Healthcare professional perspectives following implementation of an infection management care pathway for pediatric patients with cancer: a qualitative study.

PURPOSE: The Pediatric Oncology Group of Ontario (POGO) supported an effort to implement infection management care pathways based on clinical practice guidelines, to improve the consistency of infection management in pediatric cancer patients. The objective of this qualitative study was to describe the perspective of healthcare professionals (HCPs) following implementation. METHODS: Four tertiary pediatric oncology centers in Ontario, Canada, implemented the pathways. We randomly identified three HCPs per group (clinical pharmacists; nurse case managers, educators or practitioners and physician assistants; pediatric oncology fellows; or pediatric oncology staff physicians) per site and invited them to participate in a qualitative interview. One-on-one interviews were conducted remotely, followed by thematic analysis of interview transcripts. RESULTS: A total of 66 invitations were extended and 42 HCPs participated. Identified themes were: (1) implementation approach, (2) access and navigation, (3) engagement, (4) concerns, (5) workplace benefits, (6) reception, and (7) provincial harmonization. HCPs preferred in-person implementation strategies over e-mail communication. They identified teaching/educational utility and benefits to non-oncology departments and non-tertiary centers participating in shared care of patients. Other positive aspects related to evidence-based practice, safety, supporting oncology HCPs, and benefits to patients and families. Concerns included need to ensure users applied clinical judgement and loss of autonomy. Provincial harmonization of practice was viewed positively, although potential logistical and institutional cultural barriers were raised. CONCLUSIONS: Following infection management care pathway implementation, HCPs described educational utility and benefits to non-oncology departments, oncology HCPs, patients, and families. Our findings may facilitate future infection management care pathway provincial harmonization.

Antiviral activity of tenofovir alafenamide (TAF) against HIV-1 clinical isolates harboring K65R.

Tenofovir alafenamide (TAF) is a prodrug of the nucleoside reverse transcriptase (RT) inhibitor tenofovir (TFV). Compared to the earlier TFV prodrug, TFV disoproxil fumarate (TDF), TAF achieves more than fourfold-higher intracellular levels of its active metabolite TFV diphosphate (TFV-DP) in clinical studies, while achieving a significant reduction of TFV systemic exposure. Resistance to TFV has been well established, with the K65R mutation in RT as the signature mutation. Here we evaluated the in vitro activity of TAF and TDF in patient-derived HIV-1 isolates harboring the K65R mutation. Clinical isolates containing K65R were cloned into the pXXLAI construct (n = 42). In vitro phenotypic susceptibility of the constructs to TAF and TDF was evaluated in an MT-2 cell HIV assay and in viral breakthrough assays modeling physiological concentrations of TAF and TDF. TAF and TDF susceptibility were highly correlated in K65R-containing mutants, ranging from 2.7- to 3.0-fold (K65R alone) and 1.2- to 27.6-fold (K65R+ other RT mutations) relative to wild-type. In viral breakthrough assays mimicking differences in physiological concentrations, TAF inhibited breakthrough of 40 of 42 clinical isolates, while the TDF equivalent only inhibited 32 of 42 isolates tested. TAF displayed a higher barrier to resistance than TDF in this panel of K65R-containing clinical isolates.

Desmoplastic Small Round Cell Tumor With Ascending Intraspinal Metastasis at Recurrence: Case Report and Review of the Literature.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy commonly involving the abdomen and/or pelvic peritoneum. Despite aggressive therapy, the prognosis remains poor. Central nervous system relapse is rare in abdominal/pelvic primary DSRCT. OBSERVATION: We report a case of a 10-year-old female with a large pelvic DSRCT and involvement of the rectosigmoid colon and liver. Following treatment with chemotherapy, and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy an initial response was noted. With progressive lower limb weakness, recurrence with perineural invasion in the lumbosacral nerve root involving the conus was noted 2.5 years from diagnosis. Cerebrospinal fluid showed tumor cells with a molecular confirmation. CONCLUSIONS: Perineural invasion and ascending paralysis secondary to primary abdominal DSRCT has not been previously reported to our knowledge. We recommend a high index of suspicion for early and accurate diagnosis of this rare presentation.

Creating and adapting an infection management care pathway in pediatric oncology.

PURPOSE: While care pathways based upon clinical practice guidelines (CPGs) are important, little is known about optimal approaches to development and adaptation in pediatric oncology. Objectives were to develop care pathway templates for pediatric cancer supportive care that are based upon CPGs and to adapt an infection management care pathway for use at a single institution. METHODS: Study phases were as follows: (1) creation of care pathway templates across multiple supportive care topics; (2) refinement of the infection management care pathway template by interviewing pediatric oncology clinicians at a single institution; and (3) adaptation of the infection management care pathway template for use at a different institution. RESULTS: Informed by seven CPGs, an initial iteration of the infection management care pathway template was created. This template was then refined based upon 20 interviews with pediatric oncology clinicians. Adaptation of the infection management care pathway template for use at a different institution required many changes to improve its clinical usability. Specificity and additional information not considered by the source CPGs were incorporated. CONCLUSION: We developed a process to create care pathway templates across multiple supportive care topics in pediatric oncology and to refine and adapt the infection management care pathway. While we found that the process was feasible, we also identified the need to substantially modify the care pathway during the adaptation process to consider scenarios not addressed by the source CPGs. Future work should measure implementation success.

Two-dose emtricitabine/tenofovir alafenamide plus bictegravir prophylaxis protects macaques against SHIV infection.

OBJECTIVES: Current prophylaxis options for people at risk for HIV infection include two US FDA-approved daily pre-exposure prophylaxis (PrEP) regimens and guidelines for a 2-1-1 event-driven course specifically for men who have sex with men. Despite this, PrEP use rates remain suboptimal, and additional PrEP options may help to improve uptake among diverse populations. Here, we evaluated protective efficacy of two-dose PrEP and two-dose postexposure prophylaxis (PEP) schedules with emtricitabine (FTC)/tenofovir alafenamide (TAF) with or without bictegravir (BIC) in an SHIV macaque model. METHODS: Macaques received one oral dose of 200 mg emtricitabine, 25 mg tenofovir alafenamide and 25-100 mg of bictegravir to establish pharmacokinetic profiles of each drug either in the plasma or the peripheral blood mononuclear cells. Protective efficacy of multiple two-dose PrEP and PEP schedules with FTC/TAF with or without bictegravir was then assessed in two repeat low-dose rectal SHIV challenge studies. RESULTS: The data revealed over 95% per-exposure risk reduction with FTC/TAF PrEP initiated 2 h before the exposure, but a loss of significant protection with treatment initiation postexposure. In contrast, FTC/TAF plus BIC offered complete protection as PrEP and greater than 80% per-exposure risk reduction with treatment initiation up to 24 h postexposure. CONCLUSIONS: Together, these results demonstrate that two-dose schedules can protect macaques against SHIV acquisition and highlight the protective advantage of adding the integrase inhibitor bictegravir to the reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide as part of event-driven prophylaxis.

Hand Mirror Cells and Hypercalcemia: A Rare Presentation of Pediatric Acute Lymphoblastic Leukemia.

Hand mirror cell (HMC) leukemia is a variant of acute lymphoblastic leukemia previously described in the adult population where lymphoblasts manifest distinctive hand mirror morphologic features. HMC has been previously identified in 23% of childhood acute lymphoblastic leukemia patients, but its prognostic significance in children is not well understood. Hypercalcemia is also uncommon in childhood leukemias. Hypercalcemia associated with HMC leukemia has not been previously reported. We report a 5-year-old boy with HMC B-lymphoblastic leukemia who presented with hypercalcemia.

Dry Eye Disease Practice in Ghana: Diagnostic Perspectives, Treatment Modalities, and Challenges.

SIGNIFICANCE: There is a dearth of studies investigating the challenges encountered in dry eye practice. Profiling these barriers is crucial to improving dry eye diagnosis and patient care. PURPOSE: This study aimed to examine the diagnostic and treatment perspectives, and challenges in dry eye practice in Ghana. METHODS: An anonymous paper-based or web survey regarding dry eye practice pattern, practice challenges, and access to diagnostic tools was distributed to 280 potential participants. RESULTS: One hundred thirteen respondents completed the survey. Case history (92.5%), fluorescein tear breakup time (87.5%), and corneal fluorescein staining (72.5%) were the topmost procedures used for dry eye diagnosis. A preserved lubricant drop was the most commonly prescribed treatment of mild, moderate, and severe dry eye at the rates of 77.0, 83.2, and 77.0%, respectively. A few respondents prescribed cyclosporine (2.7%) or punctal plugs (5.3%) across all disease severities, and none used scleral lens, autologous serum tears, or thermal pulsation. Graduate professional training influenced the practice pattern of 82.3% of respondents, whereas continuing professional education influenced less than 1%. Approximately 70.1 and 92.8% of optometrists considered referring dry eye in children and cases that are unresponsive to treatment, respectively. Eighty-eight percent of practitioners indicated they experience a challenge in dry eye practice, with limited access to diagnostic tools (77.9%) and limited availability of effective dry eye medication on the Ghanaian market (50.4%) being the most frequent challenges. More than 85% of respondents had access to a fluorescein dye or slit-lamp biomicroscope; however, none had access to a phenol red thread, lissamine green dye, osmolarity technology, or meibography device. CONCLUSIONS: Practitioners' limited access to diagnostic tools/techniques and the limited effective dry eye treatments are major challenges encountered in dry eye practice in Ghana. Addressing these will improve dry eye practice and treatment outcomes in the country.

A Review of Imaging Biomarkers of the Ocular Surface.

A biomarker is a "characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions." Recently, calls for biomarkers for ocular surface diseases have increased, and advancements in imaging technologies have aided in allowing imaging biomarkers to serve as a potential solution for this need. This review focuses on the state of imaging biomarkers for ocular surface diseases, specifically non-invasive tear break-up time (NIBUT), tear meniscus measurement and corneal epithelial thickness with anterior segment optical coherence tomography (OCT), meibomian gland morphology with infrared meibography and in vivo confocal microscopy (IVCM), ocular redness with grading scales, and cellular corneal immune cells and nerve assessment by IVCM. Extensive literature review was performed for analytical and clinical validation that currently exists for potential imaging biomarkers. Our summary suggests that the reported analytical and clinical validation state for potential imaging biomarkers is broad, with some having good to excellent intra- and intergrader agreement to date. Examples of these include NIBUT for dry eye disease, ocular redness grading scales, and detection of corneal immune cells by IVCM for grading and monitoring inflammation. Further examples are nerve assessment by IVCM for monitoring severity of diabetes mellitus and neurotrophic keratitis, and corneal epithelial thickness assessment with anterior segment OCT for the diagnosis of early keratoconus. However, additional analytical validation for these biomarkers is required before clinical application as a biomarker.

A Randomized Trial to Evaluate the Effect of Toric Versus Spherical Contact Lenses on Vision and Eyestrain.

OBJECTIVES: To compare the effect of toric versus spherical soft contact lenses on objective measures of visual performance using visual acuity and electromyography of the orbicularis oculi muscle. METHODS: Current soft contact lens wearers with -0.75 to -1.75 D astigmatism in each eye were binocularly fitted with toric (1-Day ACUVUE MOIST for astigmatism) and spherical (1-Day ACUVUE MOIST) contact lenses in random order. After each fitting and at 1-week follow-up, high- and low-contrast visual acuities were measured. Electromyography was used to objectively evaluate eyestrain. Linear mixed models were used to assess differences between toric and spherical contact lenses. RESULTS: The mean age (±SD) of the 60 participants was 27.5±5.0 years, spherical refractive error was -3.68±2.01 D, and cylinder was -1.28±0.36 D. High- and low-contrast visual acuities with toric lenses were better than with spherical lenses at both fitting (toric high-contrast: -0.065±0.078 and low-contrast: 0.133±0.103 vs. spherical high-contrast: 0.001±0.104 and low-contrast: 0.224±0.107) and follow-up (toric high-contrast: -0.083±0.087 and low-contrast: 0.108±0.107 vs. spherical high-contrast: -0.015±0.095 and low-contrast: 0.211±0.104) (all P<0.0001). Electromyography-measured eyestrain was less with toric versus spherical contact lenses at fitting (least-square ratio of toric over spherical=0.72; P=0.0019) but not at follow-up (ratio=0.86; P=0.11). CONCLUSION: These results suggest that toric contact lenses provided improved objective measures of vision in a low-to-moderate astigmatic population.

Showers: from a violent treatment to an agent of cleansing.

In the early nineteenth century, physicians designed the first manufactured showers for the purpose of curing the insane. Sustained falls of cold water were prescribed to cool hot, inflamed brains, and to instil fear to tame impetuous wills. By the middle of the century showers had appeared in both asylums and prisons, but shower-related deaths led to their decline. Rather than being abandoned, however, the shower was transformed by the use of warm water to economically wash the skins of prison and asylum populations. In stark contrast to an involuntary, deliberately unpleasant treatment, by the end of the century the shower was a desirable product for the improvement of personal hygiene and population health.

No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection.

Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In two clinical trials, 1,298 hepatitis E antigen-positive and -negative patients with CHB were randomized 2:1 and treated with TAF (n = 866) or TDF (n = 432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (Pol/RT) were assessed using INNO-LiPA Multi-DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥ 69IU/ml) by HBV Pol/RT sequencing at week 96 or at discontinuation. In vitro phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to the study drug. At baseline, the majority of patients harbored virus with wild-type Pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF, 11.1%; TDF, 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF, 2.8%; TDF, 3.2%) that was often associated with drug nonadherence (TAF, 30%; TDF, 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96, with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility in vitro After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA < 69 IU/ml) was similar across treatment groups, and no substitutions associated with resistance to TAF or TDF were detected. (These studies have been registered at ClinicalTrials.gov under identifiers NCT01940471 and NCT01940341.).

Efficacy of Toric Contact Lenses in Fitting and Patient-Reported Outcomes in Contact Lens Wearers.

OBJECTIVES: To assess whether patient-reported measures are improved with soft toric contact lenses (TCLs) compared with soft spherical contact lenses (SCLs) and whether clinical time needed to fit TCL is greater than SCL. METHODS: Habitual contact lens wearers with vertexed spherical refraction +4.00 to +0.25 D or -0.50 to -9.00 D and cylinder -0.75 to -1.75 DC were randomly assigned to be binocularly fitted into a TCL or SCL, and masked to treatment assignment. Time to successful fit was recorded. After 5 days, the National Eye Institute Refractive Error Quality of Life Instrument (NEI-RQL-42) and modified Convergence Insufficiency Symptom Survey (CISS) were completed. After washout, subjects were fit into the alternative lens design (TCL or SCL). Outcomes were evaluated using linear mixed models for the time to fit and CISS score, generalized linear model for the successful fit, and Wilcoxon tests for the NEI-RQL-42. RESULTS: Sixty subjects (71.7% women, mean age [±SD] = 27.5±5.0 years) completed the study. The mean time to fit the TCL was 10.2±4.3 and 9.0±6.5 min for the SCL (least square [LS] mean difference (TCL-SCL)=1.2, P=0.22). Toric contact lens scored better than SCL in global NEI-RQL-42 score (P=0.006) and the clarity of vision (P=0.006) and satisfaction with correction subscales (P=0.006). CISS showed a 15% reduction in symptoms (LS mean difference [TCL-SCL]=-2.20, P=0.02). CONCLUSION: TCLs are a good option when trying to improve the vision of patients with low-to-moderate astigmatism given the subjective improvements in outcomes.

Eyelid Margin and Meibomian Gland Characteristics and Symptoms in Lens Wearers.

PURPOSE: To describe the lid margin characteristics of contact lens wearers and relate them to comfort during lens wear. METHODS: Three study sites enrolled habitual contact lens wearers. Subjects completed the Comfort domain of the Contact Lens User Experience (CLUE) questionnaire, and each eye was graded for the presence of mucocutaneous junction (MCJ) displacement, lid margin irregularity, and lid margin vascularity. Examiners counted the number of meibomian gland (MG) orifices in the central centimeter of the lower eyelid and the number of those that showed pouting/plugging and vascular invasion. MG expressibility was graded according to the Shimazaki schema. Subjects were grouped based on presence/absence of each characteristic, total number of orifices (≥5 vs. <5), and expressibility (grade 0 vs. >0). Descriptive statistics are reported. A linear model was used to assess the fixed effect of each characteristic on combined CLUE score and each CLUE statement, if the effect on combined CLUE score showed p < 0.10. RESULTS: The study included 203 subjects (67.5% female) with mean age (±SD) of 30.3 ± 9.6 years. The most commonly observed characteristics were orifice pouting/plugging, compromised MG expressibility, and lid margin vascularity (35.0, 30.3, and 20.4%, respectively). MCJ displacement and MG expressibility had an effect on the combined CLUE score such that individual CLUE statements were analyzed (p = 0.01 and p = 0.06, respectively). MCJ displacement had an effect on comfort upon insertion (p = 0.01), comfort after 5 minutes (p = 0.03), end-of-day comfort (p = 0.01), and ability to maintain ocular moisture (p = 0.030). MG expressibility had a significant effect on general comfort (p = 0.01), comfort throughout the day (p = 0.02), and the ability to maintain ocular moisture (p = 0.02). CONCLUSIONS: MCJ displacement and MG expressibility have an effect on contact lens comfort.

CORRIGENDUM: Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.

Genet Med advance online publication, January 22, 2015; doi:10.1038/gim.2014.205. In the Advance Online Publication version, of this article, there is a mistake on page 2 in the first paragraph of the Materials and Methods section. The sentence beginning "Among 3,459 probands initially referred for HCM genetic testing …" the correct number of probands is 3,473 not 3,459. The authors regret the error.

Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.

PURPOSE: Hypertrophic cardiomyopathy (HCM) is caused primarily by pathogenic variants in genes encoding sarcomere proteins. We report genetic testing results for HCM in 2,912 unrelated individuals with nonsyndromic presentations from a broad referral population over 10 years. METHODS: Genetic testing was performed by Sanger sequencing for 10 genes from 2004 to 2007, by HCM CardioChip for 11 genes from 2007 to 2011 and by next-generation sequencing for 18, 46, or 51 genes from 2011 onward. RESULTS: The detection rate is ~32% among unselected probands, with inconclusive results in an additional 15%. Detection rates were not significantly different between adult and pediatric probands but were higher in females compared with males. An expanded gene panel encompassing more than 50 genes identified only a very small number of additional pathogenic variants beyond those identifiable in our original panels, which examined 11 genes. Familial genetic testing in at-risk family members eliminated the need for longitudinal cardiac evaluations in 691 individuals. Based on the projected costs derived from Medicare fee schedules for the recommended clinical evaluations of HCM family members by the American College of Cardiology Foundation/American Heart Association, our data indicate that genetic testing resulted in a minimum cost savings of about $0.7 million. CONCLUSION: Clinical HCM genetic testing provides a definitive molecular diagnosis for many patients and provides cost savings to families. Expanded gene panels have not substantively increased the clinical sensitivity of HCM testing, suggesting major additional causes of HCM still remain to be identified.

Agreement between Automated and Traditional Measures of Tear Film Breakup.

PURPOSE: To determine the repeatability and agreement between the noninvasive Keratograph tear break-up time (NIK-BUT) as measured by the Oculus Keratograph 4 and fluorescein tear break-up time (FBUT). METHODS: Sixty subjects were recruited for two study visits separated by 7 (± 2) days. At each visit, three NIK-BUT measures and FBUT measures were obtained. Each NIK-BUT measure from the Keratograph included a first and an average NIK-BUT. The means of the measures obtained, first NIK-BUT, and average NIK-BUT and FBUT were calculated for each visit. Between- and within-visit agreement was assessed using intraclass correlation coefficients (ICCs) and Bland-Altman 95% limits of agreement (LoA) analyses of log-transformed data. RESULTS: Between-visit ICCs were 0.53 [95% confidence interval (CI), 0.32 to 0.69] for first NIK-BUT, 0.59 (95% CI, 0.40 to 0.73) for average NIK-BUT, and 0.66 (95% CI, 0.49 to 0.78) for FBUT, whereas 95% LoA were -0.65 to 0.67, -0.44 to 0.48, and -1.14 to 1.10 [back transformed: (visit 1 + 0.01)/(visit 2 + 0.01) = 0.22 to 4.68, 0.36 to 3.02, and 0.07 to 12.59] for the aforementioned methods, respectively. The visit 1 within-visit ICC between first NIK-BUT and FBUT was 0.44 (95% CI, 0.21 to 0.62), whereas the 95% LoA was -0.84 to 1.18 [back transformed: (first NIK-BUT + 0.01)/(FBUT + 0.01) = 0.14 to 15.14]. Likewise, the visit 1 within-visit ICC between average NIK-BUT and FBUT was 0.41 (95% CI, 0.18 to 0.60), whereas the 95% LoA was -0.58 to 1.44 [back transformed: (average NIK-BUT + 0.01)/(FBUT + 0.01) = 0.26 to 27.54]. CONCLUSIONS: The 95% LoA suggest that the average NIK-BUT has better between-visit agreement compared with the first NIK-BUT or FBUT. The first NIK-BUT showed better within-visit agreement with the FBUT than the average NIK-BUT. In addition, there is better between- and within-visit agreement for all measures at lower values.

EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice.

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT-inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell-like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation.

Notes from the field: atypical pneumonia in three members of an extended family - South Carolina and north Carolina, july-august 2013.

On August 5, 2013, the South Carolina Department of Health and Environmental Control was notified of a case of acute respiratory failure in a previously healthy woman. A family interview revealed the patient's uncle and cousin had also been hospitalized with similar symptoms in North Carolina. The South Carolina Department of Health and Environmental Control and the North Carolina Division of Public Health collaborated to identify the cause of the respiratory illness cluster and to prevent additional illnesses.

A negative feedback signaling network underlies oncogene-induced senescence.

Oncogene-induced senescence functions to limit tumor development. However, a complete understanding of the signals that trigger this type of senescence is currently lacking. We found that mutations affecting NF1, Raf, and Ras induce a global negative feedback response that potently suppresses Ras and/or its effectors. Moreover, these signals promote senescence by inhibiting the Ras/PI3K pathway, which can impact the senescence machinery through HDM2 and FOXO. This negative feedback program is regulated in part by RasGEFs, Sprouty proteins, RasGAPs, and MKPs. Moreover, these signals function in vivo in benign human tumors. Thus, the ultimate response to the aberrant activation of the Ras pathway is a multifaceted negative feedback signaling network that terminates the oncogenic signal and participates in the senescence response.

The role of anxiety and depression in understanding the relationship between coping and weight loss 24 months after bariatric surgery.

BACKGROUND: The relationship between coping (i.e., how a person deals with stress) and weight loss after bariatric surgery is relatively inconsistent. Anxiety and depression may contribute to the lack of consistent findings in this area. It is possible that coping, including interpersonal, intrapersonal, and maladaptive coping, predicts weight loss among individuals with higher levels of anxiety or depression but not among those with lower levels of anxiety and depression. OBJECTIVE: The aim of this study was to examine the moderating role of anxiety and depression on the association between coping and weight loss in patients 24 months after bariatric surgery. SETTING: University Hospital, West Virginia, U.S.A. METHODS: Participants included 841 patients who underwent bariatric surgery, 396 of whom had 24-month weight loss data (mean age, 43.21 yr [SD, ±11.40 yr]). We ran 3 moderation models to test whether the relationship between various coping styles and postoperative weight loss was moderated by anxiety and depression symptoms. RESULTS: There was a statistically significant interaction between anxiety and depression on the association between interpersonal coping and percent excess weight loss (%EWL). Anxiety and depression also moderated the relationship between maladaptive coping and %EWL. Anxiety and depression did not moderate the association between intrapersonal coping and %EWL, but intrapersonal coping positively predicted %EWL at 24 months after bariatric surgery. CONCLUSIONS: Maladaptive coping predicted less weight loss for patients with high levels of anxiety and/or depression. Interpersonal coping predicted more weight loss for patients with low levels of anxiety and/or depression. Clinicians should take patient levels of anxiety and depression into account when making recommendations to promote weight loss among patients pursuing bariatric surgery.