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As members of the Clinical Practice Committee (CPC) of the Society for General Internal Medicine (SGIM), we support practice innovation and transformation to achieve a more just system by which all people can achieve and maintain optimal health. The COVID-19 pandemic has tested the US healthcare delivery system and sharpened our national awareness of long-standing and ingrained system shortcomings. In the face of crisis, SGIM members innovated and energetically mobilized to focus on the immediate needs of our patients and communities. Reflecting on these experiences, we are called to consider what was learned from the pandemic that applies to the future of healthcare delivery. CPC members include leaders in primary care delivery, practice finance, quality of care, patient safety, hospital practice, and health policy. CPC members provide expertise in clinical practice, serving as primary care doctors, hospitalists, and patient advocates who understand the intensity of care needed for those with severe COVID-19 infections, the disproportionate impact of the pandemic on Black and Brown communities, the struggles created for those with poor access to care, and the physical and emotional impact it has placed on patients, families, and clinicians. In this consensus statement, we summarize lessons learned from the 2020-2021 pandemic and their broader implications for reform in healthcare delivery. We provide a platform for future work by identifying many interactive elements of healthcare delivery that must be simultaneously addressed in order to ensure that care is accessible, equitably provided, patient-centered, and cost-effective.

Macrolides have been effective clinical antibiotics for over 70 years. They inhibit protein biosynthesis in bacterial pathogens by narrowing the nascent protein exit tunnel in the ribosome. The macrolide class of natural products consist of a macrolactone ring linked to one or more sugar molecules. Most of the macrolides used currently are semi-synthetic erythromycin derivatives, composed of a 14- or 15-membered macrolactone ring. Rapidly emerging resistance in bacterial pathogens is among the most urgent global health challenges, which render many antibiotics ineffective, including next-generation macrolides. To address this threat and advance a longer-term plan for developing new antibiotics, we demonstrate how 16-membered macrolides overcome erythromycin resistance in clinically isolated Staphylococcus aureus strains. By determining the structures of complexes of the large ribosomal subunit of Deinococcus radiodurans (D50S) with these 16-membered selected macrolides, and performing anti-microbial studies, we identified resistance mechanisms they may overcome. This new information provides important insights toward the rational design of therapeutics that are effective against drug resistant human pathogens.

Food, energy, and water (FEW) are basic needs for well-being and quality of life. Assessing FEW security allows residents, communities, and policy makers to make informed decisions about how to sustain and improve well-being. We have developed a FEW security assessment framework that examines four components of security: availability, access, quality, and preference. With the help of local community members, we interviewed 114 households in three rural Alaska communities to assess FEW security, drivers and outcomes of FEW security, and potential interactions among FEW components and with renewable energy (RE) developments. While FEW security was high overall, preference and quality, especially for food, was lower. Food harvested from the local environment (i.e. subsistence) was necessary to include in security assessments given that 24% of participants reported insecurity when asked about contemporary sources (i.e. purchased) versus 5% reporting insecurity for subsistence food sources (i.e., harvested). The major influences on FEW security tended to originate from outside the community, including factors such as transportation, income, fuel prices, and weather. One internal factor, health, was both a driver and an outcome of FEW security. Satisfaction with RE varied (42%-68%) with dissatisfaction due to unreliability, uncertainty of the economic benefit, desire for other types of RE, or wanting more RE (n = 6). Communication about RE projects was key to managing expectations, promoting knowledge, and identifying benefits for residents. Participants did not identify linkages between RE and FEW security. Our assessment tool can be used by communities and policy makers to contextualize FEW security into more insightful and specific components, allowing for identification of attainable actions to improve FEW security and thus individual and community well-being.

Background The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping “cell-of-origin”. Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry. Methods We compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naive and memory B-cells) from 36 donor tonsils using >325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and genome copy number (microarrays). Findings From the resulting data, we identified gains in active chromatin in enhancers/super-enhancers that likely promote unchecked B-cell receptor signaling, including one we validated near the immunoglobulin superfamily receptors FCMR and PIGR. More striking and pervasive was the profound loss of key B-cell identity TFs, tumor suppressors and their super-enhancers, including EBF1, OCT2(POU2F2), and RUNX3. Using a novel approach to identify transcriptional feedback, we showed that these core transcriptional circuitries are self-regulating. Their selective gain and loss form a complex, iterative, and interactive process that likely curbs B-cell maturation and spurs proliferation. Interpretation Our study is the first to map the transcriptional circuitry of the most common blood cancers. We demonstrate that a critical subset of B-cell TFs and their cognate enhancers form self-regulatory transcriptional feedback loops whose disruption is a shared mechanism underlying these diverse subtypes of B-cell lymphoma. Funding National Institute of Health, Siteman Cancer Center, Barnes-Jewish Hospital Foundation, Doris Duke Foundation.

Background COVID-positive outpatients may benefit from remote monitoring, but such a program often relies on smartphone apps. This may introduce racial and socio-economic barriers to participation. Offering multiple methods for participation may address these barriers. Objectives (1) To examine associations of race and neighborhood disadvantage with patient retention in a monitoring program offering two participation methods. (2) To measure the association of the program with emergency department visits and hospital admissions. Design Retrospective propensity-matched cohort study. Participants COVID-positive outpatients at a single university-affiliated healthcare system and propensity-matched controls. Interventions A home monitoring program providing daily symptom tracking via patient portal app or telephone calls. Main Measures Among program enrollees, retention (until 14 days, symptom resolution, or hospital admission) by race and neighborhood disadvantage, with stratification by program arm. In enrollees versus matched controls, emergency department utilization and hospital admission within 30 days. Key Results There were 7592 enrolled patients and 9710 matched controls. Black enrollees chose the telephone arm more frequently than White enrollees (68% versus 44%, p = 0.009), as did those from more versus less disadvantaged neighborhoods (59% versus 43%, p = 0.02). Retention was similar in Black enrollees and White enrollees (63% versus 62%, p = 0.76) and in more versus less disadvantaged neighborhoods (63% versus 62%, p = 0.44). When stratified by program arm, Black enrollees had lower retention than White enrollees in the app arm (49% versus 55%, p = 0.01), but not in the telephone arm (69% versus 71%, p = 0.12). Compared to controls, enrollees more frequently visited the emergency department (HR 1.71 [95% CI 1.56–1.87]) and were admitted to the hospital (HR 1.16 [95% CI 1.02–1.31]). Conclusions In a COVID-19 remote patient monitoring program, Black enrollees preferentially selected, and had higher retention in, telephone- over app-based monitoring. As a result, overall retention was similar between races. Remote monitoring programs with multiple modes may reduce barriers to participation. Supplementary Information The online version contains supplementary material available at 10.1007/s11606-021-07207-4.

Background: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting a therapy that is both effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the histone acetylation landscape in CTCL remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. Methods: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray), and using ELISA in matched CTCL patient plasma. Findings: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FC≥2, FDR

The cryptophycins are a family of macrocyclic depsipeptide natural products that display exceptionally potent anti-proliferative activity against drug-resistant cancers. Unique challenges facing the synthesis and derivatization of this complex group of molecules motivated us to investigate a chemoenzymatic synthesis designed to access new analogs for biological evaluation. The cryptophycin thioesterase (CrpTE) and the cryptophycin epoxidase (CrpE) are a versatile set of enzymes that catalyze macrocyclization and epoxidation of over twenty natural cryptophycin metabolites. Thus, we envisioned a drug development strategy involving their use as standalone biocatalysts for production of unnatural derivatives. Herein, we developed a scalable synthesis of 12 new unit A-B-C-D linear chain elongation intermediates containing heterocyclic aromatic groups as alternatives to the native unit A benzyl group. N-acetyl cysteamine activated forms of each intermediate were assessed for conversion to macrocyclic products using wild type CrpTE, which demonstrated the exceptional flexibility of this enzyme. Semi-preparative scale reactions were conducted for isolation and structural characterization of new cryptophycins. Each was then evaluated as a substrate for CrpE P450 and its ability to generate the epoxidized products from these substrates that possess altered electronics at the unit A styrenyl double bond position. Finally, biological evaluation of the new cryptophycins revealed a des-β-epoxy analog with low picomolar potency, previously limited to cryptophycins bearing epoxide functionality.

Out-of-school time programs focused on science, technology, engineering and mathematics (STEM) have proliferated recently because they are seen as having potential to appeal to youth and enhance STEM interest. Although such programs are not mandatory, youth are not always involved in making the choice about their participation and it is unclear whether youth's involvement in the choice to attend impacts their program experiences. Using data collected from experience sampling, traditional surveys, and video recordings, we explore relationships among youth's choice to attend out-of-school time programs (measured through a pre-survey) and their experience of affect (i.e., youth experience sampling ratings of happiness and excitement) and engagement (i.e., youth experience sampling ratings of concentration and effort) during program activities. Data were collected from a racially and ethnically diverse sample of 10-16 year old youth (n = 203; 50% female) enrolled in nine different summer STEM programs targeting underserved youth. Multilevel analysis indicated that choice and affect are independently and positively associated with momentary engagement. Though choice to enroll was a significant predictor of momentary engagement, positive affective experiences during the program may compensate for any decrements to engagement associated with lack of choice. Together, these findings have implications for researchers, parents, and educators and administrators of out-of-school time programming.

SummaryMost B-cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions REs from normal GC B cells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression was deregulated in FL, targeted commandeered versus decommissioned REs. Our approach revealed two distinct subtypes of low-grade FL, whose pathogenic circuitries resembled GC B or activated B cells. FL-altered enhancers also were enriched for sequence variants, including somatic mutations, which disrupt transcription-factor binding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC B-cell transformation.

Congenital hydrocephalus, the accumulation of excess cerebrospinal fluid (CSF) in the ventricles of the brain, affects one of every 1000 children born today, making it one of the most common human developmental disorders. Genetic causes of hydrocephalus are poorly understood in humans, but animal models suggest a broad genetic program underlying the regulation of CSF balance. In this study, the random integration of a transgene into the mouse genome led to the development of an early onset and rapidly progressive hydrocephalus. Juvenile hydrocephalus transgenic mice (Jhy(lacZ)) inherit communicating hydrocephalus in an autosomal recessive fashion with dilation of the lateral ventricles observed as early as postnatal day 1.5. Ventricular dilation increases in severity over time, becoming fatal at 4-8 weeks of age. The ependymal cilia lining the lateral ventricles are morphologically abnormal and reduced in number in Jhy(lacZ/lacZ) brains, and ultrastructural analysis revealed disorganization of the expected 9+2 microtubule pattern. Rather, the majority of Jhy(lacZ/lacZ) cilia develop axonemes with 9+0 or 8+2 microtubule structures. Disruption of an unstudied gene, 4931429I11Rik (now named Jhy) appears to underlie the hydrocephalus of Jhy(lacZ/lacZ) mice, and the Jhy transcript and protein are decreased in Jhy(lacZ/lacZ) mice. Partial phenotypic rescue was achieved in Jhy(lacZ/lacZ) mice by the introduction of a bacterial artificial chromosome (BAC) carrying 60-70% of the JHY protein coding sequence. Jhy is evolutionarily conserved from humans to basal vertebrates, but the predicted JHY protein lacks identifiable functional domains. Ongoing studies are directed at uncovering the physiological function of JHY and its role in CSF homeostasis.

Alterations to the epigenetic landscape of diffuse large B-cell lymphoma (DLBCL) play a fundamental role in deregulating genes involved in normal lymphocyte differentiation. To determine whether targeted epigenetic therapy could reverse these pathogenic chromatin changes and suppress the expression of a lymphoma oncogene, we focused on BCL6, a transcriptional repressor whose aberrant expression is tightly linked to DLBCL proliferation and survival. We fused zinc-finger (ZF) domains specific for regulatory regions in the BCL6 locus to a repressive epigenetic modifier, the Kruppel-associated box (KRAB) repressor domain. Distinct ZF-KRAB fusions repressed the local chromatin landscape, suppressed BCL6 expression, significantly impaired DLBCL growth, and caused widespread cell death in a BCL6-dependent manner. Importantly, expression of ectopic BCL6 protein rescued ZF-KRAB-induced cell death, demonstrating the modifiers' specificity. We show that sequence-specific epigenetic modifiers can alter oncogene expression and induce apoptosis in cancer cells, underscoring their potential for future development as targeted epigenetic protein therapies.

Objective.— The present study was designed to discern the prevalence of concomitant use of a 5-hydroxytryptamine receptor agonist (triptan), and a selective serotonin reuptake inhibitor (SSRI) or a selective serotonin/norepinephrine reuptake inhibitor (SNRI) after the US Food and Drug Administration issued an alert regarding serotonin syndrome in 2006 and to contrast findings with data published prior to the federal warning. Background.— In July 2006, the US Food and Drug Administration warned patients and health-care professionals to be aware that use of a triptan in combination with an SSRI or SNRI may result in a potentially life-threatening problem known as serotonin syndrome. In 2010, the American Headache Society published a position paper noting that there existed conflicting and insufficient information to discern the risk of serotonin syndrome with the use of triptan, and SSRI or SNRI, and that said Class IV data were not to be used as the basis for limiting the prescribing of triptan with SSRI or SNRI (Level U). Clinicians were cautioned as to the seriousness of serotonin toxicity and that monitoring was warranted. Methods.— We used weighted data from the US National Ambulatory Medical Care Survey for years 2007 and 2008 to derive national estimates of the number of office-based physician–patient encounters (visits), documenting the concomitant use of triptan, and SSRI or SNRI. Results are compared with previously published findings for the years 2003 and 2004. Results.— During the time-frame 2007-2008, an annualized mean of 5,256,958 patients were prescribed a triptan (vs 3,874,367 in 2003-2004, a 35.7% increase), and 68,603,600 patients were prescribed an SSRI or SNRI (vs 50,402,149 in 2003-2004, a 36.1% increase). An annualized mean of 1,319,763 patients were simultaneously prescribed or continued use of triptan, along with SSRI or SNRI (vs 694,276 in 2003-2004, a 90.1% increase). Conclusion.— Our study documents that 1.8% (1,319,763/73,860,558) of patients in 2007-2008 were prescribed triptan, and SSRI or SNRI (vs 1.3% in 2003-04, an increase of 38.5%). While this is a small fraction overall, the actual number of patients on a nationwide basis is substantial. What remains missing from the literature is documentation as to the number of cases of serotonin syndrome and resulting consequences (clinical and economic) because of the concomitant use of triptan, and SSRI or SNRI in the time-frame 2007-2008. Absent in these data, it remains difficult to assess the risk benefit associated with the use of triptan, and SSRI or SNRI.

Seborrheic dermatitis is a chronic, recurring skin disorder that has no cure.Current clinical research has implicated Malassezia yeast in the etiology. Using a clear, concise clinical picture and a thorough patient history, even the novice NP can formulate an effective treatment plan.

Youth who participate in service activities differ from those who do not on a number of key demographic characteristics like socio-economic status and other indicators of risk; and most studies demonstrating positive outcomes among service participants employ small non-representative samples. Thus, there is little evidence as to whether the outcomes associated with service participation are similar among students with varying levels of risk. The National Household Education Survey of 1999, a large nationally representative cross-sectional data set that focused on community service, was analyzed to investigate associations between the risk status of 4,306 adolescent students (50.2% female; 63.3% European American, M age = 15.9), their participation in community service, and their academic adjustment, behavioral problems, and civic knowledge. Because adolescents who participate in service differ from those who do not with respect to demographic characteristics, propensity score analyses were used to correct for potential selection bias in the examination of these relationships. Analyses tested competing theoretical models of service-protective versus compensatory-among students at varying levels of risk, and suggested that service acts as a compensatory factor with respect to academic, behavioral, and civic outcomes. Propensity score analyses revealed patterns suggesting that, in some cases, students with certain demographic profiles that are themselves related to the likelihood of service participation may benefit from service participation more than others. Findings are discussed in terms of their significance for adolescent development, for planning service programs, and for educational policy.

Candida glabrata is an opportunistic human pathogen that is increasingly associated with candidemia, owing in part to the intrinsic and acquired high tolerance the organism exhibits for the important clinical antifungal drug fluconazole. This elevated fluconazole resistance often develops through gain-of-function mutations in the zinc cluster-containing transcriptional regulator C. glabrata Pdr1 (CgPdr1). CgPdr1 induces the expression of an ATP-binding cassette (ABC) transporter-encoding gene, Cg CDR1 . Saccharomyces cerevisiae has two CgPdr1 homologues called ScPdr1 and ScPdr3. These factors control the expression of an ABC transporter-encoding gene called Sc PDR5 , which encodes a homologue of Cg CDR1 . Loss of the mitochondrial genome (ρ 0 cell) or overexpression of the mitochondrial enzyme ScPsd1 induces Sc PDR5 expression in a strictly ScPdr3-dependent fashion. ScPdr3 requires the presence of a transcriptional Mediator subunit called Gal11 (Med15) to fully induce Sc PDR5 transcription in response to ρ 0 signaling. ScPdr1 does not respond to either ρ 0 signals or ScPsd1 overproduction. In this study, we employed transcriptional fusions between CgPdr1 target promoters, like Cg CDR1 , to demonstrate that CgPdr1 stimulates gene expression via binding to elements called pleiotropic drug response elements (PDREs). Deletion mapping and electrophoretic mobility shift assays demonstrated that a single PDRE in the Cg CDR1 promoter was capable of supporting ρ 0 -induced gene expression. Removal of one of the two ScGal11 homologues from C. glabrata caused a major defect in drug-induced expression of Cg CDR1 but had a quantitatively minor effect on ρ 0 -stimulated transcription. These data demonstrate that CgPdr1 appears to combine features of ScPdr1 and ScPdr3 to produce a transcription factor with chimeric regulatory properties.

Peer victimization has been implicated as a traumatic stressor that compromises children's long-term mental health, yet a dearth of prospective research documents lasting effects of early victimization. This study examined whether early (2nd grade) and increasing (2nd-5th grade) victimization predicted 5th grade depressive symptoms and aggressive behavior. Children (238 girls, 195 boys) reported on victimization and depressive symptoms; teachers reported on victimization and aggressive behavior. Latent growth curve analysis revealed that early and increasing victimization made unique contributions to depressive symptoms and aggressive behavior. Relational aggression was particularly likely to follow victimization in girls. This study reveals that victimization contributes to mental health over an extended period and elucidates the role of early versus increasing victimization, supporting the need for programs to prevent the pernicious mental health consequences of victimization.

The leaf oil of Heteropyxis dehniae Suess. (Heteropyxidaceae) was obtained by hydrodistillation and analyzed by GC/MS. The most abundant essential oil components are linalool (58.3%), 4-terpineol (9.8%), α-terpineol (3.6%), and caryophyllene oxide (3.1%). The antimicrobial activity against Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and Aspergillus niger, and the in vitro cytotoxicity of the oil on PC-3, MDA-MB-231, Hs 578T, MCF7, SK-MEL-28, and 5637 human tumor cells were also examined. Caryophyllene oxide shows notable cytotoxic activity with LC50 values of 147–351 μM.

Artemisia douglasiana leaf has been shown to be efficacious complementary herbal treatment for chronic bladder infection in a paraplegic youth. The leaf oil has been analyzed by GC-MS and the major components found to be camphor (29%), artemisia ketone (26%), artemisia alcohol (13%), alpha-thujone (10%), 1,8-cineole (8%), and hexanal (5%). The leaf oil and the major components have been tested for antimicrobial activity against Bacillus cereus, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger. The essential oil shows limited antimicrobial activity in vitro, so it is unclear if the oil exerts a direct antimicrobial effect in vivo, or plays some role in stimulation of host defenses.

In this paper we provide a comprehensive examination of Americans' priorities within both health and health care. We find that Americans do have a clear set of priorities in each of these areas. Americans rated cancer, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), and heart disease, and medical research to address these conditions, as top priorities among eighty health problems. However, they did not rank many leading causes of death very high as serious problems. On the issue of health care, problems of costs, prescription drugs, and the uninsured top the list. Americans are very concerned about emerging international infectious diseases that they believe threaten their health.

▪ Abstract The aryl hydrocarbon (Ah) receptor has occupied the attention of toxicologists for over two decades. Interest arose from the early observation that this soluble protein played key roles in the adaptive metabolic response to polycyclic aromatic hydrocarbons and in the toxic mechanism of halogenated dioxins and dibenzofurans. More recent investigations have provided a fairly clear picture of the primary adaptive signaling pathway, from agonist binding to the transcriptional activation of genes involved in the metabolism of xenobiotics. Structure-activity studies have provided an understanding of the pharmacology of this receptor; recombinant DNA approaches have identified the enhancer sequences through which this factor regulates gene expression; and functional analysis of cloned cDNAs has allowed the characterization of the major signaling components in this pathway. Our objective is to review the Ah receptor's role in regulation of xenobiotic metabolism and use this model as a framework for understanding the less well-characterized mechanism of dioxin toxicity. In addition, it is hoped that this information can serve as a model for future efforts to understand an emerging superfamily of related signaling pathways that control biological responses to an array of environmental stimuli.

Background: Fidaxomicin is a macrocyclic antibiotic approved in 2011 by the US Food and Drug Administration for treatment of Clostridium difficile-associated diarrhoea (CDAD). Objective: Herein, we present an epidemiological method to estimate, on a case mix basis, and from the perspective of the US health system, the warranted (justifiable) price per day for fidaxomicin, as a percent of the wholesale acquisition cost (WAC) per day for fidaxomicin ($US280). Methods: Data from two randomized controlled studies (Optimer-003 [n = 596] and Optimer-004 [n = 509]) were used to discern the number-needed-to-treat (NNT = 7.1) for sustained clinical response. Sustained clinical res ponse was defined as clinical response at the end of treatment, and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment. National data for primary and secondary cases (the case mix) of CDAD (mean hospital length of stay [LOS], and mean cost) were derived from the 2009 US Healthcare Cost and Utilization Project. The method for attribution of hospital LOS for secondary cases of CDAD was derived from a study published by O’Brien et al. in 2007. Comparative regi mens of vancomycin were: (i) injectable used orally, 125 mg four times daily (qid; WAC of $US6/day), with use of vancomycin hydrochloride (HCl) cap sules, 125 mg qid (WAC of $US106/day) post-hospital discharge; (ii) vanco mycin HCl capsules, 125 mg qid; and (iii) vancomycin HCl capsules, 250 mg qid (WAC of $US196/day). Findings are expressed in 2011 US dollars. The study perspective is that of the US health system. Results: The warranted price per day for fidaxomicin represented 95% of the WAC per day for fidaxomicin compared with use of injectable vancomycin (orally) 125mg qid (with subsequent use of vancomycin HCl capsules, 125mg qid post-hospital discharge); 109% of the WAC per day for fidaxomicin compared with use of vancomycin HCl capsules, 125mg qid; and 141% of the WAC per day for fidaxomicin when compared with use of vancomycin HCl capsules, 250mg qid. Conclusion: From the perspective of the US health system, fidaxomicin represents value for money in the treatment of CDAD. The methodology employed in this research has application beyond antimicrobial pharmacotherapy.

Both the rate of diagnosis of depression in the US and the rate of prescribing an antidepressant for its treatment have increased substantially over the past two decades. Previous research has also indicated that the rates of diagnosis and treatment of depression with an antidepressant vary widely by ethnicity/race. The objective of this study was to discern ethnic/race-specific (non-Hispanic Black; Hispanic; non-Hispanic White) population-adjusted rates of US office-based physician-patient encounters (office-based visits) documenting a diagnosis of depression, and the extent of the use of antidepressant pharmacotherapy for its treatment.Data from the US National Ambulatory Medical Care Survey (NAMCS) for the years 1992-1997 and 2003-2008 were utilized for this analysis. The years 1998-2002 were excluded due to the magnitude of missing data for the variable ethnicity. The US NAMCS is a national probability sample designed and conducted by the US National Center for Health Statistics of the US Centers for Disease Control and Prevention. Depression was defined via International Classification of Diseases, 9th Revision, Clinical Modification codes 296.2-296.36; 300.4; 311. Antidepressants were defined as US National Drug Code category 0630 prior to 2005, and category 249 in Lexicon Plus® thereafter. Data were partitioned into six 2-year time intervals for trend analysis of population-adjusted rates (per 100) among patients aged 20-79 years. Rates per 2-year time interval are based on US Census Bureau national resident population estimates for the ethnicity/race categories examined. Comparisons within and across time-frames were assessed by chi-squared (χ2) analysis. The a priori level of significance for all statistical tests was set at p 0.05. Analyses were performed using SAS Release 9.1.3.Over the 12-year time-frame examined, the rate of office-based visits documenting a diagnosis of depression increased 28.4% for non-Hispanic Whites (from 10.9 to 14.0 per 100; p 0.001), 54.8% for non-Hispanic Blacks (from 4.2 to 6.5 per 100; p 0.001), and 37.5% for Hispanics (from 4.8 to 6.6 per 100; p 0.001). The rate of office-based visits with a recorded diagnosis of depression in concert with the prescribing of an antidepressant increased 66.2% for non-Hispanic Whites (from 6.5 to 10.8 per 100; p 0.001), 69.2% for non-Hispanic Blacks (from 2.6 to 4.4 per 100; p 0.001), and 36.7% for Hispanics (from 3.0 to 4.1 per 100; p 0.001).By 2003-2004, the population-adjusted rates for non-Hispanic Blacks and Hispanics were similar, and remained so through 2007-2008. However, over the 12-year time-frame examined, the rates for both minority groups were, in each 2-year interval, far less than that observed in non-Hispanic Whites. Disparities remain by ethnicity/race in the diagnosis and treatment of depression in the US.

The AHR locus encodes the structural gene for the Ah receptor, a ligand activated transcription factor that regulates the expression of a number of enzymes involved in the metabolism of chemical carcinogens and that appears to mediate the tumor promoting properties of compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Using polymerase chain reaction (PCR), we amplified exon-10 and intron-D of the AHR gene from human genomic DNA. By using PCR analysis of somatic cell hybrids and fluorescence in situ hybridization of metaphase cells, we localized AHR to human chromosome 7, bands p21→pl5. This mapping data should prove useful in determining the role that the AHR locus plays in human cancer incidence and in the identification of human populations with altered susceptibilities to the toxic/carcinogenic effects of planar aromatic hydrocarbons.

Despite much progress in the study and treatment of depression, the mechanisms underlying this debilitating disease are still unclear. Altered activity of several major neurotransmitters in the brain including serotonin is involved, but pinpointing the parts of the brain affected in depression has proved challenging. Alexander and colleagues now implicate a brain region called the nucleus accumbens and a protein called p11 expressed in this region as important mediators of depression in humans and mice. The authors were alerted to the potential importance of p11 in depression because mice that lack this protein show depressive-like behavior. This protein is involved in the activation of two receptors for serotonin, 5-HT1B and 5-HT4. Alexander et al . decided to down-regulate expression of p11 specifically in the nucleus accumbens by injecting a viral vector containing a small interfering RNA against p11 directly into this brain region in healthy mice. They then tested the treated mice to see if they exhibited depressive-like behaviors in response to two stress tests (suspension by the tail and swimming in a water tank). In both tests, treated mice showed greater immobility compared with control animals, a sign of depressive-like behavior. To show that these depressive symptoms were indeed caused by loss of p11 in the nucleus accumbens, the investigators overexpressed p11 in the nucleus accumbens of mice that completely lacked this protein. They demonstrated restoration of normal immobility times on the two stress tests and an increased desire to sip sucrose solution (a treat that rodents normally enjoy but depressed animals do not). They also showed increased activity of 5-HT1B serotonin receptors expressed by striatal neurons in the nucleus accumbens of mice overexpressing p11. But do these results have any relevance to depression in humans? Alexander and colleagues tackled this question by comparing postmortem nucleus accumbens brain tissue from individuals with and without depression at the time of death. They discovered that expression of p11 was much lower in the nucleus accumbens of depressed individuals compared with healthy persons. These new findings pinpoint the nucleus accumbens and the p11 protein as important mediators of depression and provide new therapeutic targets for drug development.

Objective: Our aim was to explore the consequences for speech understanding of leaving a gap in frequency between a region of acoustic hearing and a region stimulated electrically. Our studies were conducted with normal-hearing listeners, using an acoustic simulation of combined electric and acoustic (EAS) stimulation. Design: Simulations of EAS were created by low-pass filtering speech at 0.5 kHz (90 dB octave roll-off) and adding amplitude-modulated sine waves at higher frequencies. The gap in frequency between acoustic and simulated electric hearing was varied over the range 0.5 kHz to 3.2 kHz. Stimuli included sentences in quiet, sentences in noise, and consonants and vowels. Three experiments were conducted with sample sizes of 12 listeners. Results: Scores were highest in conditions that minimized the frequency gap between acoustic and electric stimulation. In quiet, vowels and consonant place of articulation showed the most sensitivity to the frequency gap. In noise, scores in the simulated EAS condition were higher than the sum of the scores from the acoustic-only and simulated electric-only conditions. Conclusions: Our results suggest that both deep and shallow insertions of electrodes could improve the speech understanding abilities of patients with residual hearing to 500 Hz. However, performance levels will be maximized if the gap between acoustic and electric stimulation is minimized.

The crude dichloromethane extract from the stem bark of Cupania glabra (Sapindaceae), showed in vitro cytotoxic activity against Hep G2, MDA-MB-231, Hs 578T, MCF-7, and PC-3 cells, and antibacterial activity against Bacillus cereus, Staphylococcus aureus, and Escherichia coli. Bioactivity-directed fractionation led to isolation of the new 1-O-[2'',3'',4''-tri-O-acetyl-alpha-L-rhamnopyranosyl-(1-->2)-beta- D-glucopyranosyl]-hexadecanol (cupanioside) as the cytotoxic agent. The structure was elucidated by analysis of 2D-NMR spectra.

The crude dichloromethane bark extract of Pilidiostigma tropicum (Myrtaceae) from north Queensland, Australia, shows antibacterial and cytotoxic activity. Bioactivity-directed separation led to the isolation of rhodomyrtoxin B and ursolic acid-3-p-coumarate as the biologically active materials. The structures of these compounds were elucidated on the basis of spectral analysis. The intercalation interaction of rhodomyrtoxin B with DNA was investigated using molecular mechanics and ab initio molecular-orbital techniques. A favorable pi-pi interaction between rhodomyrtoxin B and the cytosine-guanine base pair is predicted, but the orientation of the interaction cannot be predicted based on frontier molecular orbitals.

The crude methanol bark extract of the Zimbabwean medicinal plant, Ozoroa insignis, showed in-vitro cytotoxic activity against Hep-G2 (human hepatocellular carcinoma), MDA-MB-231 (human mammary adenocarcinoma), and 5637 (human primary bladder carcinoma). Bioactivity-directed chromatographic separation led to isolation of anacardic acid and ginkgoic acid as the cytotoxic components.

Previous studies of Staphylococcus aureus transposon insertion mutants showing decreased methicillin or teicoplanin resistance have suggested a role for the RNA polymerase alternative sigma factor SigB in the expression of resistance to these antibiotics. A knockout mutation was created in the S. aureus strain COL sigB gene and its influence on oxacillin and vancomycin resistance was studied in a variety of parental backgrounds. Typically, sigB mutants of methicillin-resistant strains had oxacillin minimum inhibitory concentrations (MICs) one-half of their parent strains. The effect of the sigB mutation appeared to be more dramatic when assessed by population analysis profiles or by growth in liquid culture in shaking flasks than by MIC determinations. Oxacillin MICs of COL and the COLDeltasigB mutant were 400 and 200 mg/l, respectively, by conventional determination and 800 and 100-200 mg/l from population analysis profiles. The COLDeltasigB mutant strain was significantly more inhibited by a range of oxacillin concentrations in a shake flask culture than strain COL. Mutation of sigB caused a decrease in vancomycin resistance in two laboratory derived glycopeptide-intermediate S. aureus strains. The results suggest that some protein products whose expression is controlled by SigB play a role in resistance to cell wall-active antibiotics.

A series of 12 Staphylococcus aureus strains of various genetic backgrounds, methicillin resistance levels, and autolytic activities were subjected to selection for the glycopeptide-intermediate S. aureus (GISA) susceptibility phenotype on increasing concentrations of vancomycin. Six strains acquired the phenotype rapidly, two did so slowly, and four failed to do so. The vancomycin MICs for the GISA strains ranged from 4 to 16 μg/ml, were stable to 20 nonselective passages, and expressed resistance homogeneously. Neither ease of acquisition of the GISA phenotype nor the MIC attained correlated with methicillin resistance hetero- versus homogeneity or autolytic deficiency or sufficiency. Oxacillin MICs were generally unchanged between parent and GISA strains, although the mec members of both isogenic methicillin-susceptible and methicillin-resistant pairs acquired the GISA phenotype more rapidly and to higher MICs than did their susceptible counterparts. Transmission electron microscopy revealed that the GISA strains appeared normal in the absence of vancomycin but had thickened and diffuse cell walls when grown with vancomycin at one-half the MIC. Common features among GISAs were reduced doubling times, decreased lysostaphin susceptibilities, and reduced whole-cell and zymographic autolytic activities in the absence of vancomycin. This, with surface hydrophobicity differences, indicated that even in the absence of vancomycin the GISA cell walls differed from those of the parents. Autolytic activities were further reduced by the inclusion of vancomycin in whole-cell and zymographic studies. The six least vancomycin-susceptible GISA strains exhibited an increased capacity to remove vancomycin from the medium versus their parent lines. This study suggests that while some elements of the GISA phenotype are strain specific, many are common to the phenotype although their expression is influenced by genetic background. GISA strains with similar glycopeptide MICs may express individual components of the phenotype to different extents.

This chapter explores factors that predict adolescent participation in cooperative activities, which may indicate a predisposition to become involved in community activities later in life. It specifically examines the idea that middle schoolers' subjective experience of challenge may be linked to cooperative behavior later in adolescence.

Genes involved in sex determination and differentiation have been identified in mice, humans, chickens, reptiles, amphibians and teleost fishes. However, little is known of their functional conservation, and it is unclear whether there is a common set of genes shared by all vertebrates. Coelacanths, basal Sarcopterygians and unique “living fossils”, could help establish an inventory of the ancestral genes involved in these important developmental processes and provide insights into their components. In this study 33 genes from the genome of Latimeria chalumnae and from the liver and testis transcriptomes of Latimeria menadoensis, implicated in sex determination and differentiation, were identified and characterized and their expression levels measured. Interesting findings were obtained for GSDF, previously identified only in teleosts and now characterized for the first time in the sarcopterygian lineage; FGF9, which is not found in teleosts; and DMRT1, whose expression in adult gonads has recently been related to maintenance of sexual identity. The gene repertoire and testis-specific gene expression documented in coelacanths demonstrate a greater similarity to modern fishes and point to unexpected changes in the gene regulatory network governing sexual development.