carcharhinus tilstoni and were congruent with differences in reproductive ecology between the species. In addition to differing lengths at maturity and adult body size, the two species had asynchronous parturition, were born at different sizes and the relative frequencies of neonates differed in two coastal nursery areas. Despite evidence that hybridization can occur, these differences suggest the species are largely reproductively isolated.


Vps45p stabilizes the syntaxin homologue Tlg2p and positively regulates SNARE complex formation.
Sec1p-like/Munc-18 (SM) proteins bind to t-SNAREs and inhibit ternary complex formation. Paradoxically, the absence of SM proteins does not result in constitutive membrane fusion. Here, we show that in yeast cells lacking the SM protein Vps45p, the t-SNARE Tlg2p is down-regulated, to undetectable levels, by rapid proteasomal degradation. In the absence of Vps45p, Tlg2p can be stabilized through abolition of proteasome activity. Surprisingly, the stabilized Tlg2p was targeted to the correct intracellular location. However, the stabilized Tlg2p is non-functional and unable to bind its cognate SNARE binding partners, Tlg1p and Vti1p, in the absence of Vps45p. A truncation mutant lacking the first 230 residues of Tlg2p no longer bound Vps45p but was able to form complexes with Tlg1p and Vti1p in the absence of the SM protein. These data provide us with two valuable insights into the function of SM proteins. First, SM proteins act as chaperone-like molecules for their cognate t-SNAREs. Secondly, SM proteins play an essential role in the activation process allowing their cognate t-SNARE to participate in ternary complex formation.


Molecularly imprinted polymers for tobacco mosaic virus recognition.
Molecular imprinted Polymers (MIP) targeted for Tobacco mosaic virus (TMV) have been synthesized. Batch equilibrium studies using imprinted and non-imprinted polymer hydrogels in TMV and TNV solutions were conducted to determine virus-binding capacities. TMV-imprinted hydrogels showed increased binding to TMV (8.8 mg TMV/gpolymer) compared to non-imprinted hydrogels (4.2 mg TMV/gpolymer). Furthermore, TMV-imprinted hydrogels exhibited increased binding to TMV compared to TNV, while non-imprinted hydrogels bound similar amounts of TMV or TNV. This research has demonstrated that molecular imprinting of viruses can be used to selectively induce binding of target viruses based on shape differences of their virions.


Household Surveys in the General Population and Web-Based Surveys in IQOS Users Registered at the Philip Morris International IQOS User Database: Protocols on the Use of Tobacco- and Nicotine-Containing Products in Germany, Italy, and the United Kingdom (Greater London), 2018-2020.
Philip Morris International (PMI) has developed a novel heat-not-burn tobacco product, Tobacco Heating System (THS), which is marketed under the brand name of IQOS with HEETS (IQOS). The aerosol generated by THS has substantially fewer toxicants than combustible cigarette smoke, although the extent of the reduction of harmful and potentially harmful constituents reported varies between studies. To evaluate the potential harm reduction associated with IQOS use, the assessment of the uptake and continued use of IQOS in the context of all other tobacco- and nicotine-containing products is crucial. In March 2018, PMI launched cross-sectional surveys in Germany, Italy, and the United Kingdom (Greater London) to estimate the prevalence and use patterns of IQOS and other tobacco- and nicotine-containing products use in these 3 markets following the commercialization of IQOS. This study describes the protocol of the surveys. The objectives of these surveys are to estimate the prevalence of tobacco- and nicotine-containing products use; describe past and current patterns of use; and explore their associations with self-reported health, motivation to use, risk perceptions, and perceived aesthetic changes. The overall design of the surveys is similar in all 3 countries. Repeated cross-sectional surveys are being conducted annually over 3 consecutive years (2018 to 2020) and in 2 samples: a representative sample of the general population and a sample of IQOS users. A total of 6085 adults per year will be selected from the general population for each survey through multistage stratified sampling, and participants will respond to face-to-face computer-assisted personal interviews. In addition, 1404, 1384, and 1246 IQOS users per year in Germany, Italy, and Greater London, respectively, will be randomly selected from the PMI IQOS user database and will be invited to complete the Web-based survey using computer-assisted self-interviews. The Smoking Questionnaire is used to assess the tobacco use patterns of the participants. The recruitment of the general population sample began in March 2018 and that of the IQOS user sample began in April 2018. The data collection is ongoing, and the results of the first year data analysis are expected to be available by June 2019. As the design of the 3 surveys is similar, the results will allow for cross-countries comparison of the prevalence of IQOS and other tobacco- and nicotine-containing products use as well as patterns of use and associated factors. DERR1-10.2196/12061.


Decision-making cognition in neurodegenerative diseases.
A large proportion of human social neuroscience research has focused on the issue of decision-making. Impaired decision-making is a symptomatic feature of a number of neurodegenerative diseases, but the nature of these decision-making deficits depends on the particular disease. Thus, examining the qualitative differences in decision-making impairments associated with different neurodegenerative diseases could provide valuable information regarding the underlying neural basis of decision-making. Nevertheless, few comparative reports of decision-making across patient groups exist. In this Review, we examine the neuroanatomical substrates of decision-making in relation to the neuropathological changes that occur in Alzheimer disease, frontotemporal dementia, Parkinson disease and Huntington disease. We then examine the main findings from studies of decision-making in these neurodegenerative diseases. Finally, we suggest a number of recommendations that future studies could adopt to aid our understanding of decision-making cognition.


Comparison of the effects of auditory subliminal stimulation and rational-emotive therapy, separately and combined, on self-concept.
The present study investigated the effects on self-concept of Rational-Emotive Therapy and auditory subliminal stimulation (separately and in combination) on 141 undergraduate students with self-concept problems. They were randomly assigned to one of four groups receiving either Rational-Emotive Therapy, subliminal stimulation, both, or a placebo treatment. Rational-Emotive Therapy significantly improved scores on all the dependent measures (cognition, self-concept, self-esteem, anxiety), except for behavior. Results for the subliminal stimulation group were similar to those of the placebo treatment except for a significant self-concept improvement and a decline in self-concept related irrational cognitions. The combined treatment yielded results similar to those of Rational-Emotive Therapy, with tentative indications of continued improvement in irrational cognitions and self-concept from posttest to follow-up.


Development of a risk prediction model for Barrett's esophagus in an Australian population.
Esophageal adenocarcinoma has poor 5-year survival rates. Increased survival might be achieved with earlier treatment, but requires earlier identification of the precursor, Barrett's esophagus. Population screening is not cost effective, this may be improved by targeted screening directed at individuals more likely to have Barrett's esophagus. To develop a risk prediction tool for Barrett's esophagus, this study compared individuals with Barrett's esophagus against population controls. Participants completed a questionnaire comprising 35 questions addressing medical history, symptom history, lifestyle factors, anthropomorphic measures, and demographic details. Statistical analysis addressed differences between cases and controls, and entailed initial variable selection, checking of model assumptions, and establishing calibration and discrimination. The area under the curve (AUC) was used to assess overall accuracy. One hundred and twenty individuals with Barrett's esophagus and 235 population controls completed the questionnaire. Significant differences were identified for age, gender, reflux history, family reflux history, history of hypertension, alcoholic drinks per week, and body mass index. These were used to develop a risk prediction model. The AUC was 0.82 (95% CI 0.78-0.87). Good calibration between predicted and observed risk was noted (Hosmer-Lemeshow test P = 0.67). At the point minimizing false positives and false negatives, the model achieved a sensitivity of 84.96% and a specificity of 66%. A well-calibrated risk prediction model with good discrimination has been developed to identify patients with Barrett's esophagus. The model needs to be externally validated before consideration for clinical practice.


Spatial pattern of microchannel formation in fused silica irradiated by nanosecond ultraviolet pulses.
We present numerical simulations of propagation of ultraviolet pulses through fused silica using a model that allows for the accumulative action of compaction back on the light. Compaction-induced self-focusing causes the light field to develop into a pattern of hot spots around the incident aperture that correlates with the damage patterns observed during marathon experiments designed to determine the onset of microchannel formation.


Hormones, herbal preparations and nutriceuticals for a better life after the menopause: part I.
In developed countries, women spend more than one-third of their life in the menopause and at least half of them experience vasomotor symptoms that impair their normal function and well-being. Long-term estrogen replacement therapy (HRT) with estrogen can suppress typical menopausal symptoms and prevents osteoporosis. When estrogen-only HRT is started within 10 years after the menopause, the prevalence of cardiovascular disease is reduced, mortality is lower, and the risk of breast cancer is not significantly increased. Postmenopausal genital and urinary problems with recurrent infections, incontinence, and dyspareunia can effectively be treated by vaginal application of estriol, which seems to be safe for women treated for breast cancer. HRT after the age of 60 years is associated with a lower number needed to treat than number needed to harm, implying that there would be one unfavorable side-effect for up to ten women experiencing a positive effect. However, further studies are needed regarding the risk-benefit ratio of HRT in women over 70 years. It is concluded that transdermal substitution therapy with estradiol may increase the number of quality-adjusted life years of postmenopausal women. The combination with nutriceutical food supplementation may add to this benefit, but complementary prospective trials are still needed.


Susceptibility of the Bacteroides fragilis group in the United States: analysis by site of isolation.
An ongoing survey of the susceptibility of the Bacteroides fragilis group of bacteria was continued at New England Medical Center in 1984 and 1985. A total of 1,229 strains were obtained from eight centers in the United States. These results were compared with those for 1,847 isolates tested in 1981 through 1983. The most active beta-lactam drugs were imipenem and ticarcillin-clavulanic acid (Timentin), which had a less than 1% resistance rate. No metronidazole- or chloramphenicol-resistant isolates were found during the 5 years of the study. Isolates obtained from blood, perinatal, and bone sites of infection were more resistant to a variety of antimicrobial agents. Susceptibility patterns of the members of the B. fragilis group varied at the eight hospitals and among species. These data indicate the need for determining the susceptibility patterns for the B. fragilis group of organisms at each hospital.


Evidence that the HLA DQA1*03 allele confers protection from chronic HCV-infection in Northern European Caucasoids.
In the search for factors which may influence susceptibility to and outcome from chronic hepatitis C virus (HCV) infection, few studies have considered the influence of host genes. In the present investigation we have performed HLA DRB1, DQA1, DQB1, and DPB1 genotyping on 104 northern European patients with chronic HCV infection and 177 racially and geographically matched controls. Three HLA class II alleles, DRB1*0403, DQA1*03, and DQB1*0302 were present at a significantly lower frequency in patients compared with controls (4.9% vs. 13%, 20.7% vs. 41.2%, and 11.4% vs. 30.5%, respectively) though only two DQB1*0302 and DQA1*03 were significant after correction for multiple testing (pc = 0.038, and pc = 0.046, respectively). No further HLA associations with chronic HCV infection were observed and there was no correlation between stage of disease and HLA genotype. These data provide the first suggestion that susceptibility to chronic HCV infection may be influenced by the hosts' HLA DQ alleles.


Effectiveness and cost effectiveness of expanding harm reduction and antiretroviral therapy in a mixed HIV epidemic: a modeling analysis for Ukraine.
Injection drug use (IDU) and heterosexual virus transmission both contribute to the growing mixed HIV epidemics in Eastern Europe and Central Asia. In Ukraine-chosen in this study as a representative country-IDU-related risk behaviors cause half of new infections, but few injection drug users (IDUs) receive methadone substitution therapy. Only 10% of eligible individuals receive antiretroviral therapy (ART). The appropriate resource allocation between these programs has not been studied. We estimated the effectiveness and cost-effectiveness of strategies for expanding methadone substitution therapy programs and ART in mixed HIV epidemics, using Ukraine as a case study. We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs using opiates, and IDUs on methadone substitution therapy, stratified by HIV status, and populated it with data from the Ukraine. We considered interventions expanding methadone substitution therapy, increasing access to ART, or both. We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost-effectiveness. Without incremental interventions, HIV prevalence reached 67.2% (IDUs) and 0.88% (non-IDUs) after 20 years. Offering methadone substitution therapy to 25% of IDUs reduced prevalence most effectively (to 53.1% IDUs, 0.80% non-IDUs), and was most cost-effective, averting 4,700 infections and adding 76,000 QALYs compared with no intervention at US$530/QALY gained. Expanding both ART (80% coverage of those eligible for ART according to WHO criteria) and methadone substitution therapy (25% coverage) was the next most cost-effective strategy, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy and averting 8,300 infections versus no intervention. Expanding only ART (80% coverage) added 38,000 QALYs at US$2,240/QALY gained versus the methadone substitution therapy-only strategy, and averted 4,080 infections versus no intervention. Offering ART to 80% of non-IDUs eligible for treatment by WHO criteria, but only 10% of IDUs, averted only 1,800 infections versus no intervention and was not cost effective. Methadone substitution therapy is a highly cost-effective option for the growing mixed HIV epidemic in Ukraine. A strategy that expands both methadone substitution therapy and ART to high levels is the most effective intervention, and is very cost effective by WHO criteria. When expanding ART, access to methadone substitution therapy provides additional benefit in infections averted. Our findings are potentially relevant to other settings with mixed HIV epidemics. Please see later in the article for the Editors' Summary.


Genetic variability of glutamate-gated chloride channel genes in ivermectin-susceptible and -resistant strains of Cooperia oncophora.
The glutamate-gated chloride channels (GluCls) are members of the ligand-gated ion channel superfamily that are thought to be involved in the mode of action of ivermectin and mechanism of resistance. Using reverse-transcriptase PCR techniques, 2 full-length GluCl cDNAs, encoding GluClalpha3 and GluClbeta subunits, were cloned from Cooperia oncophora, a nematode parasite of cattle. The two sequences show a high degree of identity to similar subunits from other nematodes. The C. oncophora GluClalpha3 subunit is most closely related to the Haemonchus contortus GluClalpha3B subunit, while C. oncophora GluClbeta subunit shares high sequence identity with the H. contortus GluClbeta subunit. Using single-strand conformation polymorphism, the genetic variability of these two genes was analysed in an ivermectin-susceptible isolate and an ivermectin-resistant field isolate of C. oncophora. Statistical analysis suggested an association between the C. oncophora GluClalpha3 gene and ivermectin resistance. No such association was seen with the GluClbeta gene.


Value of witness observations in the differential diagnosis of transient loss of consciousness.
This retrospective study explores to what extent additional information from event witnesses provided using the novel 31-item Paroxysmal Event Observer (PEO) Questionnaire improves the differentiation among epilepsy, syncope, and psychogenic nonepileptic seizures (PNES) achievable with information provided by patients alone. Patients with transient loss of consciousness caused by proven epilepsy (n = 86), syncope (n = 79), or PNES (n = 84) attending specialist neurology/syncope services in the United Kingdom and event observers provided Paroxysmal Event Profile (PEP), PEO, and personal information (PI) (e.g., sex, age, medical history) data. PEO data were subjected to exploratory factor analysis (EFA) followed by confirmatory factor analysis (CFA). PEO, PEP, and PI data were used separately and in combination to differentiate diagnoses by pairwise and multinomial logistic regressions. Predicted diagnoses were compared with gold standard medical diagnoses. EFA/CFA identified a 4-factor structure of the PEO based on 26/31 questionnaire items with loadings ≥0.4. Observer-reported factors alone differentiated better between syncope and epilepsy than patient-reported factors (accuracy: 96% vs 85%, p = 0.0004). Observer-reported data improved accuracy over differentiation based on patient-reported data alone from 90% to 100% between syncope and epilepsy (p = 0.005), 76% to 83% between epilepsy and PNES (p = 0.006), and 93% to 95% between syncope and PNES (p = 0.098). Information from observers can make an important contribution to the differentiation of epilepsy from syncope or PNES but adds less to that of syncope from PNES.


Prehospital electronic patient care report systems: early experiences from emergency medical services agency leaders.
As the United States embraces electronic health records (EHRs), improved emergency medical services (EMS) information systems are also a priority; however, little is known about the experiences of EMS agencies as they adopt and implement electronic patient care report (e-PCR) systems. We sought to characterize motivations for adoption of e-PCR systems, challenges associated with adoption and implementation, and emerging implementation strategies. We conducted a qualitative study using semi-structured in-depth interviews with EMS agency leaders. Participants were recruited through a web-based survey of National Association of EMS Physicians (NAEMSP) members, a didactic session at the 2010 NAEMSP Annual Meeting, and snowball sampling. Interviews lasted approximately 30 minutes, were recorded and professionally transcribed. Analysis was conducted by a five-person team, employing the constant comparative method to identify recurrent themes. Twenty-three interviewees represented 20 EMS agencies from the United States and Canada; 14 EMS agencies were currently using e-PCR systems. The primary reason for adoption was the potential for e-PCR systems to support quality assurance efforts. Challenges to e-PCR system adoption included those common to any health information technology project, as well as challenges unique to the prehospital setting, including: fear of increased ambulance run times leading to decreased ambulance availability, difficulty integrating with existing hospital information systems, and unfunded mandates requiring adoption of e-PCR systems. Three recurring strategies emerged to improve e-PCR system adoption and implementation: 1) identify creative funding sources; 2) leverage regional health information organizations; and 3) build internal information technology capacity. EMS agencies are highly motivated to adopt e-PCR systems to support quality assurance efforts; however, adoption and implementation of e-PCR systems has been challenging for many. Emerging strategies from EMS agencies and others that have successfully implemented EHRs may be useful in expanding e-PCR system use and facilitating this transition for other EMS agencies.


Advances in the treatment of sickle cell disease in children.
Support from the national sickle cell disease program in the United States is resulting in significant advances in health care. Ten regional comprehensive sickle cell centers provide a variety of management strategies. An example is the inauguration of neonatal diagnosis for sickle hemoglobinopathies, with parental education and the utilization of special follow-up clinics for affected infants. The administration of prophylactic antibiotics and improved vaccines for control of life-threatening infection is enhancing survival in infants and children. A number of antisickling agents are under preliminary clinical investigation in adult patients. Bone marrow transplantation represents another potential method for management of selected types of sickle cell disease. The results of a national cooperative study on the clinical course of the disease, which was inaugurated in 1978, is providing new information that will be helpful to clinicians and health planners. The federally funded sickle cell centers have effectively utilized interdisciplinary personnel to provide comprehensive medical care, psychosocial support, and patient education. These centers serve as models or bridges whereby the fruits of research activity can be more readily applied to the care of patients. This comprehensive approach, no doubt, can contribute to improvement in the survival of and quality of life for patients. There is, however, a need to continue national support for research efforts to attain a definitive cure for this serious, painful, and disabling illness, which affects about 50,000 people in the United States and many more in other countries. Currently, many families of affected patients are unable to cope personally with socioeconomic problems imposed by the long-term nature of this illness, insufficient income, inadequate insurance coverage, and escalating costs of health care. Clearly, there is a need for additional state and/or federal programs to provide supplements for the medical expenses incurred by persons with long-term handicapping diseases of genetic origin.


Temporal changes in urinary 1-hydroxypyrene concentrations in coke-oven workers.
Coke-oven workers are exposed to high concentrations of coke-oven emissions, which are comprised mainly of polycyclic aromatic hydrocarbons. We conducted a pilot study to determine the time changes in urinary 1-hydroxypyrene (1-OHP) concentrations, as a metabolite of pyrene, in coke-oven workers after exposure to a benzene-soluble fraction (BSF) of total particulates. Thirteen subjects, including 2 men (referents) from an administrative area, 6 workers who work at the sideoven, and 5 who work on the top of the oven in one coke-oven plant were studied. After 1.5 to 2 days off, subjects were monitored individually for breathing zone air BSF over 3 consecutive days in August 1995. Seven spot urine samples, including preshift and postshift urine over 3 days and preshift urine on a fourth-day morning, were collected to determine 1-OHP concentrations by fluorescent spectrophotometry. The mean ambient BSF concentrations in the sideoven and topside oven workers ranged from 18 to 159 microg/m3 and from 251 to 1362 microg/ m3, respectively, whereas the BSF concentrations in the referents were low but detectable (11 and 29 microg/m3). Urinary 1-OHP concentrations increased during the work period, from 10+/-3 and 41+/-9 microg/g creatinine (mean+/-SE) on the preshift first day to 57+/-26 and 334+/-63 microg/g creatinine on the postshift third day in the sideoven and topside oven workers, respectively. However, the urinary 1-OHP concentrations were relatively flat in the two referents. The across-shift change in urinary 1-OHP defined as postshift 1-OHP on the third day minus preshift 1-OHP on the first day was highly associated with individual mean occupational exposure to air BSF (r = 0.80, P = 0.001). Repeated-measures regression analyses revealed that daily postshift 1-OHP concentrations were marginally associated with daily air BSF. A 10-fold increase of daily air BSF resulted in a 1.67-fold increase of daily postshift 1-OHP levels (95% confidence interval = 0.99-2.83; P = 0.07). After adjusting for daily preshift 1-OHP concentrations, we found that a 10-fold increase of daily air BSF resulted in a 1.90-fold increase of daily postshift 1-OHP levels (95% confidence interval = 1.10-3.28; P = 0.03). Although the sample size is small in this study, these results indicate that daily postshift 1-OHP levels in urine are determined mainly by current occupational exposure to coke-oven emissions.


[Are SPA therapy and pulsed electromagnetic field therapy effective for chronic neck pain? Randomised clinical trial First part: clinical evaluation].
The purpose of this study was to compare SPA therapy (ST) with pulsed electromagnetic field (PEMF) therapy in chronic neck pain. Inclusion criteria were age between 18 and 80 years, neck pain of more than 3 months' duration and pain score>30 mm on a visual analog scale (VAS). Exclusion criteria were contraindication to ST or PEMF. The protocol was approved by the ethics committee of Grenoble Hospital. Randomisation to the ST (n=44) and PEMF groups (n=42) was blinded. The main outcome measure was number of improved patients at 6 months in each group. A patient was considered improved if pain score decreased by more than 20%. Secondary measures were score on the Copenhagen and MOS SF-36 scales. Evaluation and intent-to-treat analysis were also blinded. Patients' preferences were for PEMF. At 6 months, in the PEMF group, 33 patients were improved, 5 not improved and 4 lost to follow-up. In the ST group, 24 patients were improved, 14 not improved and 6 lost to follow-up, for significantly greater improvement in the PEMF than ST group (p=0.02). Significant improvement was seen in both groups in terms of pain score, Copenhagen scale score and score on some dimensions of the MOS SF-36 survey. PEMF seems to be superior to standard ST without massage in control of neck pain. The difference between groups, although perhaps biased, seem to suggest the importance of our conclusions.


Genetic variability and structure of the Olive Field Mouse: a sigmodontine rodent in a biodiversity hotspot of southern Chile.
The temperate rainforests of southern Chile, a recognized biodiversity hotspot, were significantly affected by Pleistocene glacial cycles in their southern portion and have been severely disrupted mainly due to recent human activities. Additionally, the landscape is characterized by a series of potential barriers to gene flow, such as the Chacao Channel, Cordillera de Piuche in Chiloé and both the Ancud and the Corcovado gulfs. We used mitochondrial DNA sequences and microsatellite data across several populations to evaluate the genetic variability and structure of the sigmodontine rodent Abrothrix olivacea brachiotis, one of the most common species of small mammals and an inhabitant of these biodiverse forests. Sequencing data showed that along with the recovery of high haplotype variation for this species, there was a low nucleotide diversity between haplotypes, showing no genetic differences between the Chiloé Island and continental populations in southern Chile or through any other geographic barrier in the study area. However, microsatellite data exhibited some level of population structuring. The most evident clusterings were those of the Chiloé Island and that of North Patagonia. These findings are corroborated by a barrier analysis that showed a genetic barrier in the latter areas, whereas the Chacao Channel was not a significant barrier for this rodent. Overall, the genetic variability and structure of A. o. brachiotis was concordant with historical factors, such as the Last Glacial Maximum and the presence of geographic elements that isolate populations.


Complex heterozygous WNT1 mutation in severe recessive osteogenesis imperfecta of a Chinese patient.
Osteogenesis imperfecta (OI) is a heritable connective tissue disorder with a predominately autosomal-dominant inheritance pattern. Recessive forms of OI are rare and involve many different causative genes. WNT1 mutations were found to cause either autosomal-recessive OI or dominantly inherited early-onset osteoporosis. Here we describe a 32-year-old boy with severe osteopenia and deformity of the extremities. The relative long thumb and ring finger are obvious. We identified a novel combination of complex heterozygous WNT1 mutation of c.397 A>T (p.Ala133Thr) and c.506dupG (p.Cys170Leufs*) in the proband, both parents and young brother were shown to be heterozygous asymptomatic carriers of the mutation. This is the eleventh family and the thirteenth patient we have ever found in China. Mutation of c.397 A>T (p.Ala133Thr) was found for the third time following our previous findings in two individual families with four patients in total, and may be a hotspot mutation in Chinese WNT1-related OI patients. In silico programs supported the damaging effects for both mutations. The three-D structure demonstrated the severely destroyed stability of WNT1. Serum levels of WNT1, LRP5, and β-catenin were decreased, while higher levels of GSK-3β were detected. The molecular mechanisms of the complex heterozygous mutations need further study.


Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children.
Pediatric slow progressors (PSP) are rare ART-naïve, HIV-infected children who maintain high CD4 T-cell counts and low immune activation despite persistently high viral loads. Using a well-defined cohort of PSP, we investigated the role of regulatory T-cells (TREG) and of IL-7 homeostatic signaling in maintaining normal-for-age CD4 counts in these individuals. Compared to children with progressive disease, PSP had greater absolute numbers of TREG, skewed toward functionally suppressive phenotypes. As with immune activation, overall T-cell proliferation was lower in PSP, but was uniquely higher in central memory TREG (CM TREG), indicating active engagement of this subset. Furthermore, PSP secreted higher levels of the immunosuppressive cytokine IL-10 than children who progressed. The frequency of suppressive TREG, CM TREG proliferation, and IL-10 production were all lower in PSP who go on to progress at a later time-point, supporting the importance of an active TREG response in preventing disease progression. In addition, we find that IL-7 homeostatic signaling is enhanced in PSP, both through preserved surface IL-7receptor (CD127) expression on central memory T-cells and increased plasma levels of soluble IL-7receptor, which enhances the bioactivity of IL-7. Combined analysis, using a LASSO modeling approach, indicates that both TREG activity and homeostatic T-cell signaling make independent contributions to the preservation of CD4 T-cells in HIV-infected children. Together, these data demonstrate that maintenance of normal-for-age CD4 counts in PSP is an active process, which requires both suppression of immune activation through functional TREG, and enhanced T-cell homeostatic signaling.


[From biodiversity to biodiversification: a new economy of nature?].
This paper explores the relations between economy and ecology in the last quarter of the 20th century with the example of biodiversity. From its definition in the 1980s, the concept of biodiversity responded not only to conservational concerns but also to hopes and demands of economic profitability. The paper argues that archival systems of inventorying and surveying nature, the biodiversity database and the biodiversity portfolio, changed the view on nature from a resource to an investment. The paper studies the alliances of ecologists and environmental economists in managing nature according to economic principles of successful asset management, "diversification", with the aim to distribute risk, minimize ecological loss and maximize overall ecosystem performance. Finally, the paper discusses the assumptions and the consequences of transferring principles from financial risk management to landscape management. How has the substitution of the existential values of nature by shareholder value affected the relations between ecology, environment, and ecosystem conservation? Who gains and who looses in exchanging natural capital and financial capital, yields, and profits?


A randomised controlled trial of maternal satisfaction with the routine examination of the newborn baby at three months post birth.
to determine whether any differences in maternal satisfaction with the examination of a newborn baby between midwives and junior paediatricians are maintained over a three-month period. randomised controlled trial. Eight hundred and twenty-six mother and baby pairs in a district general hospital in South East England were randomised to a junior paediatrician or a midwife for the routine examination. Four hundred and eighty-six mothers completed a maternal satisfaction questionnaire on day-one and again three-months later. Maternal satisfaction with the examination was analysed in relation to randomised group, process and background variables. high satisfaction with the examination was reported by most mothers (day-one: 82%; three-months: 79%). At day-one, mothers whose babies were examined by a midwife were more satisfied with the examination (crude odds ratio (OR) for the lowest tertile of satisfaction 0.49, 95% CI 0.32-0.73). However, after controlling for provision of health education during the examination (e.g. discussing feeding, sleeping and skin care) and continuity of care provided, maternal satisfaction was no longer related to status of examiner (adjusted OR 0.83, 95% CI 0.52-1.33). Three months later, there was no significant difference in maternal satisfaction with midwife and junior paediatrician examinations of the newborn baby (crude OR 0.89, 95% CI 0.58-1.37). Discussion of health-care issues by the examiner during the examination was significantly related to increased satisfaction even at three-months. Three month ratings of low satisfaction with the examination were most strongly predicted by current maternal depressive mood, even when other factors were adjusted for (adjusted OR 2.58, 95% CI 1.19-5.59). from the mother's perspective, the quality of midwife examination is at least as satisfactory as that of junior paediatricians and this perception is maintained over a three-month period. Satisfaction can be significantly enhanced if the examiner provides information on behavioural and health-care issues. The examination of the newborn baby provides an important window of opportunity for sharing information on newborn behaviour and care issues.


That's my hand! Activity in premotor cortex reflects feeling of ownership of a limb.
When we look at our hands, we immediately know that they are part of our own body. This feeling of ownership of our limbs is a fundamental aspect of self-consciousness. We have studied the neuronal counterparts of this experience. A perceptual illusion was used to manipulate feelings of ownership of a rubber hand presented in front of healthy subjects while brain activity was measured by functional magnetic resonance imaging. The neural activity in the premotor cortex reflected the feeling of ownership of the hand. This suggests that multisensory integration in the premotor cortex provides a mechanism for bodily self-attribution.


[GRADE guidelines: 8. Rating the quality of evidence - indirectness].
Direct evidence comes from research that directly compares the interventions in which we are interested when applied to the populations in which we are interested and measures outcomes important to patients. Evidence can be indirect in one of four ways. First, patients may differ from those of interest (the term applicability is often used for this form of indirectness). Second, the intervention tested may differ from the intervention of interest. Decisions regarding indirectness of patients and interventions depend on an understanding of whether biological or social factors are sufficiently different that one might expect substantial differences in the magnitude of effect. Third, outcomes may differ from those of primary interest - for instance, surrogate outcomes that are not themselves important, but measured in the presumption that changes in the surrogate reflect changes in an outcome important to patients. A fourth type of indirectness, which is conceptually different from the first three, occurs when clinicians must choose between interventions that have not been tested in head to head comparisons. Making comparisons between treatments under these circumstances requires specific statistical methods and will be rated down in quality by one or two levels depending on the extent of differences between the patient populations, co-interventions, measurements of the outcome, and the methods of the trials of the candidate interventions against some other comparator.


Predicting phospholipidosis using machine learning.
Phospholipidosis is an adverse effect caused by numerous cationic amphiphilic drugs and can affect many cell types. It is characterized by the excess accumulation of phospholipids and is most reliably identified by electron microscopy of cells revealing the presence of lamellar inclusion bodies. The development of phospholipidosis can cause a delay in the drug development process, and the importance of computational approaches to the problem has been well documented. Previous work on predictive methods for phospholipidosis showed that state of the art machine learning methods produced the best results. Here we extend this work by looking at a larger data set mined from the literature. We find that circular fingerprints lead to better models than either E-Dragon descriptors or a combination of the two. We also observe very similar performance in general between Random Forest and Support Vector Machine models.


Zinc deprivation mediates alcohol-induced hepatocyte IL-8 analog expression in rodents via an epigenetic mechanism.
Neutrophil infiltration caused by IL-8 production is a central mechanism in alcohol-induced hepatitis. This study was performed to examine if an epigenetic mechanism is involved in alcohol-induced IL-8 production. Mice were pair-fed an alcohol-containing liquid diet for 4 weeks. Alcohol exposure induced hepatitis as indicated by increased expression of keratinocyte-derived cytokine (mouse IL-8) and neutrophil infiltration. Alcohol exposure induced histone 3 hyperacetylation owing to inhibition of histone deacetylase (HDAC) in association with NF-κB activation. Cell culture studies showed that alcohol exposure induced IL-8 and cytokine-induced neutrophil chemoattractant-1 (CINC-1, rat IL-8) production in human VL-17A cells and rat H4IIEC3 cells, respectively, dependent on acetaldehyde production, oxidative stress, and zinc release. Zinc deprivation alone induced CINC-1 production and acted synergistically with lipopolysaccharide or tumor necrosis factor-α on CINC-1 production. Zinc deprivation induced histone 3 hyperacetylation at lysine 9 through suppression of HDAC activity. Zinc deprivation caused nuclear translocation of NF-κB, and reduced HDAC binding to NF-κB. Chromatin immunoprecipitation (ChIP) showed that zinc deprivation caused histone 3 hyperacetylation as well as increased NF-κB binding to the CINC-1 promoter. In conclusion, inactivation of HDAC caused by zinc deprivation is a novel mechanism underlying IL-8 up-regulation in alcoholic hepatitis.


Long-range surface plasmon triple-output Mach-Zehnder interferometers.
A triple-output Mach-Zehnder interferometer (MZI) operating with long-range surface plasmon-polariton waves, consisting of a MZI in cascade with a triple coupler, is demonstrated at a wavelength of ~1370 nm, using the thermo-optic effect to produce phase shifting. A theoretical model for three-waveguide coupling is also proposed and was applied to compute the transfer characteristic of various designs. Dimensions for the device were selected to optimize performance, experiments were performed, and the results were compared to theory. The outputs were sinusoidally related to the thermally-induced phase shift and separated by ~2π/3 rad, as expected theoretically. Four detection schemes that take advantage of the 3 times larger dynamic range and suppress time-varying common perturbations are proposed and analyzed in order to improve the detection limit of the device. A minimum detectable phase shift ~2/3 that of a single output was obtained from a power difference scheme and a normalization scheme. The smallest minimum detectable phase shift was 7.3 mrad. The device is promising for sensing applications, including (bio)chemical sensing.


Epigenetic mechanisms in stroke and epilepsy.
Epigenetic remodeling and modifications of chromatin structure by DNA methylation and histone modifications represent central mechanisms for the regulation of neuronal gene expression during brain development, higher-order processing, and memory formation. Emerging evidence implicates epigenetic modifications not only in normal brain function, but also in neuropsychiatric disorders. This review focuses on recent findings that disruption of chromatin modifications have a major role in the neurodegeneration associated with ischemic stroke and epilepsy. Although these disorders differ in their underlying causes and pathophysiology, they share a common feature, in that each disorder activates the gene silencing transcription factor REST (repressor element 1 silencing transcription factor), which orchestrates epigenetic remodeling of a subset of 'transcriptionally responsive targets' implicated in neuronal death. Although ischemic insults activate REST in selectively vulnerable neurons in the hippocampal CA1, seizures activate REST in CA3 neurons destined to die. Profiling the array of genes that are epigenetically dysregulated in response to neuronal insults is likely to advance our understanding of the mechanisms underlying the pathophysiology of these disorders and may lead to the identification of novel therapeutic strategies for the amelioration of these serious human conditions.


Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease.
The chronic inflammatory liver disease primary sclerosing cholangitis (PSC) is associated with portal inflammation and the development of neolymphoid tissue in the liver. More than 70% of patients with PSC have a history of inflammatory bowel disease and we have previously reported that mucosal addressin cell adhesion molecule-1 is induced on dendritic cells and portal vascular endothelium in PSC. We now show that the lymph node-associated chemokine, CCL21 or secondary lymphoid chemokine, is also strongly up-regulated on CD34(+) vascular endothelium in portal associated lymphoid tissue in PSC. In contrast, CCL21 is absent from LYVE-1(+) lymphatic vessel endothelium. Intrahepatic lymphocytes in PSC include a population of CCR7(+) T cells only half of which express CD45RA and which respond to CCL21 in migration assays. The expression of CCL21 in association with mucosal addressin cell adhesion molecule-1 in portal tracts in PSC may promote the recruitment and retention of CCR7(+) mucosal lymphocytes leading to the establishment of chronic portal inflammation and the expanded portal-associated lymphoid tissue. This study provides further evidence for the existence of portal-associated lymphoid tissue and is the first evidence that ectopic CCL21 is associated with lymphoid neogenesis in human inflammatory disease.


SAR11 bacteria linked to ocean anoxia and nitrogen loss.
Bacteria of the SAR11 clade constitute up to one half of all microbial cells in the oxygen-rich surface ocean. SAR11 bacteria are also abundant in oxygen minimum zones (OMZs), where oxygen falls below detection and anaerobic microbes have vital roles in converting bioavailable nitrogen to N2 gas. Anaerobic metabolism has not yet been observed in SAR11, and it remains unknown how these bacteria contribute to OMZ biogeochemical cycling. Here, genomic analysis of single cells from the world's largest OMZ revealed previously uncharacterized SAR11 lineages with adaptations for life without oxygen, including genes for respiratory nitrate reductases (Nar). SAR11 nar genes were experimentally verified to encode proteins catalysing the nitrite-producing first step of denitrification and constituted ~40% of OMZ nar transcripts, with transcription peaking in the anoxic zone of maximum nitrate reduction activity. These results link SAR11 to pathways of ocean nitrogen loss, redefining the ecological niche of Earth's most abundant organismal group.


Nutrient sensing by the mitochondrial transcription machinery dictates oxidative phosphorylation.
Sirtuin 3 (SIRT3), an important regulator of energy metabolism and lipid oxidation, is induced in fasted liver mitochondria and implicated in metabolic syndrome. In fasted liver, SIRT3-mediated increases in substrate flux depend on oxidative phosphorylation (OXPHOS), but precisely how OXPHOS meets the challenge of increased substrate oxidation in fasted liver remains unclear. Here, we show that liver mitochondria in fasting mice adapt to the demand of increased substrate oxidation by increasing their OXPHOS efficiency. In response to cAMP signaling, SIRT3 deacetylated and activated leucine-rich protein 130 (LRP130; official symbol, LRPPRC), promoting a mitochondrial transcriptional program that enhanced hepatic OXPHOS. Using mass spectrometry, we identified SIRT3-regulated lysine residues in LRP130 that generated a lysine-to-arginine (KR) mutant of LRP130 that mimics deacetylated protein. Compared with wild-type LRP130 protein, expression of the KR mutant increased mitochondrial transcription and OXPHOS in vitro. Indeed, even when SIRT3 activity was abolished, activation of mitochondrial transcription and OXPHOS by the KR mutant remained robust, further highlighting the contribution of LRP130 deacetylation to increased OXPHOS in fasted liver. These data establish a link between nutrient sensing and mitochondrial transcription that regulates OXPHOS in fasted liver and may explain how fasted liver adapts to increased substrate oxidation.


Underwater microscopy for in situ studies of benthic ecosystems.
Microscopic-scale processes significantly influence benthic marine ecosystems such as coral reefs and kelp forests. Due to the ocean's complex and dynamic nature, it is most informative to study these processes in the natural environment yet it is inherently difficult. Here we present a system capable of non-invasively imaging seafloor environments and organisms in situ at nearly micrometre resolution. We overcome the challenges of underwater microscopy through the use of a long working distance microscopic objective, an electrically tunable lens and focused reflectance illumination. The diver-deployed instrument permits studies of both spatial and temporal processes such as the algal colonization and overgrowth of bleaching corals, as well as coral polyp behaviour and interspecific competition. By enabling in situ observations at previously unattainable scales, this instrument can provide important new insights into micro-scale processes in benthic ecosystems that shape observed patterns at much larger scales.


The importance of podocyte adhesion for a healthy glomerulus.
Podocytes are specialized epithelial cells that cover the outer surfaces of glomerular capillaries. Unique cell junctions, known as slit diaphragms, which feature nephrin and Neph family proteins in addition to components of adherens, tight, and gap junctions, connect adjacent podocyte foot processes. Single gene disorders affecting the slit diaphragm result in nephrotic syndrome in humans, characterized by massive loss of protein across the capillary wall. In addition to specialized cell junctions, interconnecting podocytes also adhere to the glomerular basement membrane (GBM) of the capillary wall. The GBM is a dense network of secreted, extracellular matrix (ECM) components and contains tissue-restricted isoforms of collagen IV and laminin in addition to other structural proteins and ECM regulators such as proteases and growth factors. The specialized niche of the GBM provides a scaffold for endothelial cells and podocytes to support their unique functions and human genetic mutations in GBM components lead to renal failure, thus highlighting the importance of cell-matrix interactions in the glomerulus. Cells adhere to ECM via adhesion receptors, including integrins, syndecans, and dystroglycan and in particular the integrin heterodimer α3β1 is required to maintain barrier integrity. Therefore, the sophisticated function of glomerular filtration relies on podocyte adhesion both at cell junctions and at the interface with the ECM. In health, the podocyte coordinates signals from cell junctions and cell-matrix interactions, in response to environmental cues in order to regulate filtration and as our understanding of mechanisms that control cell adhesion in the glomerulus develops, then insight into the effects of disease will improve. The ultimate goal will be to develop targeted therapies to prevent or repair defects in the filtration barrier and to restore glomerular function.


Non-hispanic whites have higher risk for pulmonary impairment from pulmonary tuberculosis.
Disparities in outcomes associated with race and ethnicity are well documented for many diseases and patient populations. Tuberculosis (TB) disproportionately affects economically disadvantaged, racial and ethnic minority populations. Pulmonary impairment after tuberculosis (PIAT) contributes heavily to the societal burden of TB. Individual impacts associated with PIAT may vary by race/ethnicity or socioeconomic status. We analyzed the pulmonary function of 320 prospectively identified patients with pulmonary tuberculosis who had completed at least 20 weeks standard anti-TB regimes by directly observed therapy. We compared frequency and severity of spirometry-defined PIAT in groups stratified by demographics, pulmonary risk factors, and race/ethnicity, and examined clinical correlates to pulmonary function deficits. Pulmonary impairment after tuberculosis was identified in 71% of non-Hispanic Whites, 58% of non-Hispanic Blacks, 49% of Asians and 32% of Hispanics (p < 0.001). Predictors for PIAT varied between race/ethnicity. PIAT was evenly distributed across all levels of socioeconomic status suggesting that PIAT and socioeconomic status are not related. PIAT and its severity were significantly associated with abnormal chest x-ray, p < 0.0001. There was no association between race/ethnicity and time to beginning TB treatment, p = 0.978. Despite controlling for cigarette smoking, socioeconomic status and time to beginning TB treatment, non-Hispanic White race/ethnicity remained an independent predictor for disproportionately frequent and severe pulmonary impairment after tuberculosis relative to other race/ethnic groups. Since race/ethnicity was self reported and that race is not a biological construct: these findings must be interpreted with caution. However, because race/ethnicity is a proxy for several other unmeasured host, pathogen or environment factors that may contribute to disparate health outcomes, these results are meant to suggest hypotheses for further research.


Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms.
Large-scale sequencing studies of hematologic malignancies have revealed notable epistasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are among the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple-concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies. In this study, we performed bulk and single-cell analyses of patients with myeloid malignancy who were harboring ≥2 splicing factor mutations, to understand the frequency and basis for the coexistence of these mutations. Although mutations in splicing factors were strongly mutually exclusive across 4231 patients (q < .001), 0.85% harbored 2 concomitant bona fide splicing factor mutations, ∼50% of which were present in the same individual cells. However, the distribution of mutations in patients with double mutations deviated from that in those with single mutations, with selection against the most common alleles, SF3B1K700E and SRSF2P95H/L/R, and selection for less common alleles, such as SF3B1 non-K700E mutations, rare amino acid substitutions at SRSF2P95, and combined U2AF1S34/Q157 mutations. SF3B1 and SRSF2 alleles enriched in those with double-mutations had reduced effects on RNA splicing and/or binding compared with the most common alleles. Moreover, dual U2AF1 mutations occurred in cis with preservation of the wild-type allele. These data highlight allele-specific differences as critical in regulating the molecular effects of splicing factor mutations as well as their cooccurrences/exclusivities with one another.


Contrasting Gene Decay in Subterranean Vertebrates: Insights from Cavefishes and Fossorial Mammals.
Evolution sometimes proceeds by loss, especially when structures and genes become dispensable after an environmental shift relaxes functional constraints. Subterranean vertebrates are outstanding models to analyze this process, and gene decay can serve as a readout. We sought to understand some general principles on the extent and tempo of the decay of genes involved in vision, circadian clock, and pigmentation in cavefishes. The analysis of the genomes of two Cuban species belonging to the genus Lucifuga provided evidence for the largest loss of eye-specific genes and nonvisual opsin genes reported so far in cavefishes. Comparisons with a recently evolved cave population of Astyanax mexicanus and three species belonging to the Chinese tetraploid genus Sinocyclocheilus revealed the combined effects of the level of eye regression, time, and genome ploidy on eye-specific gene pseudogenization. The limited extent of gene decay in all these cavefishes and the very small number of loss-of-function mutations per pseudogene suggest that their eye degeneration may not be very ancient, ranging from early to late Pleistocene. This is in sharp contrast with the identification of several vision genes carrying many loss-of-function mutations in ancient fossorial mammals, further suggesting that blind fishes cannot thrive more than a few million years in cave ecosystems.


Sustained activation of Akt elicits mitochondrial dysfunction to block Plasmodium falciparum infection in the mosquito host.
The overexpression of activated, myristoylated Akt in the midgut of female transgenic Anopheles stephensi results in resistance to infection with the human malaria parasite Plasmodium falciparum but also decreased lifespan. In the present study, the understanding of mitochondria-dependent midgut homeostasis has been expanded to explain this apparent paradox in an insect of major medical importance. Given that Akt signaling is essential for cell growth and survival, we hypothesized that sustained Akt activation in the mosquito midgut would alter the balance of critical pathways that control mitochondrial dynamics to enhance parasite killing at some cost to survivorship. Toxic reactive oxygen and nitrogen species (RNOS) rise to high levels in the midgut after blood feeding, due to a combination of high NO production and a decline in FOXO-dependent antioxidants. Despite an apparent increase in mitochondrial biogenesis in young females (3 d), energy deficiencies were apparent as decreased oxidative phosphorylation and increased [AMP]/[ATP] ratios. In addition, mitochondrial mass was lower and accompanied by the presence of stalled autophagosomes in the posterior midgut, a critical site for blood digestion and stem cell-mediated epithelial maintenance and repair, and by functional degradation of the epithelial barrier. By 18 d, the age at which An. stephensi would transmit P. falciparum to human hosts, mitochondrial dysfunction coupled to Akt-mediated repression of autophagy/mitophagy was more evident and midgut epithelial structure was markedly compromised. Inhibition of RNOS by co-feeding of the nitric-oxide synthase inhibitor L-NAME at infection abrogated Akt-dependent killing of P. falciparum that begins within 18 h of infection in 3-5 d old mosquitoes. Hence, Akt-induced changes in mitochondrial dynamics perturb midgut homeostasis to enhance parasite resistance and decrease mosquito infective lifespan. Further, quality control of mitochondrial function in the midgut is necessary for the maintenance of midgut health as reflected in energy homeostasis and tissue repair and renewal.


Is access to essential medicines as part of the fulfilment of the right to health enforceable through the courts?
Most countries in the world have become States parties to one or more international human rights treaties, thus creating an obligation by the State to its people towards the realisation of the right to health, which includes access to essential medicines. But whether such access is enforceable in practice is unknown. We did a systematic search to identify completed court cases in low-income and middle-income countries in which individuals or groups had claimed access to essential medicines with reference to the right to health in general, or to specific human rights treaties ratified by the government. We identified and analysed 71 court cases from 12 countries in which access to essential medicines was claimed with reference to the right to health. In 59 cases, access to essential medicines as part of the fulfilment of the right to health could indeed be enforced through the courts, with most coming from Central and Latin America. Success was mainly linked to constitutional provisions on the right to health, supported by the human rights treaties. Other success factors were a link between the right to health and the right to life, and support by public-interest non-government organisations. Individual cases have generated entitlements across a population group, the right to health was not restricted by limitations in social security coverage, and government policies have successfully been challenged in court. Skilful litigation can help to ensure that governments fulfil their constitutional and international treaty obligations. Such assurances are especially valuable in countries in which social security systems are still being developed. However, redress mechanisms through the courts should be used as a last resort. Rather, policymakers should ensure that human rights standards guide their health policies and programmes from the outset.


African glucose-6-phosphate dehydrogenase alleles associated with protection from severe malaria in heterozygous females in Tanzania.
X-linked Glucose-6-phosphate dehydrogenase (G6PD) A- deficiency is prevalent in sub-Saharan Africa populations, and has been associated with protection from severe malaria. Whether females and/or males are protected by G6PD deficiency is uncertain, due in part to G6PD and malaria phenotypic complexity and misclassification. Almost all large association studies have genotyped a limited number of G6PD SNPs (e.g. G6PD202 / G6PD376), and this approach has been too blunt to capture the complete epidemiological picture. Here we have identified 68 G6PD polymorphisms and analysed 29 of these (i.e. those with a minor allele frequency greater than 1%) in 983 severe malaria cases and controls in Tanzania. We establish, across a number of SNPs including G6PD376, that only female heterozygotes are protected from severe malaria. Haplotype analysis reveals the G6PD locus to be under balancing selection, suggesting a mechanism of protection relying on alleles at modest frequency and avoiding fixation, where protection provided by G6PD deficiency against severe malaria is offset by increased risk of life-threatening complications. Our study also demonstrates that the much-needed large-scale studies of severe malaria and G6PD enzymatic function across African populations require the identification and analysis of the full repertoire of G6PD genetic markers.


The health status of latino immigrant women in the United States and future health policy implications of the affordable care act.
Immigrant women of Mexican birth face unique health challenges in the United States. They are at increased risk for developing many preventable health conditions due in part to limited access to healthcare and benefits, legal status, and inadequate income. Increased vulnerability of women has established a growing need to focus on their healthcare needs because of their role, position, and influence in the family. The purpose of this article is to review factors that impact the health status of Mexican-born women living in the United States and review policy implications of the Affordable Care Act for this population. Mexican-born women are the largest female immigrant group in the United States. Therefore, they comprise the group that will need health coverage in the greatest proportion. As a result, there will be a need for culturally and linguistically appropriate healthcare services and culturally sensitive providers.