Exploring associations between affect and marijuana use in everyday life via specification curve analysis.

Although frequently hypothesized, the evidence for associations between affect and marijuana use in everyday life remains ambiguous. Inconsistent findings across existing work may be due, in part, to differences in study design and analytic decisions, such as study inclusion criteria, the operationalization of affect, or the timing of affect assessment. We used specification curves to assess the robustness of the evidence for affect predicting same-day marijuana use and marijuana use predicting next-day affect across several hundred models that varied in terms of decisions that reflect those typical in this literature (e.g., whether to average affect prior to marijuana use or select the affect report closest in time to marijuana use). We fitted these curves to data from two ecological momentary assessment studies of regular marijuana and/or alcohol using college students (N = 287). Results provided robust evidence that marijuana use was slightly less likely following experiences of negative affect and slightly more likely following positive affect. Specification curves suggested that differences in previous findings are most likely a function of the specific emotion items used to represent affect rather than differences in inclusion criteria, the temporal assessment and modeling of affect, or the covariates added to the model. There was little evidence for an association between marijuana use and next-day affect. Overall, our findings provide evidence against the predictions made by affect reinforcement models in college students and suggest that future research should model the associations of marijuana use with discrete emotional states rather than general negative and positive affect. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Case Report: Secondary Hemophagocytic Lymphohistiocytosis With Disseminated Infection in Chronic Granulomatous Disease-A Serious Cause of Mortality.

Chronic granulomatous disease (CGD) is a primary immune deficiency due to defects in phagocyte respiratory burst leading to severe and life-threatening infections. Patients with CGD also suffer from disorders of inflammation and immune dysregulation including colitis and granulomatous lung disease, among others. Additionally, patients with CGD may be at increased risk of systemic inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). The presentation of HLH often overlaps with symptoms of systemic inflammatory response syndrome (SIRS) or sepsis and therefore can be difficult to identify, especially in patients with a primary immune deficiency in which incidence of infection is increased. Thorough evaluation and empiric treatment for bacterial and fungal infections is necessary as HLH in CGD is almost always secondary to infection. Simultaneous treatment of infection with anti-microbials and inflammation with immunosuppression may be needed to blunt the hyperinflammatory response in secondary HLH. Herein, we present a series of X-linked CGD patients who developed HLH secondary to or with concurrent disseminated CGD-related infection. In two patients, CGD was a known diagnosis prior to development of HLH and in the other two CGD was diagnosed as part of the evaluation for HLH. Concurrent infection and HLH were fatal in three; one case was successfully treated, ultimately receiving hematopoietic stem cell transplantation. The current literature on presentation, diagnosis, and treatment of HLH in CGD is reviewed.

Recent Advances in Antiemetics: New Formulations of 5-HT3 Receptor Antagonists in Adults.

BACKGROUND: Despite the availability of effective antiemetic regimens, patients still experience chemotherapy-induced nausea and vomiting (CINV). 5-Hydroxytryptamine 3 (5-HT3) receptor antagonists (RAs) are the mainstay of CINV prevention, and updated antiemetic guidelines include new options. OBJECTIVE: The aim of this study was to highlight advances in CINV management, focusing on new 5-HT3 RA formulations in adults, updated antiemetic guidelines, and the role of nurses. METHODS: MEDLINE searches were conducted for English-language publications for the past 15 years using relevant search terms ("serotonin receptor antagonist," "5-HT3 receptor antagonist," "antiemetic," "chemotherapy-induced nausea and vomiting") in the abstract or title. Abstracts at relevant major congresses for the past 3 years and additional pivotal publications were included. The most informative, relevant, and current publications were included. RESULTS: 5-Hydroxytryptamine 3 RAs are effective in preventing acute (0-24 hours) CINV but less effective in the delayed phase (24-120 hours) given their short half-lives. Updated antiemetic guidelines include fixed-dose intravenous fosnetupitant and palonosetron (IV NEPA) and granisetron extended-release subcutaneous injection, a recently approved 5-HT3 RA formulation providing slow, controlled release of therapeutic granisetron concentrations for 5 days or longer. Nurses play a pivotal role in implementing updated guideline-recommended antiemetic regimens for highly and some moderately emetogenic chemotherapy regimens, comprising a 4- or 3-drug regimen of 5-HT3 RA, neurokinin-1 RA, and dexamethasone, with/without olanzapine. CONCLUSION: Newer antiemetic combinations and formulations provide flexibility for CINV prevention. Granisetron extended-release subcutaneous injection is a convenient subcutaneous granisetron option. IMPLICATIONS FOR PRACTICE: Nurses play a critical role in understanding and using new antiemetic formulations and updated antiemetic guidelines in their practices.

The Effect of Age, Sex, Area Deprivation, and Living Arrangements on Total Knee Replacement Outcomes: A Study Involving the United Kingdom National Joint Registry Dataset.

BACKGROUND: Total knee replacement (TKR) is a common procedure for the treatment of osteoarthritis that provides a substantial reduction of knee pain and improved function in most patients. We investigated whether sociodemographic factors could explain variations in the benefit resulting from TKR. METHODS: Data were collected from 3 sources: the National Joint Registry for England, Wales, Northern Ireland, and the Isle of Man; National Health Service (NHS) England Patient Reported Outcome Measures; and Hospital Episode Statistics. These 3 sources were linked for analysis. Pain and function of the knee were measured with use of the Oxford Knee Score (OKS). The risk factors of interest were age group, sex, deprivation, and social support. The outcomes of interest were sociodemographic differences in preoperative scores, 6-month postoperative scores, and change in scores. RESULTS: Ninety-one thousand nine hundred and thirty-six adults underwent primary TKR for the treatment of osteoarthritis in an NHS England unit from 2009 to 2012. Sixty-six thousand seven hundred and sixty-nine of those patients had complete knee score data and were included in the analyses for the present study. The preoperative knee scores were worst in female patients, younger patients, and patients from deprived areas. At 6 months postoperatively, the mean knee score had improved by 15.2 points. There were small sociodemographic differences in the benefit of surgery, with greater area deprivation (-0.71 per quintile of increase in deprivation; 95% confidence interval [CI], -0.76 to -0.66; p < 0.001) and younger age group (-3.51 for ≤50 years compared with 66 to 75 years; 95% CI, -4.00 to -3.02; p < 0.001) associated with less benefit. Cumulatively, sociodemographic factors explained <1% of the total variability in improvement. CONCLUSIONS: Sociodemographic factors have a small influence on the benefit resulting from TKR. However, as they are associated with the clinical threshold at which the procedure is performed, they do affect the eventual outcomes of TKR. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of evidence.

Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth.

The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival. LY3023414 is a complex fused imidazoquinolinone with high solubility across a wide pH range designed to inhibit class I PI3K isoforms and mTOR kinase. Here, we describe the in vitro and in vivo activity of LY3023414. LY3023414 was highly soluble at pH 2-7. In biochemical testing against approximately 266 kinases, LY3023414 potently and selectively inhibited class I PI3K isoforms, mTORC1/2, and DNA-PK at low nanomolar concentrations. In vitro, inhibition of PI3K/AKT/mTOR signaling by LY3023414 caused G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel screens. In vivo, LY3023414 demonstrated high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates such as AKT, S6K, S6RP, and 4E-BP1 for 4 to 6 hours, reflecting the drug's half-life of 2 hours. Of note, equivalent total daily doses of LY3023414 given either once daily or twice daily inhibited tumor growth to similar extents in multiple xenograft models, indicating that intermittent target inhibition is sufficient for antitumor activity. In combination with standard-of-care drugs, LY3023414 demonstrated additive antitumor activity. The novel, orally bioavailable PI3K/mTOR inhibitor LY3023414 is highly soluble and exhibits potent in vivo efficacy via intermittent target inhibition. It is currently being evaluated in phase I and II trials for the treatment of human malignancies. Mol Cancer Ther; 15(10); 2344-56. ©2016 AACR.

Molecular testing and cervical screening: will one test fit all?

INTRODUCTION: Cervical screening has undergone significant changes in recent years, with molecular human papillomavirus (HPV) testing for HPV 16 and 18 at the forefront of clinical practice. But is molecular testing more effective than morphologic testing for cervical screening? Does current information on HPV hold true across all populations? As a public health laboratory serving high-risk, underserved populations, these remain important considerations for our practice. MATERIALS AND METHODS: The subject population largely consisted of young women within 200% or less of the poverty line. Correlation of Papanicolaou and HPV results was performed via retrospective review, focusing on Papanicolaou cases with high-grade diagnoses and an associated HPV test using the cobas 4800 HPV test. Secondary HPV testing and typing was performed via PCR at an outside laboratory for 205 cases with sufficient residual material and negative for HPV 16/18 by cobas. RESULTS: Of 20,211 cytology tests reviewed from July 2013 to May 2015, 521 were diagnosed as high-grade; 387 had concurrent HPV tests. Of those with concurrent HPV tests, 58% (225 of 387) of the high-grade Papanicolaou cases were not HPV 16/18 positive; furthermore, no HPV was detected in 14% (55 of 387) of these cases. Secondary testing revealed the presence of 25 unique genotypes. CONCLUSIONS: With recent emphasis on molecular HPV testing, the results of this review are concerning. As we move forward with evolution of cervical screening practices, it will be important to explore these questions for the continued quality and integrity of women's health services.

Multiple risk behaviour in adolescence and socio-economic status: findings from a UK birth cohort.

BACKGROUND: Patterns of risk behaviour during teenage years may vary by socio-economic status (SES). We aimed to examine possible associations between individual and multiple risk behaviours and three measures of SES in mid-adolescence. METHODS: The sample (n = 6406) comprised participants from the Avon Longitudinal Study of Parents and Children, a UK birth cohort. Thirteen risk behaviours spanning sexual health, substance use, self-harm, vehicle-related injury, criminality and physical inactivity were assessed in mid-adolescence (age 15-16 years). Associations between three measures of SES (maternal education, household income and parental social class) and (i) individual risk behaviours and (ii) the total number of risk behaviours were examined. RESULTS: For a one-category reduction in social class, maternal education or income, the odds of having a greater number of multiple risk behaviours increased by 22, 15 and 12%, respectively. At the individual level, there was evidence of a strong relationship with decreasing SES across all three measures of SES and criminality, car passenger risk, TV viewing, scooter risk, early sexual behaviour and weekly tobacco use but insufficient evidence of a relationship for physical inactivity, cycling without a helmet and illicit substance use. There was weak evidence of association between SES and hazardous drinking, self-harm, cannabis use and unprotected sex, but this was not consistent across the SES measures. CONCLUSION: The association between multiple risk behaviours and SES suggests that prevention strategies should apply the principal of proportionate universalism with a focus on more deprived populations, within a population-wide strategy, to prevent widening of social inequalities.

Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme essential for NAD+ biosynthesis, in human cancer cells: metabolic basis and potential clinical implications.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for cellular metabolism, energy production, and DNA repair. NAMPT has been extensively studied because of its critical role in these cellular processes and the prospect of developing therapeutics against the target, yet how it regulates cellular metabolism is not fully understood. In this study we utilized liquid chromatography-mass spectrometry to examine the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and serine biosynthesis in cancer cells and tumor xenografts. We show for the first time that NAMPT inhibition leads to the attenuation of glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step due to the reduced availability of NAD(+) for the enzyme. The attenuation of glycolysis results in the accumulation of glycolytic intermediates before and at the glyceraldehyde 3-phosphate dehydrogenase step, promoting carbon overflow into the pentose phosphate pathway as evidenced by the increased intermediate levels. The attenuation of glycolysis also causes decreased glycolytic intermediates after the glyceraldehyde 3-phosphate dehydrogenase step, thereby reducing carbon flow into serine biosynthesis and the TCA cycle. Labeling studies establish that the carbon overflow into the pentose phosphate pathway is mainly through its non-oxidative branch. Together, these studies establish the blockade of glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step as the central metabolic basis of NAMPT inhibition responsible for ATP depletion, metabolic perturbation, and subsequent tumor growth inhibition. These studies also suggest that altered metabolite levels in tumors can be used as robust pharmacodynamic markers for evaluating NAMPT inhibitors in the clinic.

Tasisulam sodium, an antitumor agent that inhibits mitotic progression and induces vascular normalization.

LY573636-sodium (tasisulam) is a small molecule antitumor agent with a novel mechanism of action currently being investigated in a variety of human cancers. In vitro, tasisulam induced apoptosis via the intrinsic pathway, resulting in cytochrome c release and caspase-dependent cell death. Using high content cellular imaging and subpopulation analysis of a wide range of in vitro and in vivo cancer models, tasisulam increased the proportion of cells with 4N DNA content and phospho-histone H3 expression, leading to G(2)-M accumulation and subsequent apoptosis. Tasisulam also blocked VEGF, epidermal growth factor, and fibroblast growth factor-induced endothelial cell cord formation but did not block acute growth factor receptor signaling (unlike sunitinib, which blocks VEGF-driven angiogenesis at the receptor kinase level) or induce apoptosis in primary endothelial cells. Importantly, in vivo phenocopying of in vitro effects were observed in multiple human tumor xenografts. Tasisulam was as effective as sunitinib at inhibiting neovascularization in a Matrigel plug angiogenesis assay in vivo and also caused reversible, non G(2)-M-dependent growth arrest in primary endothelial cells. Tasisulam also induced vascular normalization in vivo. Interestingly, the combination of tasisulam and sunitinib significantly delayed growth of the Caki-1 renal cell carcinoma model, whereas neither agent was active alone. These data show that tasisulam has a unique, dual-faceted mechanism of action involving mitotic catastrophe and antiangiogenesis, a phenotype distinct from conventional chemotherapies and published anticancer agents.

Comparison of methods trial for high-risk HPV.

In efforts to improve service, we compared the performance of four methods of HPV detection: Invader HPV (Hologic), Hybrid Capture 2 (Qiagen), Inform HPV detection (Ventana), and standard PCR.Using blinded/de-identified cervical samples in Preservcyt (Hologic), we compared Ventana's Inform HPV Test, against Hologic's HPV Invader and PCR. In a separate evaluation, we compared Inform versus Invader versus hc2. Ventana employs in situ hybridization; Hologic's technology uses three specifically designed oligonucleotides and a fluorescent signal for detection. Qiagen's hc2 method incorporates enzyme-linked antibody detection of RNA-DNA hybrids. PCR testing was provided by Access Genetics (Minneapolis, MN). The United States Food and Drug Administration recently approved the Third Wave/Hologic Invader HPV high-risk test (rebranded as Cervista HPV HR Test).In this small study, involving a few hundred tests, Third Wave, Qiagen, and PCR tests were comparable. Kappa statistics comparing Third Wave to PCR and Third Wave to Qiagen were 0.88 and 0.74, respectively. Ventana's method did not correlate well with any of the other methods with Kappa's ranging from a low of 0.25 versus Qiagen to 0.31 versus PCR. Kappa statistics measure correlation and not accuracy of measurement.Although we felt that the specificity of our original HPV method, Ventana Inform was satisfactory and lowered our subsequent colposcopy rate, worries about its lower sensitivity caused us to look at other techniques. Other methods, PCR, hc2, and Invader, appeared comparable with one another in our series. We chose to implement the Third Wave test in our laboratory.

Deficiency in the nuclease activity of xeroderma pigmentosum G in mice leads to hypersensitivity to UV irradiation.

Xeroderma pigmentosum (XP) is a human disorder which is characterized by hypersensitivity to sunlight and elevated incidence of skin cancer. The disease is caused by mutations in genes that encode components of the nucleotide excision repair pathway. The gene product of XP complementation group G (XPG) is a structure-specific endonuclease which makes an incision 3' to DNA photoproducts and other helix-distorting DNA adducts. In addition, the XPG protein has been implicated in transcription and repair of oxidative DNA damage. Moreover, XPG is capable of cleaving R loops in vitro, a potential intermediate during immunoglobulin heavy-chain class switch recombination. Due to its multiple functions, complete elimination of XPG in mice results in severe postnatal growth defects and premature death. To understand the contribution of the XPG nuclease activity to its function in vivo, we introduced a point mutation into the mouse XPG gene which inactivates the nuclease catalytic site but leaves the remainder of the protein intact. The XPG nuclease-deficient animals develop normally and exhibit no obvious defect in class switch recombination. However, the mutant mice are hypersensitive to UV irradiation. This phenotype suggests that the nuclease activity of XPG is required only for nucleotide excision repair and that other regions of the protein perform independent functions.

Nutrition and physical activity counseling practices of family practice residents.

BACKGROUND: Nutritional behaviors and physical activity can influence risk for the development and prognosis of cancer. This study reports findings of a literature review and a survey of nutrition and physical activity counseling practices of family practice (FP) residents. METHODS: 110 FP residents (response rate = 93.2%) from four clinics that received funding from the Texas Department of Health completed the survey. Hierarchical linear regression models were used to identify determinants of nutrition and physical activity counseling practices. RESULTS: About a fifth of the residents reported that they usually or always asked their patients about nutrition and physical activity. In general, residents were most likely to address these issues with asymptomatic obese adult patients. Perceived effectiveness was a significant predictor of both assessment and counseling, except for nutrition counseling for asymptomatic patients. Attitude toward behavioral counseling predicted assessment, but not counseling. Use of resources predicted counseling on both topics with all patients. CONCLUSION: FP residents assess and counsel about nutrition and physical activity at suboptimal rates. There is a need to convince residents of the value of such assessment and counseling and to increase their belief that patients will follow through on their recommendations.