Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.

The systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized the Sleeping Beauty transposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progression in vivo in the absence of UV-IR, and identified both known tumor suppressor genes and novel oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for the ZMIZ genes, and tumor suppressive roles for KMT2C, CREBBP and NCOA2, in the initiation or progression of human cuSCC. Taken together, our in vivo screen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which can be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates.

The bleeding risk treatment paradox at the physician and hospital level: Implications for reducing bleeding in patients undergoing percutaneous coronary intervention.

BACKGROUND: Bleeding is a common and costly complication of percutaneous coronary intervention (PCI). Bleeding avoidance strategies (BAS) are used paradoxically less in patients at high-risk of bleeding: "bleeding risk-treatment paradox" (RTP). We determined whether hospitals and physicians, who do not align BAS to PCI patients' bleeding risk (ie, exhibit a RTP) have higher bleeding rates. METHODS: We examined 28,005 PCIs from the National Cardiovascular Data Registry CathPCI Registry for 7 hospitals comprising BJC HealthCare. BAS included transradial intervention, bivalirudin, and vascular closure devices. Patients' predicted bleeding risk was based on National Cardiovascular Data Registry CathPCI bleeding model and categorized as low (<2.0%), moderate (2.0%-6.4%), or high (≥6.5%) risk tertiles. BAS use was considered risk-concordant if: at least 1 BAS was used for moderate risk; 2 BAS were used for high risk and bivalirudin or vascular closure devices were not used for low risk. Absence of risk-concordant BAS use was defined as RTP. We analyzed inter-hospital and inter-physician variation in RTP, and the association of RTP with post-PCI bleeding. RESULTS: Amongst 28,005 patients undergoing PCI by 103 physicians at 7 hospitals, RTP was observed in 12,035 (43%) patients. RTP was independently associated with a higher likelihood of bleeding even after adjusting for predicted bleeding risk, mortality risk and potential sources of variation (OR 1.66, 95% CI 1.44-1.92, P < .001). A higher prevalence of RTP strongly and independently correlated with worse bleeding rates, both at the physician-level (Wilk's Lambda 0.9502, F-value 17.21, P < .0001) and the hospital-level (Wilk's Lambda 0.9899, F-value 35.68, P < .0001). All the results were similar in a subset of PCIs conducted since 2015 - a period more reflective of the contemporary practice. CONCLUSIONS: Bleeding RTP is a strong, independent predictor of bleeding. It exists at the level of physicians and hospitals: those with a higher rate of RTP had worse bleeding rates. These findings not only underscore the importance of recognizing bleeding risk upfront and using BAS in a risk-aligned manner, but also inform and motivate national efforts to reduce PCI-related bleeding.

Facilitating the identification of patients hospitalized for acute myocardial infarction and heart failure and the assessment of their readmission risk through the Patient Navigator Program.

BACKGROUND: Optimal transition care mitigates early hospital readmission risk. Given limited resources, hospitals need to identify patients with high readmission risk. This article examines whether a coordinated quality improvement campaign can help achieve this objective. METHODS: The American College of Cardiology Patient Navigator Program, a 2-year quality improvement campaign, sought to assess the impact of transition care interventions on 30-day readmission rates for patients with acute myocardial infarction (AMI) or heart failure (HF) at 35 hospitals. This article examines the change in 2 of the 36 performance metrics the campaign tracked: the number of AMI and HF patients identified predischarge and those whose readmission risk was assessed. RESULTS: The number of facilities identifying AMI and HF patients predischarge increased from 24 (68.6%) and 28 (80.0%), respectively, at baseline, to 34 (97.1%) (P = .0016) and 34 (97.1%) (P = .014), respectively, at 2 years. The number of facilities assessing the readmission risk of AMI and HF patients risk increased from 9 (25.7%) and 11 (31.4%), respectively, at baseline, to 32 (91.4%) (P < .0001) and 33 (94.5%) (P < .0001), respectively, at 2 years. Importantly, baseline reporting of performance for both metrics was poor, with >25% of the hospitals missing data. CONCLUSIONS: Implementation of a coordinated quality improvement campaign may increase the number of facilities identifying AMI and HF patients predischarge and assessing their readmission risk. Further research is needed to determine if increased identification reduces 30-day readmission or facilitates improvement in other important clinical outcomes.

Use of Postexposure Prophylaxis After Occupational Exposure to Zaire ebolavirus.

From September 2014 to April 2015, 6 persons who had occupational exposures to Zaire ebolavirus in West Africa received investigational agent rVSV-ZEBOV or TKM-100802 for postexposure prophylaxis and were monitored in the United States. All patients experienced self-limited symptoms after postexposure prophylaxis; none developed Ebola virus disease.

Emergency postexposure vaccination with vesicular stomatitis virus-vectored Ebola vaccine after needlestick.

IMPORTANCE: Safe and effective vaccines and drugs are needed for the prevention and treatment of Ebola virus disease, including following a potentially high-risk exposure such as a needlestick. OBJECTIVE: To assess response to postexposure vaccination in a health care worker who was exposed to the Ebola virus. DESIGN AND SETTING: Case report of a physician who experienced a needlestick while working in an Ebola treatment unit in Sierra Leone on September 26, 2014. Medical evacuation to the United States was rapidly initiated. Given the concern about potentially lethal Ebola virus disease, the patient was offered, and provided his consent for, postexposure vaccination with an experimental vaccine available through an emergency Investigational New Drug application. He was vaccinated on September 28, 2014. INTERVENTIONS: The vaccine used was VSVΔG-ZEBOV, a replicating, attenuated, recombinant vesicular stomatitis virus (serotype Indiana) whose surface glycoprotein gene was replaced by the Zaire Ebola virus glycoprotein gene. This vaccine has entered a clinical trial for the prevention of Ebola in West Africa. RESULTS: The vaccine was administered 43 hours after the needlestick occurred. Fever and moderate to severe symptoms developed 12 hours after vaccination and diminished over 3 to 4 days. The real-time reverse transcription polymerase chain reaction results were transiently positive for vesicular stomatitis virus nucleoprotein gene and Ebola virus glycoprotein gene (both included in the vaccine) but consistently negative for Ebola virus nucleoprotein gene (not in the vaccine). Early postvaccination cytokine secretion and T lymphocyte and plasmablast activation were detected. Subsequently, Ebola virus glycoprotein-specific antibodies and T cells became detectable, but antibodies against Ebola viral matrix protein 40 (not in the vaccine) were not detected. CONCLUSIONS AND RELEVANCE: It is unknown if VSVΔG-ZEBOV is safe or effective for postexposure vaccination in humans who have experienced a high-risk occupational exposure to the Ebola virus, such as a needlestick. In this patient, postexposure vaccination with VSVΔG-ZEBOV induced a self-limited febrile syndrome that was associated with transient detection of the recombinant vesicular stomatitis vaccine virus in blood. Strong innate and Ebola-specific adaptive immune responses were detected after vaccination. The clinical syndrome and laboratory evidence were consistent with vaccination response, and no evidence of Ebola virus infection was detected.

Gender differences in HIV disclosure, stigma, and perceptions of health.

HIV disclosure is a gateway to HIV prevention - particularly among couples living in regions severely affected by the HIV epidemic. This cross-sectional study utilizes data collected from 862 people living with HIV across three countries (Ethiopia, Mozambique, and Uganda) in 2011 to determine the role of partner disclosure on self-reported health perceptions and changes in sexual risk behavior. The study's secondary aims are to understand whether or not internalized stigma mediates this relationship and if there is a different pattern of results by gender. The multivariate analysis reveals that the three key HIV-related independent variables, belonging to a support group, doing volunteer work, and disclosing to one's spouse or partner, were significantly associated with lower levels of internalized stigma. Internalized stigma was associated with self-perceptions of poorer health for both women and men, with women reporting higher levels of internalized stigma than men. Disclosure to spouse was positively associated with perceptions of better health for women but not for men. For men, doing HIV-related volunteer work and disclosing their status to their spouse were positively associated with self-reported changes in sexual risk behavior, although stigma was not found to mediate this relationship. Findings from this study suggest that disclosure and stigma have gender-specific effects on individual well-being and changes in sexual risk behaviors. As such, programs must address gender inequity in disclosure patterns and stigma to enhance prevention efforts.

Dietary trends and management of hyperphosphatemia among patients with chronic kidney disease: an international survey of renal care professionals.

OBJECTIVE: The objective of this study was to review the opinions and experiences of renal care professionals to examine dietary trends among patients with chronic kidney disease (CKD) and problems associated with the clinical management of hyperphosphatemia. DESIGN: This was an online survey comprising open and closed questions requesting information on patient dietary trends and the clinical management of hyperphosphatemia. The study was conducted in 4 European countries (the Netherlands, Spain, Sweden, and the United Kingdom). SUBJECTS: Participants were 84 renal care professionals. INTERVENTION: This was an online survey. MAIN OUTCOME MEASURE: Responder-reported experiences and perceptions of patient dietary trends and hyperphosphatemia management were assessed. RESULTS: Most survey responders (56%) observed an increase in the consumption of processed convenience food, 48% noticed an increase in the consumption of foods rich in phosphorus-containing additives, and 60% believed that there has been a trend of increasing patient awareness of the phosphorus content of food. Patients undergoing hemodialysis (HD) were most likely to experience difficulties in following advice on dietary phosphorus restriction (38% of responders estimated that 25-50% of their patients experienced difficulties, and 29% estimated that 51-75% experienced difficulties). Maintaining protein intake and restricting dietary phosphorus were perceived as being equally important by at least half of responders for predialysis patients (56%) and for those undergoing peritoneal dialysis and HD (54% and 50%, respectively). There were international variations in dietary trends and hyperphosphatemia management. CONCLUSION: Although most responders have observed a trend of increasing awareness of the phosphorus content of food among patients with CKD, the survey results indicate that many patients continue to experience difficulties when attempting to restrict dietary phosphorus. The survey responses reflect the global trend of increasing consumption of processed convenience foods and phosphorus-containing additives, which has implications for the management of hyperphosphatemia in patients with CKD.

Implementation of a Multidimensional Strategy to Reduce Post-PCI Bleeding Risk.

BACKGROUND: The American College of Cardiology Reduce the Risk: PCI Bleed Campaign was a hospital-based quality improvement campaign designed to reduce post-percutaneous coronary intervention (PCI) bleeding events. The aim of the campaign was to provide actionable evidence-based tools for participants to review, adapt, and adopt, depending upon hospital resources and engagement. METHODS: We used data from 8 757 737 procedures in the National Cardiovascular Data Registry between 2015 and 2021 to compare patient and hospital characteristics and bleeding outcomes among campaign participants (n=195 hospitals) and noncampaign participants (n=1384). Post-PCI bleeding risk was compared before and after campaign participation. Multivariable hierarchical logistic regression was used to determine the adjusted association between campaign participation and post-PCI bleeding events. Prespecified subgroups were examined. RESULTS: Campaign hospitals were more often higher volume teaching facilities located in urban or suburban locations. After adjustment, campaign participation was associated with a significant reduction in the rate of bleeding (bleeding: adjusted odds ratio, 0.61 [95% CI, 0.53-0.71]). Campaign hospitals had a greater decrease in bleeding events than noncampaign hospitals. In a subgroup analysis, the reduction in bleeding was noted in non-ST-segment-elevation acute coronary syndrome and ST-segment-elevation myocardial infarction patients, but no significant reduction was seen in patients without acute coronary syndrome. CONCLUSIONS: Participation in the American College of Cardiology Reduce the Risk: PCI Bleed Campaign was associated with a significant reduction in post-PCI bleeding. Our results underscore that national quality improvement efforts can be associated with a significant impact on PCI outcomes.

Testing a service integration model: results from the HIV/AIDS initiative, ConnectHIV.

Staff of 20 AIDS Service Organizations (ASOs), grantees of the initiative ConnectHIV in the United States, developed a theoretical model of five categories of factors - external, community, organizational, staff, and client - that lead to effective service integration (SI) and took part in a self-assessment related to the model. The model was tested empirically using GEE analysis to assess the effect of ASO SI scores on client outcomes from participation in HIV/AIDS interventions involving case management with persons living with HIV/AIDS. Results showed that clients served by ASOs with more effective SI were more knowledgeable of HIV disease, healthier (higher CD4, lower viral load) and perceived themselves as healthier than clients in ASOs with less effective SI. In addition, clients at ASOs with more effective SI more often showed stronger gains in CD4 count over their time in the HIV/AIDS intervention than those at ASOs with less effective SI. Further research is needed on models and measurement of SI in order to effectively investigate the impact of HIV SI on client health outcomes.

Incarceration, high-risk sexual partnerships and sexually transmitted infections in an urban population.

OBJECTIVES: The authors examined the associations between personal and partner incarceration, high-risk sexual partnerships and biologically confirmed sexually transmitted infection (STI) in a US urban population. METHODS: Data from a probability survey of young adults 15-35 years of age in Baltimore, Maryland, USA, were analysed to assess the prevalence of personal and partner incarceration and its association with several measures of high-risk sexual partnerships including multiple partners, partner concurrency and current STI. RESULTS: A history of incarceration was common (24.1% among men and 11.3% among women). Among women with an incarcerated partner in the past year (15.3%), the risk of current STI was significantly increased (adjusted prevalence ratio=2.3, 95% CI 1.5 to 3.5). Multiple partners (5+) in the past year and partner concurrency were disproportionately high among men and women who had been incarcerated or who had sexual partner(s) or who had recently been incarcerated. These associations remained robust independent of personal socio-demographic factors and illicit drug use. CONCLUSIONS: Incarceration may contribute to STI risk by influencing engagement in high-risk behaviours and by influencing contact with partners who engage in risky behaviours and who hence have elevated risk of infection.

Physiological characterization and light response of the CO2-concentrating mechanism in the filamentous cyanobacterium Leptolyngbya sp. CPCC 696.

We studied the interactions of the CO(2)-concentrating mechanism and variable light in the filamentous cyanobacterium Leptolyngbya sp. CPCC 696 acclimated to low light (15 µmol m(-2) s(-1) PPFD) and low inorganic carbon (50 µM Ci). Mass spectrometric and polarographic analysis revealed that mediated CO(2) uptake along with both active Na(+)-independent and Na(+)-dependent HCO(3)(-) transport, likely through Na(+)/HCO(3)(-) symport, were employed to concentrate Ci internally. Combined transport of CO(2) and HCO(3)(-) required about 30 kJ mol(-1) of energy from photosynthetic electron transport to support an intracellular Ci accumulation 550-fold greater than the external Ci. Initially, Leptolyngbya rapidly induced oxygen evolution and Ci transport to reach 40-50% of maximum values by 50 µmol m(-2) s(-1) PPFD. Thereafter, photosynthesis and Ci transport increased gradually to saturation around 1,800 µmol m(-2) s(-1) PPFD. Leptolyngbya showed a low intrinsic susceptibility to photoinhibition of oxygen evolution up to PPFD of 3,000 µmol m(-2) s(-1). Intracellular Ci accumulation showed a lag under low light but then peaked at about 500 µmol photons m(-2) s(-1) and remained high thereafter. Ci influx was accompanied by a simultaneous, light-dependent, outward flux of CO(2) and by internal CO(2)/HCO(3)(-) cycling. The high-affinity and high-capacity CCM of Leptolyngbya responded dynamically to fluctuating PPFD and used excitation energy in excess of the needs of CO(2) fixation by increasing Ci transport, accumulation and Ci cycling. This capacity may allow Leptolyngbya to tolerate periodic exposure to excess high light by consuming electron equivalents and keeping PSII open.

Chlamydia trachomatis infection among 15- to 35-year-olds in Baltimore, MD.

BACKGROUND: Chlamydia trachomatis (Ct) is the most frequently reported infectious disease in the United States. This article reports population and subpopulation prevalence estimates of Ct and correlates of infection among 15- to 35-year-olds in Baltimore, MD. METHODS: The Monitoring STIs Survey Program (MSSP) monitored sexually transmitted infection (STI) prevalence among probability samples of residents of Baltimore, a city with high STI rates. MSSP respondents completed telephone audio computer-assisted self-interviews and provided biospecimens for STI testing. RESULTS: Among 2120 Baltimore residents aged 15 to 35 years, the estimated prevalence of chlamydia was 3.9% (95% confidence interval [CI]: 2.8, 5.0). Prevalence was 5.8% (95% CI: 4.1, 7.6) among black MSSP respondents versus 0.7% (95% CI: 0.0, 1.4) among nonblack respondents; all but 4 infections detected were among black respondents. Sexual behaviors and other factors associated with infection were far more prevalent among black than nonblack Baltimore residents. Racial disparities persisted after adjustment for sociodemographic, behavioral, and health factors. CONCLUSION: The MSSP highlights a higher Ct prevalence among young people in Baltimore than in the United States overall, with notable racial disparities in infection and associated risk behaviors. Public health efforts are needed to improve the diagnosis and treatment of asymptomatic infections in this population.

Variability of effluent cancer antigen 125 and interleukin-6 determination in peritoneal dialysis patients.

BACKGROUND: Cancer antigen (CA) 125 is a glycoprotein that provides data on the state of the peritoneal membrane in peritoneal dialysis (PD). Interleukin-6 (IL-6) acts as a mediator in acute-phase responses. The study evaluated the usefulness of CA125 and IL-6 in random effluent samples, by assessing their variability in individual patients during clinical practice at the outpatient department. METHODS: This longitudinal prospective study was conducted from 2007 till 2009. Participants included 52 stable PD patients aged ≥ 18 years. Effluent samples were obtained during regular outpatient visits and appearance rates (ARs) were calculated. Inter- and intra-individual variability was determined by the coefficient of variation (CV). A linear mixed model was used to analyse time courses. Furthermore, release patterns of these effluent markers were studied. RESULTS: CA125-AR of short-term patients (≤ 24 months) ranged from 39.2 to 766.7 U/min and IL-6-AR from 15.5 to 220.0 pg/min. Long-term patients (≥ 25 months) had a CA125-AR of 7.3-1534.0 U/min and IL-6-AR of 6.9-956.4 pg/min. Overall, CV(intra) was 15% in effluent CA125-AR and 28% in IL-6-AR. Intermediate sampling during a 4-h dwell showed a linear increase of CA125 and IL-6 effluent concentrations. The trend of CA125-AR was different (P = 0.001) between short- and long-term patients. A negative relationship was found between CA125 (r = -0.44, P = 0.02) and PD duration. CONCLUSIONS: The clinical relevance of effluent CA125 determinations from an unstandardized dwell during every outpatient visit is reasonable, as judged from the CV(intra). The inferior CV(intra) values of ARs as compared to effluent values indicate that ARs should only be calculated under standardized conditions. A single IL-6 measurement, as a predictor of outcome, should be interpreted cautiously.

Maternal factors and experiences associated with observed parenting behavior in mothers attending a residential parenting program.

Parents experiencing early parenting difficulties often seek support through parenting programs. Characteristics of mothers seeking parenting support and information at an early parenting center in Victoria, Australia and the relationships between these factors and parenting behavior were explored using an observational measure of parent-child interaction. Participants were 43 mothers and children attending a 5-day residential parenting program at the Queen Elizabeth Centre. Maternal and sociodemographic data as well as an observational mother-child interaction task from the Nursing Child Assessment Satellite Training Parent Child Interaction Teaching scale were completed and scored on the first day of the program. Certain maternal factors and experiences were associated with observed parenting behavior. Poorer maternal sleeping quality, unplanned pregnancy and preterm birth were all associated with less optimal parenting behavior in certain domains. Findings are discussed with reference to the impact of past experiences around pregnancy and birth as well as the current context and well-being of mothers attending early parenting centers.

Covid-19 and Priorities for Research in Aging.

This article describes priority areas for research on the impact of the Covid-19 pandemic on older adults that have been identified by the CIHR Institute of Aging (CIHR-IA). The process used by CIHR-IA consists of several iterative phases and thus far has resulted in identification of three key areas for Covid-19 research needs and four cross-cutting thematic areas. The key research priority areas are as follows: response of older adults to disease, vaccination, and therapeutics; mental health and isolation; and supportive care environments. The four cross-cutting themes are equity, diversity, and inclusion (EDI); ethical/moral considerations; evidence-informed practices; and digital health technologies. The priorities outlined in this article will inform CIHR-IA's responses to Covid-19 research needs.

La COVID-19 et les priorités de recherche sur le vieillissement.

Cet article présente les domaines prioritaires de recherche sur les impacts de la pandémie de COVID-19 chez les personnes âgées telles qu'ils ont été identifiés par l'Institut du vieillissement des IRSC (IV-IRSC). Le processus utilisé par l'IV-IRSC a comporté plusieurs phases itératives qui ont permis d'identifier trois secteurs prioritaires parmi les besoins de la recherche relative à la COVID-19, et quatre axes thématiques transversaux. Les secteurs de recherche prioritaires sont : 1) la réponse des personnes âgées à la maladie, à la vaccination et aux traitements, 2) la santé mentale et l'isolement, et 3) les milieux de soins soutenants. Les quatre thèmes transversaux sont : a) l'Équité, la diversité et l'inclusion (EDI), b) les considérations éthiques et morales, c) les pratiques fondées sur les données probantes, et d) les technologies numériques de la santé. Les priorités décrites dans cet article guideront les réponses de l'IV-IRSC aux besoins de la recherche sur la COVID-19.

Outcomes following an early parenting center residential parenting program.

Outcomes for maternal well-being and behavior as well as difficult child behavior following participation in a 5-day early parenting center residential parenting program were explored. Participants were 44 mothers and their children, the majority presenting with child sleeping difficulties. Data were collected at four stages: intake (2-4 weeks prior to the program), the first day of the program, the last day of the program, and 4 weeks after the program. Measures included questionnaires, monitoring sheets, and videotaped observations of parent- child interactions. Improvements were seen in mothers' behavior during parent-child interaction over the week they attended the program. Maternal symptoms of depression, anxiety, and stress were lower after the program. The perceived frequency and seriousness of maternal reported difficult child behavior decreased over the measurement period, and 52% of parents had achieved 80% or more of their behavioral goal for their children. Implications for future research in early parenting centers are discussed.

Superantigen genes in group A streptococcal isolates and their relationship with emm types.

Superantigens are important virulence factors in the pathogenesis of invasive disease caused by group A streptococcus (GAS). There has been a recent re-emergence of this disease worldwide. A number of novel superantigens have been described recently. This study investigated 107 isolates of GAS for possession of each of the 11 currently known superantigen genes to determine the prevalence, co-occurrence and genetic restriction amongst different emm types of GAS. The results were compared with those in previously published studies. Superantigen genes were not randomly distributed amongst GAS isolates. Certain combinations of superantigen genes were more common and the majority of emm types showed restricted superantigen profiles. This is the first prevalence study of GAS isolates to include the complete range of known superantigen genes and their restriction amongst emm types. This study contributes to the understanding of the relationship between superantigen genes and emm types, and highlights the importance of comprehensive studies in different populations.

Eye movement desensitization and reprocessing (EMDR) in the treatment of war veterans.

Recent practice guidelines and meta-analyses have designated eye movement desensitization and reprocessing (EMDR) as a first-line treatment for trauma. Eye movement desensitization and reprocessing is an eight-phase therapeutic approach guided by an information-processing model that addresses the combat veteran's critical incidents, current triggers, and behaviors likely to prove useful in his or her future. Two case examples of combat veterans illustrate the ability of EMDR to achieve symptom reduction in a variety of clinical domains (e.g., anxiety, depression, anger, physical pain) simultaneously without requiring the patient to carry out homework assignments or discuss the details of the event. The treatment of phantom limb pain and other somatic presentations is also reviewed. The ability of EMDR to achieve positive effects without homework indicates that it can be effectively employed on consecutive days, making it especially useful during combat situations.