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The psychedelic compound psilocybin has shown therapeutic benefit in the treatment of numerous psychiatric diseases. A recent randomized clinical trial conducted at Johns Hopkins Bayview Medical Center demonstrated the efficacy of psilocybin-assisted therapy in the treatment of Major Depressive Disorder (MDD). Similarly, a phase IIb study evaluating psilocybin-assisted therapy for treatment-resistant depression (TRD) presented statistically meaningful and long-term reduction in depressive symptoms. Also, many studies have reported the successful treatment of severe anxiety after a single oral dose of psilocybin, especially in patients struggling with cancer-related distress (CRD). Despite these compelling clinical results, concerns regarding the duration of the psychedelic experience produced by psilocybin pose a significant barrier to its widespread therapeutic application. Psilocybin, derived from magic mushrooms is the naturally occurring prodrug of the neuroactive compound psilocin. When orally administered, exposure to the acidic gastrointestinal (GI) environment together with enzymatic processing by intestinal and hepatic alkaline phosphatase lead to the dephosphorylation of psilocybin producing elevated levels of systemic psilocin. These plasma levels are detectable up to 24 h and produce a psychoactive episode lasting as long as 6 h post-ingestion. In order to positively modify the kinetics of the acute psychedelic response, we have engineered a library of novel prodrug derivatives (NPDs) of psilocin, introducing a diversity of alternative metabolically cleavable moieties modified at the 4-carbon position of the core indole ring. This library consists of twenty-eight unique compounds represented by nine distinct prodrug classes. Each molecule was screenedin vitrofor metabolic stability using isolated human serum, and human cellular fractions derived from liver and intestinal tissues. This screen revealed fifteen prodrugs that produced measurable levels of psilocinin vitro, with ester and thiocarbonate-based prodrug derivatives significantly represented. These fifteen NPDs were further evaluated for pharmacokinetic (PK) profiles in mice, assessing plasma levels of both residual prodrug and resultant psilocin. PK results confirmed the efficiency of ester and thiocarbonate-based prodrug metabolism upon oral and intravenous administration, achieving levels reduced, albeit comparable to levels of psilocybin-derived psilocin. Of note, almost all NPDs tested maintained reduced overall exposure of psilocin relative to psilocybin, with no measurable levels detected at 24 h post-dose. Finally, all NPDs were screened for CNS bioavailability in healthy mice using the Head Twitch Response (HTR), a behavioural biomarker of 5-HT2Areceptor stimulation and an established proxy for psychoactive potential. Interestingly, five NPDs produced peak HTR that approached or exceeded levels induced by an equivalent dose of psilocybin. Among these bioactive prodrugs, an ester-based and thiocarbonate-based molecule produced long-term anxiolytic benefit in chronically stressed mice evaluated in the marble burying psychiatric model. Overall, this screening campaign identified novel candidate prodrugs of psilocin with altered metabolic profiles and reduced pharmacological exposure, potentially attenuating the duration of the psychedelic response. These molecules still maintained the long-term psychiatric and physiological benefits characteristic of psilocybin therapy. Additionally, these modified parameters also offer the opportunity for altered routes of administration bypassing conventional oral dosing.

PDF file - 481K, Table S-1. SRM Transitions and Collision Energies Table S-2. Equations for Mercapturic Acid Calibration Curves Table S-3. Precision and Accuracy for Mercapturic Acids in Urine, Intra-day (N=6) Table S-4. Concentrations of Mercapturic Acids in Urine of Cigarette Smokers. Comparison with Literature Values. Table S-5. Concentrations of PAH Metabolites in Urine of Smokers. Comparison with Literature Values. Figure S-1A. Chromatograms of urine extracts containing mercapturic acids: Metabolites of acrylamide (AAMA), ethylene oxide (HEMA), and acrolein (3-HPMA). Figure S-1B. Chromatograms of urine extracts containing mercapturic acids: Metabolites of 1,3-butadiene (MHBMA), acrylonitrile (CNEMA), and benzene (PMA). Figure S-1C. Chromatograms of urine extracts containing mercapturic acids: Metabolite of propylene oxide (2-HPMA) and separation from the isomer 3-HPMA. Figure S-2. Butadiene metabolite (MHBMA) calibration curves. Figure S-3. Benzene metabolite (PMA) calibration curves.

Background: Smoking tobacco preparations in a water pipe (hookah) is widespread in many places of the world and is perceived by many as relatively safe. We investigated biomarkers of toxicant exposure with water pipe compared with cigarette smoking.Methods: We conducted a crossover study to assess daily nicotine and carcinogen exposure with water pipe and cigarette smoking in 13 people who were experienced in using both products.Results: When smoking an average of 3 water pipe sessions compared with smoking 11 cigarettes per day (cpd), water pipe use was associated with a significantly lower intake of nicotine, greater exposure to carbon monoxide (CO), and a different pattern of carcinogen exposure compared with cigarette smoking, with greater exposure to benzene, and high molecular weight polycyclic aromatic hydrocarbon (PAH), but less exposure to tobacco-specific nitrosamines, 1,3-butadiene, acrolein, acrylonitrile, propylene oxide, ethylene oxide, and low molecular weight PAHs.Conclusions: A different pattern of carcinogen exposure might result in a different cancer risk profile between cigarette and water pipe smoking. Of particular concern is the risk of leukemia related to high levels of benzene exposure with water pipe use.Impact: Smoking tobacco in water pipes has gained popularity in the United States and around the world. Many believe that water pipe smoking is not addictive and less harmful than cigarette smoking. We provide data on toxicant exposure that will help guide regulation and public education regarding water pipe health risk. Cancer Epidemiol Biomarkers Prev; 22(5); 765–72. ©2013 AACR.

Virtually all living cells are encased in glycans. They perform key cellular functions such as immunomodulation and cell–cell recognition. Yet, how their composition and configuration affect their functions remains enigmatic. Here, we constructed isogenic capsule-switch mutants harboring 84 types of capsular polysaccharides (CPSs) in Streptococcus pneumoniae . This collection enables us to systematically measure the affinity of structurally related CPSs to primary human nasal and bronchial epithelial cells. Contrary to the paradigm, the surface charge does not appreciably affect epithelial cell binding. Factors that affect adhesion to respiratory cells include the number of rhamnose residues and the presence of human-like glycomotifs in CPS. Besides, pneumococcal colonization stimulated the production of interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractantprotein-1 (MCP-1) in nasal epithelial cells, which also appears to be dependent on the serotype. Together, our results reveal glycomotifs of surface polysaccharides that are likely to be important for colonization and survival in the human airway.

Psychedelic indolethylamines have emerged as potential medicines to treat several psychiatric pathologies. Natural sources of these compounds include ‘magic mushrooms’, plants used to prepare ahayuasca, and toads. Owing to the occurrence of indolethylamines such as N,N-dimethyltryptamine, toad skin and parotid gland preparations have a history of ceremonial use, yet their biosynthesis remains uncharacterized. We report the isolation of an indolethylamine N-methyltransferase (RmNMT) from cane toad (Rhinella marina). Unlike functionally similar mammalian and fungal enzymes, the efficiency and promiscuity of RmNMT made it suitable for the bioproduction of new-to-nature indolethylamine derivatives. N,N-Dimethylated indolethylamines showed reduced affinity and engagement at 5-HT1A and 5-HT2A receptors respectively, compared with primary amine equivalents. Despite reduced 5-HT2A receptor engagement of tertiary amines, only these molecules induced hallucinogenic behavior in mice underscoring the importance of metabolic stability. The discovery of RmNMT facilitated the establishment of a bioproduction platform for the isolation and pharmacological screening of novel indolethylamines.

Rationale: Restriction or prohibition of family visiting intensive care units (ICUs) during the coronavirus disease (COVID-19) pandemic poses substantial barriers to communication and family- and patient-centered care. Objectives: To understand how communication among families, patients, and the ICU team was enabled during the pandemic. The secondary objectives were to understand strategies used to facilitate virtual visiting and associated benefits and barriers. Methods: A multicenter, cross-sectional, and self-administered electronic survey was sent (June 2020) to all 217 UK hospitals with at least one ICU. Results: The survey response rate was 54%; 117 of 217 hospitals (182 ICUs) responded. All hospitals imposed visiting restrictions, with visits not permitted under any circumstance in 16% of hospitals (28 ICUs); 63% (112 ICUs) of hospitals permitted family presence at the end of life. The responsibility for communicating with families shifted with decreased bedside nurse involvement. A dedicated ICU family-liaison team was established in 50% (106 ICUs) of hospitals. All but three hospitals instituted virtual visiting, although there was substantial heterogeneity in the videoconferencing platform used. Unconscious or sedated ICU patients were deemed ineligible for virtual visits in 23% of ICUs. Patients at the end of life were deemed ineligible for virtual visits in 7% of ICUs. Commonly reported benefits of virtual visiting were reducing patient psychological distress (78%), improving staff morale (68%), and reorientation of patients with delirium (47%). Common barriers to virtual visiting were related to insufficient staff time, rapid implementation of videoconferencing technology, and challenges associated with family members’ ability to use videoconferencing technology or access a device. Conclusions: Virtual visiting and dedicated communication teams were common COVID-19 pandemic innovations addressing the restrictions to family ICU visiting, and they resulted in valuable benefits in terms of patient recovery and staff morale. Enhancing access and developing a more consistent approach to family virtual ICU visits could improve the quality of care, both during and outside of pandemic conditions.

Genes in plant secondary metabolic pathways enable biosynthesis of a range of medically and industrially important compounds, and are often clustered on chromosomes. Here, we study genomic clustering in the benzylisoquinoline alkaloid (BIA) pathway in opium poppy (Papaver somniferum), exploring relationships between gene expression, copy number variation, and metabolite production. We use Hi-C to improve the existing draft genome assembly, yielding chromosome-scale scaffolds that include 35 previously unanchored BIA genes. We find that co-expression of BIA genes increases within clusters and identify candidates with unknown function based on clustering and covariation in expression and alkaloid production. Copy number variation in critical BIA genes correlates with stark differences in alkaloid production, linking noscapine production with an 11-gene deletion, and increased thebaine/decreased morphine production with deletion of a T6ODM cluster. Our results show that the opium poppy genome is still dynamically evolving in ways that contribute to medically and industrially important phenotypes.

Biomarkers for the use of electronic nicotine delivery systems (ENDS) are desirable for studies of the health effects of electronic cigarettes and related devices. However, the aerosols inhaled from these devices do not contain substances that are unique to this class of products, i.e., substances that are not present in cigarette smoke or those that do not have common environmental or dietary sources. Consequently, identifying selective biomarkers for ENDS use remains a challenge. If co-use of conventional tobacco products can be definitively ruled out, then nicotine and its metabolites are suitable for assessing exposure. Self-reports from questionnaires are often used to obtain information on product use. But self-reports may not always be accurate, and are not amenable to obtaining quantitative information on exposure. An alternative approach is to use selective biomarkers for conventional tobacco products to definitively rule out their use. In this article, we describe two new LC-MS/MS methods for the minor tobacco alkaloids anabasine, anatabine, nicotelline, anatalline, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a tobacco-specific nitrosamine metabolite, all biomarkers that are selective for the use of conventional tobacco products. Applications of these biomarkers in studies of ENDS use and dual use of ENDS and conventional tobacco products are also discussed.

Although opiate biosynthesis has been largely elucidated, and cell-to-cell transport has been long postulated, benzylisoquinoline alkaloid (BIA) transporters from opium poppy (Papaver somniferum) have not been reported. Investigation of a purine permease-type sequence within a recently discovered opiate biosynthetic gene cluster led to the discovery of a family of nine homologs designated as BIA uptake permeases (BUPs). Initial expression studies in engineered yeast hosting segments of the opiate pathway showed that six of the nine BUP homologs facilitated dramatic increases in alkaloid yields. Closer examination revealed the ability to uptake a variety of BIAs and certain pathway precursors (e.g. dopamine), with each BUP displaying a unique substrate acceptance profile. Improvements in uptake for yeast expressing specific BUPs versus those devoid of the heterologous transporters were high for early intermediates (300- and 25-fold for dopamine and norcoclaurine, respectively), central pathway metabolites [10-fold for (S)-reticuline], and end products (30-fold for codeine). A coculture of three yeast strains, each harboring a different consecutive segment of the opiate pathway and BUP1, was able to convert exogenous Levodopa to 3 ± 4 mg/L codeine via a 14-step bioconversion process involving over a dozen enzymes. BUP1 is highly expressed in opium poppy latex and is localized to the plasma membrane. The discovery of the BUP transporter family expands the role of purine permease-type transporters in specialized metabolism, and provides key insight into the cellular mechanisms involved in opiate alkaloid biosynthesis in opium poppy.

Purpose Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. Patients and Methods In vitro MMR activity was quantified using a 3′-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. Results All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. Conclusion On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

Many accessibility features available on mobile platforms require applications (apps) to provide complete and accurate metadata describing user interface (UI) components. Unfortunately, many apps do not provide sufficient metadata for accessibility features to work as expected. In this paper, we explore inferring accessibility metadata for mobile apps from their pixels, as the visual interfaces often best reflect an app's full functionality. We trained a robust, fast, memory-efficient, on-device model to detect UI elements using a dataset of 77,637 screens (from 4,068 iPhone apps) that we collected and annotated. To further improve UI detections and add semantic information, we introduced heuristics (e.g., UI grouping and ordering) and additional models (e.g., recognize UI content, state, interactivity). We built Screen Recognition to generate accessibility metadata to augment iOS VoiceOver. In a study with 9 screen reader users, we validated that our approach improves the accessibility of existing mobile apps, enabling even previously inaccessible apps to be used.

Genes in plant secondary metabolic pathways enable biosynthesis of a range of medically and industrially important compounds, and are often clustered on chromosomes. Here, we study genomic clustering in the benzylisoquinoline alkaloid (BIA) pathway in opium poppy (Papaver somniferum), exploring relationships between gene expression, copy number variation, and metabolite production. We use Hi-C to improve the existing draft genome assembly, yielding chromosome-scale scaffolds that include 35 previously unanchored BIA genes. We find that co-expression of BIA genes increases within clusters and identify candidates with unknown function based on clustering and covariation in expression and alkaloid production. Copy number variation in critical BIA genes correlates with stark differences in alkaloid production, linking noscapine production with an 11-gene deletion, and increased thebaine/decreased morphine production with deletion of a T6ODM cluster. Our results show that the opium poppy genome is still dynamically evolving in ways that contribute to medically and industrially important phenotypes., The opium poppy has been a source of painkilling drugs synthesized by the benzylisoquinoline alkaloid pathway. Here, the authors report an improved genome assembly and reveal gene clustering and copy number variation in alkaloid metabolic pathways.

Adenoviruses (AdVs) are prevalent and give rise to chronic and recurrent disease. The human AdV (HAdV) species B and C, such as HAdV-C2, C5 and B14, cause respiratory disease, and constitute a health threat for immuno-compromised individuals. HAdV-Cs are well known for lysing cells, owing to the E3 CR1-β-encoded adenovirus death protein (ADP). We previously reported a high-throughput image-based screening framework and identified an inhibitor of HAdV-C2 multi-round infection, Nelfinavir Mesylate. Nelfinavir is the active ingredient of Viracept, an FDA-approved inhibitor of the human immuno-deficiency virus (HIV) aspartyl protease, and used to treat acquired immunodeficiency syndrome (AIDS). It is not effective against single round HAdV infections. Here, we show that Nelfinavir inhibits the lytic cell-free transmission of HAdV, indicated by the suppression of comet-shaped infection foci in cell culture. Comet-shaped foci occur upon convection-based transmission of cell-free viral particles from an infected cell to neighbouring uninfected cells. HAdV lacking ADP was insensitive to Nelfinavir, but gave rise to comet-shaped foci indicating that ADP enhances but is not required for cell lysis. This was supported by the notion that HAdV-B14 and B14p1 lacking ADP were highly sensitive to Nelfinavir, although HAdV-A31, B3, B7, B11, B16, B21, D8, D30 or D37 were less sensitive. Conspicuously, Nelfinavir uncovered slow-growing round-shaped HAdV-C2 foci, independent of neutralizing antibodies in the medium, indicative of non-lytic cell-to-cell transmission. Our study demonstrates the repurposing potential of Nelfinavir with post-exposure efficacy against different HAdVs, and describes an alternative non-lytic cell-to-cell transmission mode of HAdV.Graphical AbstractFigure 1.

Miscarriage and intrauterine growth restriction (IUGR) are devastating complications in fetal/neonatal alloimmune thrombocytopenia (FNAIT). We previously reported the mechanisms for bleeding diatheses, but it is unknown whether placental, decidual immune cells or other abnormalities at the maternal–fetal interface contribute to FNAIT. Here we show that maternal immune responses to fetal platelet antigens cause miscarriage and IUGR that are associated with vascular and immune pathologies in murine FNAIT models. Uterine natural killer (uNK) cell recruitment and survival beyond mid-gestation lead to elevated NKp46 and CD107 expression, perforin release and trophoblast apoptosis. Depletion of NK cells restores normal spiral artery remodeling and placental function, prevents miscarriage, and rescues hemorrhage in neonates. Blockade of NK activation receptors (NKp46, FcɣRIIIa) also rescues pregnancy loss. These findings shed light on uNK antibody-dependent cell-mediated cytotoxicity of invasive trophoblasts as a pathological mechanism in FNAIT, and suggest that anti-NK cell therapies may prevent immune-mediated pregnancy loss and ameliorate FNAIT., Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a gestational disease caused by maternal immune responses against fetal platelets. Using a FNAIT mouse model and human trophoblast cell lines, here the authors show that uterine natural killer cell-mediated trophoblast apoptosis contributes to FNAIT pathogenesis.

Introduction Dual use of electronic cigarettes (e-cigarettes) and combustible cigarettes is a major public health issue. It is generally accepted that exclusive e-cigarette use is less harmful than exclusive combustible cigarette use, but most e-cigarette users continue to smoke combustible cigarettes as well. To what extent the use of e-cigarettes reduces harm in people who continue to smoke combustible cigarettes has been debated. The aim of this study was to explore the utility of biomarkers as measures of dual use. Methods In two human studies of participants who used e-cigarettes only or both combustible cigarettes and e-cigarettes, we measured urine concentrations of the metabolites of nicotine (total nicotine equivalents) as well as two biomarkers of tobacco exposure: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a tobacco-specific carcinogen metabolite, and nicotelline, a tobacco alkaloid not found in significant concentrations in e-cigarette products. Results The presence of nicotine metabolites indicates either e-cigarette or combustible cigarette use. Nicotelline (half-life of 2–3 hours) indicates recent combustible cigarette use and NNAL (half-life of 10 days or more), indicates combustible cigarette use occurring within several weeks prior to sample collection. Conclusions Nicotelline and NNAL are useful biomarkers for combustible tobacco use in users e-cigarettes. The application of these biomarkers provides a tool to help assess whether, or to what extent, dual use of e-cigarettes and combustible cigarettes reduces harm compared to sole use of combustible cigarettes. These biomarkers can also verify exclusive use of e-cigarettes over short (24 hour) or long (several week) time periods. Implications: To what extent dual use of e-cigarettes and combustible cigarettes reduce harm compared to smoking combustible cigarettes only is of considerable public health interest. We show that the levels of the minor tobacco alkaloid nicotelline and the nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are extremely low in electronic cigarette fluids. The urine biomarkers nicotelline and the NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are indicative of cigarette smoking and can be used to assess recent and past smoking in dual users.

Groups of people tend to generate more diverse ideas than individuals because each group member brings a different perspective to the table. But while someone working alone can suffer from fixation and have difficulty of thinking outside-the-box, in this paper we show that it is possible to help them think more like a group by asking them to approach a problem from different perspectives. We present a study of 54 crowd workers in which some individual workers were asked to assume the role of various relevant experts while solving a problem. We find that participants who were asked to assume different roles came up with more creative ideas than those who were not. These findings suggest there is an opportunity for problem solving tools to bring the wisdom of the crowd to individuals.

Double minute chromosomes (DMs) are extrachromosomal cytogenetic structures found in tumour cells. As hallmarks of gene amplification, DMs often carry oncogenes and drug-resistance genes and play important roles in malignant tumour progression and drug resistance. The mitogen-activated protein kinase (MAPK) signalling pathway is frequently dysregulated in human malignant tumours, which induces genomic instability, but it remains unclear whether a close relationship exists between MAPK signalling and DMs. In the present study, we focused on three major components of MAPK signalling, ERK1/2, JNK1/2/3 and p38, to investigate the relationship between MAPK and DM production in tumour cells. We found that the constitutive phosphorylation of ERK1/2, but not JNK1/2/3 and p38, was closely associated with DMs in tumour cells. Inhibition of ERK1/2 activation in DM-containing and ERK1/2 constitutively phosphorylated tumour cells was able to markedly decrease the number of DMs, as well as the degree of amplification and expression of DM-carried genes. The mechanism was found to be an increasing tendency of DM DNA to break, become enveloped into micronuclei (MNs) and excluded from the tumour cells during the S/G2 phases of the cell cycle, events that accompanied the reversion of malignant behaviour. Our study reveals a linkage between ERK1/2 activation and DM stability in tumour cells.

Double minute chromosomes (DMs) are a hallmark of gene amplification. The relationship between the formation of DMs and the amplification of DM-carried genes remains to be clarified. The human colorectal cancer cell line NCI-H716 and human malignant primitive neuroectodermal tumor cell line SK-PN-DW are known to contain many DMs. To examine the amplification of DM-carried genes in tumor cells, we performed Affymetrix SNP Array 6.0 analyses and verified the regions of amplification in NCI-H716 and SK-PN-DW tumor cells. We identified the amplification regions and the DM-carried genes that were amplified and overexpressed in tumor cells. Using RNA interference, we downregulated seven DM-carried genes, (NDUFB9, MTSS1, NSMCE2, TRIB1, FAM84B, MYC and FGFR2) individually and then investigated the formation of DMs, the amplification of the DM-carried genes, DNA damage and the physiological function of these genes. We found that suppressing the expression of DM-carried genes led to a decrease in the number of DMs and reduced the amplification of the DM-carried genes through the micronuclei expulsion of DMs from the tumor cells. We further detected an increase in the number of γH2AX foci in the knockdown cells, which provides a strong link between DNA damage and the loss of DMs. In addition, the loss of DMs and the reduced amplification and expression of the DM-carried genes resulted in a decrease in cell proliferation and invasion ability.

This paper presents evidence that household energy use in Uganda conforms to the energy ladder theory. As household income increases, solid and transitional fuel use evolves in an inverse U manner, while electricity consumption shows a direct relationship with income. Public infrastructure provision, income, and education are the key variables which can be targeted to reduce household dependence on solid-fuels while increasing non-solid fuel use. While education and public infrastructure have varying impacts on rural and urban households' energy mix, these variables generally reduce rudimentary fuel use and increase modern fuel consumption. Timely investment in electricity infrastructure is necessary to cater for burgeoning electricity demand as households become affluent. Strategies for reforestation, dissemination of improved cookstoves, relieving supply side constraints for modern fuels, and staggered payment options to lower the cost of entry for modern fuels can improve Ugandan households' energy security.

Trends in the number of dogs entering and departing Taiwan public shelters are analyzed in this article. There were 40 public shelters surveyed from 2000 to 2005 for dog entries and departures. The results indicate that (a) adoption rates and relinquished animal numbers increased, and euthanasia rates decreased at the beginning of the study, but they are showing signs of reversal; (b) shelters in cities have higher adoption rates than those in rural areas; (c) euthanasia remains the main means of controlling dog numbers in most shelters; and (d) potential adopters in Taiwan prioritize animal health and body size when selecting dogs for adoption. There is a need for increased and persistent public education to ensure continued progress is made in encouraging people to treat companion animals responsibly. In addition to educational efforts, creating new, specialized shelters for housing highly adoptable animals can alleviate the space constraint problems in existing kennels and improve the welfare of stray dogs.

The pattern sensitivity for the data retention test of non-volatile memory was investigated. Through kinds of examples and combing theory analysis, it's found no universal sensitive pattern is capable to detect all kinds of process weakness, the selection of test pattern depends on the failure mechanism we most concern. Basically 00H or FFH state is the worst case to detect the intrinsic isolating ability of vertical dielectric, and CKBD (checkerboard, '0' and '1' state are alternated programmed) pattern can check not only vertical isolating effect, while half possibility when comparing to 00H or FFH, but also lateral cross-bit effect. Data retention pattern selection method during reliability test plays a critical role when applying more and more advanced technology to guarantee NVM (Non-Volatile Memory) product storage lifetime.

INTRODUCTION Measuring adherence to smoking cessation pharmacotherapy is important to evaluating its effectiveness. Blood levels are considered the most accurate measure of adherence but are invasive and costly. Pill counts and self-report are more practical, but little is known about their relationship to blood levels. This study compared the validity of pill count and self-report against plasma varenicline concentration for measuring pharmacotherapy adherence. METHODS Data were obtained from a randomized pilot study of varenicline for smoking cessation among African American smokers. Adherence was measured on Day 12 via plasma varenicline concentration, pill count, 3-day recall, and a visual analogue scale (VAS; adherence was represented on a line with two extremes "no pills" and "all pills"). RESULTS The sample consisted of 55 African American moderate to heavy smokers (average 16.8 cigarettes/day, SD = 5.6) and 63.6% were female. Significant correlations (p < .05) were found between plasma varenicline concentration and pill count (r = .56), 3-day recall (r = .46), and VAS (r = .29). Using plasma varenicline concentration of 2.0 ng/ml as the cutpoint for adherence, pill count demonstrated the largest area under the receiver operating characteristic curve (AUC = 0.85, p = .01) and had 88% sensitivity (95% CI = 75.0-95.0) and 80% specificity (95% CI = 30.0-99.0) for detecting adherence. CONCLUSIONS Of 3 commonly used adherence measures, pill count was the most valid for identifying adherence in this sample of African American smokers. Pill count has been used across other health domains and could be incorporated into treatment to identify nonadherence, which, in turn, could maximize smoking cessation pharmacotherapy use and improve abstinence rates.