Renal cell carcinoma.

The landscape of the management of renal cell carcinoma has evolved substantially in the last decade, leading to improved survival in localised and advanced disease. We review the epidemiology, pathology, and diagnosis of renal cell carcinoma and discuss the evidence for current management strategies from localised to metastatic disease. Developments in adjuvant therapies are discussed, including use of pembrolizumab-the first therapy to achieve overall survival benefit in the adjuvant setting. The treatment of advanced disease, including landmark trials that have established immune checkpoint inhibition as a standard of care, are also reviewed. We also discuss the current controversies that exist surrounding the management of metastatic renal cell carcinoma, including the use of risk assessment models for disease stratification and treatment selection for frontline therapy. Management of non-clear cell renal cell carcinoma subtypes is also reviewed. Future directions of research, including a discussion of ongoing clinical trials and the need for reliable biomarkers to guide treatment in kidney cancer, are also highlighted.

Does the impact of bereavement vary between same and different gender partnerships? A representative national, cross-sectional study.

BACKGROUND: Data suggest poorer bereavement outcomes for lesbian, gay and bisexual people, but this has not been estimated in population-based research. This study compared bereavement outcomes for partners of same-gender and different-gender decedents. METHODS: In this population-based, cross-sectional survey of people bereaved of a civil partner or spouse 6-10 months previously, we used adjusted logistic and linear regression to investigate outcomes of interest: (1) positive screen on Inventory of Complicated Grief (ICG), (2) positive screen on General Health Questionnaire (GHQ), (3) grief intensity (ICG) and (4) psychiatric symptoms (GHQ-12). RESULTS: Among 233 same-gender partners and 329 of different-gender partners, 66.1% [95% confidence interval (CI) 60.0-72.2] and 59.2% [95% CI (53.9-64.6)] respectively screened positive for complicated grief on the ICG, whilst 76.0% [95% CI (70.5-81.5)] and 69.3% [95% CI (64.3-74.3)] respectively screened positive on the GHQ-12. Same-gender bereaved partners were not significantly more likely to screen positive for complicated grief than different-gender partners [adjusted odds ratio (aOR) 1.56, 95% CI (0.98-2.47)], p = 0.059, but same-gender bereaved partners were significantly more likely to screen for psychiatric caseness [aOR 1.67 (1.02, 2.71) p = 0.043]. We similarly found no significant association of partner gender with grief intensity [B = 1.86, 95% CI (-0.91to 4.63), p = 0.188], but significantly greater psychological distress for same-gender partners [B = 1.54, 95% CI (-0.69-2.40), p < 0.001]. CONCLUSIONS: Same-gender bereaved partners report significantly more psychological distress. In view of their poorer sub-clinical mental health, clinical and bereavement services should refine screening processes to identify those at risk of poor mental health outcomes.

LGBT+ partner bereavement and appraisal of the Acceptance-Disclosure Model of LGBT+ bereavement: A qualitative interview study.

BACKGROUND: Support from social networks is vital after the death of a partner. Lesbian, gay, bisexual and/or transgender (LGBT+) people can face disenfranchisement and isolation in bereavement. The Acceptance-Disclosure Model (of LGBT+ bereavement) posits that experiences are shaped by the extent to which individuals feel able to disclose their bereavement to others, and whether that loss is acknowledged appropriately. AIM: To explore LGBT+ specific experiences of partner bereavement; determine decision-making processes regarding disclosure of relationships/identities; and appraise the Acceptance-Disclosure Model using primary qualitative data. DESIGN: Exploratory in-depth qualitative interview study positioned within a social constructivist paradigm. Data were analysed using inductive and deductive reflexive thematic analysis. SETTING/PARTICIPANTS: 21 LGBT+ people from across England bereaved of their civil partner/spouse. RESULTS: Participants described LGBT+ specific stressors in bereavement: lack of recognition of their loss; inappropriate questioning; unwanted disclosure of gender history; and fears of discrimination when accessing support. Disclosure of LGBT+ identities varied across social networks. Some participants described hiding their identities and bereavement to preserve relationships, and challenging intersections between LGBT+ identities and other aspects of culture or self. These findings provide primary evidence to support the Acceptance-Disclosure Model. CONCLUSIONS: LGBT+ people face additional stressors in bereavement. Not all LGBT+ people want to talk directly about their relationships/identities. Sensitive exploration of support needs, aligned with preferences around disclosure of identities, can help foster trust. Five recommendations for inclusive practice are presented. Further research should consider whether the Acceptance-Disclosure Model has utility to explain bereavement experiences for other isolated or disenfranchised groups.

Accommodation in Children after 4.7 Years of Multifocal Contact Lens Wear in the BLINK Study Randomized Clinical Trial.

SIGNIFICANCE: When worn for myopia control in children, soft multifocal contact lenses with a +2.50 D add reduced the accommodative response over a 3-year period, but wearing them for more than 4 years did not affect accommodative amplitudes, lag, or facility. PURPOSE: This study aimed to compare the accommodative response to a 3D stimulus between single-vision, +1.50-D add, and +2.50-D add multifocal contact lens wearers during 3 years of contact lens wear and then to compare accommodative amplitude, lag, and facility between the three groups after an average of 4.7 years of wear. METHODS: Bifocal Lenses In Nearsighted Kids study participants aged 7 to 11 years old were randomly assigned to wear single-vision, +1.50-D add, or +2.50-D add soft contact lenses (CooperVision, Pleasanton, CA). The accommodative response to a 3D stimulus was measured at baseline and annually for 3 years. After 4.7 years, we measured objective accommodative amplitudes, lead/lag, and binocular facility with ±2.00-D flippers. We compared the three accommodative measures using multivariate analysis of variance (MANOVA), adjusting for clinic site, sex, and age group (7 to 9 or 10 to 11 years). RESULTS: The +2.50-D add contact lens wearers exhibited lower accommodative response than the single-vision contact lens wearers for 3 years, but the +1.50-D add contact lens wearers exhibited only lower accommodative response than did the single-vision contact lens wearers for 2 years. After adjustment for clinic site, sex, and age group, there were no statistically significant or clinically meaningful differences between the three treatment groups for accommodative amplitude (MANOVA, P = .49), accommodative lag (MANOVA, P = .41), or accommodative facility (MANOVA, P = .87) after an average of 4.7 years of contact lens wear. CONCLUSIONS: Almost 5 years of multifocal contact lens wear did not affect the accommodative amplitude, lag, or facility of children.

Quality of life after wearing multifocal contact lenses for myopia control for 2 weeks in the BLINK Study.

PURPOSE: To validate Pediatric Refractive Error Profile 2 (PREP2) subscales that can be used to evaluate contact lens wearers and compare vision-specific quality of life measurements between children wearing multifocal and single vision contact lenses for 2 weeks. METHODS: Two hundred and ninety-four myopic children aged 7-11 years (inclusive) were enrolled in the 3-year, double-masked Bifocal Lenses In Nearsighted Kids (BLINK) Study. Participants completed the PREP2 survey after having worn contact lenses for 2 weeks. The Vision, Symptoms, Activities and Overall PREP2 subscales were used to compare participants' subjective assessment while wearing +1.50 or +2.50 D add multifocal or single vision contact lenses. Rasch analysis was used to validate each subscale and to compare participants' subjective assessment of contact lens wear. RESULTS: Item fit to the Rasch model was good for all scales, with no individual items having infit mean square statistics outside the recommended range (0.7-1.3). Response category function was acceptable for all subscales, with ordered category thresholds. Measurement precision, assessed by the Rasch person reliability statistic, was less than ideal (≥0.8) for three of the subscales, but met the minimum acceptable standard of 0.5. Scores for the Vision subscale differed by treatment assignment (p = 0.03), indicating that participants with the highest add power reported statistically worse quality of vision, although the difference was only 3.9 units on a scale of 1-100. Girls reported fewer symptoms than boys (p = 0.006), but there were no other differences between boys and girls. CONCLUSIONS: Rasch analysis demonstrates that the PREP2 survey is a valid instrument for assessing refractive error-specific quality of life. These results suggest that vision-related quality of life is not meaningfully affected by 2 weeks of soft multifocal contact lens wear for myopia control.

Gadolinium-Based Paramagnetic Relaxation Enhancement Agent Enhances Sensitivity for NUS Multidimensional NMR-Based Metabolomics.

Gadolinium is a paramagnetic relaxation enhancement (PRE) agent that accelerates the relaxation of metabolite nuclei. In this study, we noted the ability of gadolinium to improve the sensitivity of two-dimensional, non-uniform sampled NMR spectral data collected from metabolomics samples. In time-equivalent experiments, the addition of gadolinium increased the mean signal intensity measurement and the signal-to-noise ratio for metabolite resonances in both standard and plasma samples. Gadolinium led to highly linear intensity measurements that correlated with metabolite concentrations. In the presence of gadolinium, we were able to detect a broad array of metabolites with a lower limit of detection and quantification in the low micromolar range. We also observed an increase in the repeatability of intensity measurements upon the addition of gadolinium. The results of this study suggest that the addition of a gadolinium-based PRE agent to metabolite samples can improve NMR-based metabolomics.

COVID-19 and Nurse-Sensitive Indicators: Using Performance Improvement Teams to Address Quality Indicators During a Pandemic.

BACKGROUND: Nurse-sensitive quality indicators have historically been used as a metric of nursing care quality in health care organizations. PROBLEM: At our academic medical center, critically ill COVID-19 patients led to a dramatic change in the organizational standard of care resulting in an increase in nurse-sensitive health care-associated infections. APPROACH: Nursing performance improvement teams provided the structure for development of innovative strategies implemented in real time by our frontline clinicians to address the quality and safety issues found with these elevated health care-associated infections. OUTCOMES: A new COVID-19 CLABSI (central line-associated bloodstream infection) Tip Sheet and a Prone Positioning Kit for HAPI Prevention are strategies developed to address quality of care issues experienced with the COVID-19 patients. CONCLUSIONS: Deployment of these innovative practice strategies has led to a decline in health care-associated infections and instituted a new care standard for the COVID-19 patients.

Parental Knowledge Discrepancies: Examining the Roles of Warmth and Self-Disclosure.

Discrepancies between parents' and adolescents' reports in parental knowledge of adolescents' daily activities and whereabouts are common and have implications for adolescents' well-being and school success. Grounded in a family systems perspective utilizing reports from parents and adolescents, the goal of this study was to explore the extent to which parent-adolescent warmth and adolescent self-disclosure could account for discrepancies in parental knowledge by testing the indirect effects linking warmth to discrepancies in parental knowledge via adolescent self-disclosure. Participants were early adolescents (N = 172; 53% female) and their parents (90% mothers). Adolescents (57% African American/Black, 18% multiracial, 17% White/Caucasian, 7% Hispanic/Latino and 1% Asian American) attended a Midwestern, Title 1, urban, public middle school. Using structural equation modeling, findings showed that parent-adolescent warmth significantly predicted adolescent self-disclosure, which in turn predicted fewer discrepancies in parental knowledge. The findings from this study help in understanding the factors that contribute to parental knowledge discrepancies and highlight potential targets for family interventions.

Parental Involvement and Adolescent Academic Outcomes: Exploring Differences in Beneficial Strategies across Racial/Ethnic Groups.

Gaps in educational outcomes between racial/ethnic and socioeconomic groups persist in the United States, and parental involvement is often cited as an important avenue for improving outcomes among racially/ethnically diverse adolescents. This study utilized data from the Education Longitudinal Study 2002-2013 (56% female, N = 4429), which followed 10th-graders through high school and ten years post-high school, to examine the links between parental involvement strategies and academic outcomes (grade point average and educational attainment). Participants included white, African American, and Hispanic/Latino adolescents from low-SES families. This study used recursive partitioning, a novel analytic strategy used for exploring higher-order interactions and non-linear associations among factors (e.g., parental educational involvement strategies) to predict an outcome (e.g., grade point average or educational attainment) through step-wise partitioning. The results showed that the combination of greater academic socialization and school-based involvement was beneficial for all adolescents' grade point average, whereas the combination of home-based involvement with academic socialization and school-based involvement yielded mixed results. Greater academic socialization and home-based involvement appeared beneficial for educational attainment among African American and Hispanic/Latino adolescents, but not white adolescents. More home-based involvement and less academic socialization were associated with less educational attainment for white adolescents. Overall, the findings showed different combinations of parental educational involvement strategies were beneficial for adolescents across racial/ethnic groups, which may have implications for practice and policy.

Lifting and exertion injuries decrease after implementation of an integrated hospital-wide safe patient handling and mobilisation programme.

OBJECTIVE: With increasing emphasis on early and frequent mobilisation of patients in acute care, safe patient handling and mobilisation practices need to be integrated into these quality initiatives. We completed a programme evaluation of a safe patient handling and mobilisation programme within the context of a hospital-wide patient care improvement initiative that utilised a systems approach and integrated safe patient equipment and practices into patient care plans. METHODS: Baseline and 12-month follow-up surveys of 1832 direct patient care workers assessed work practices and self-reported pain while an integrated employee payroll and injury database provided recordable injury rates collected concurrently at 2 hospitals: the study hospital with the programme and a comparison hospital. RESULTS: Safe and unsafe patient handling practice scales at the study hospital improved significantly (p<0.0001 and p=0.0031, respectively), with no differences observed at the comparison hospital. We observed significant decreases in recordable neck and shoulder (Relative Risk (RR)=0.68, 95% CI 0.46 to 1.00), lifting and exertion (RR=0.73, 95% CI 0.60 to 0.89) and pain and inflammation (RR=0.78, 95% CI 0.62 to 1.00) injury rates at the study hospital. Changes in rates at the comparison hospital were not statistically significant. CONCLUSIONS: Within the context of a patient mobilisation initiative, a safe patient handling and mobilisation programme was associated with improved work practices and a reduction in recordable worker injuries. This study demonstrates the potential impact of utilising a systems approach based on recommended best practices, including integration of these practices into the patient's plan for care.

miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to "seedless" 3'UTR microRNA recognition elements.

miR-24, upregulated during terminal differentiation of multiple lineages, inhibits cell-cycle progression. Antagonizing miR-24 restores postmitotic cell proliferation and enhances fibroblast proliferation, whereas overexpressing miR-24 increases the G1 compartment. The 248 mRNAs downregulated upon miR-24 overexpression are highly enriched for DNA repair and cell-cycle regulatory genes that form a direct interaction network with prominent nodes at genes that enhance (MYC, E2F2, CCNB1, and CDC2) or inhibit (p27Kip1 and VHL) cell-cycle progression. miR-24 directly regulates MYC and E2F2 and some genes that they transactivate. Enhanced proliferation from antagonizing miR-24 is abrogated by knocking down E2F2, but not MYC, and cell proliferation, inhibited by miR-24 overexpression, is rescued by miR-24-insensitive E2F2. Therefore, E2F2 is a critical miR-24 target. The E2F2 3'UTR lacks a predicted miR-24 recognition element. In fact, miR-24 regulates expression of E2F2, MYC, AURKB, CCNA2, CDC2, CDK4, and FEN1 by recognizing seedless but highly complementary sequences.

G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments.

Angiogenin (ANG) is a stress-activated ribonuclease that promotes the survival of motor neurons. Ribonuclease inactivating point mutations are found in a subset of patients with ALS, a fatal neurodegenerative disease with no cure. We recently showed that ANG cleaves tRNA within anticodon loops to produce 5'- and 3'-fragments known as tRNA-derived, stress-induced RNAs (tiRNAs). Selected 5'-tiRNAs (e.g., tiRNA(Ala), tiRNA(Cys)) cooperate with the translational repressor Y-box binding protein 1 (YB-1) to displace the cap-binding complex eIF4F from capped mRNA, inhibit translation initiation, and induce the assembly of stress granules (SGs). Here, we show that translationally active tiRNAs assemble unique G-quadruplex (G4) structures that are required for translation inhibition. We show that tiRNA(Ala) binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5'-tiDNA(Ala) (the DNA equivalent of 5'-tiRNA(Ala)) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5'-tiDNA(Ala) also assembles a G4 structure that allows it to enter motor neurons spontaneously and trigger a neuroprotective response in a YB-1-dependent manner. Remarkably, the ability of 5'-tiRNA(Ala) to induce SG assembly is inhibited by G4 structures formed by pathological GGGGCC repeats found in C9ORF72, the most common genetic cause of ALS, suggesting that functional interactions between G4 RNAs may contribute to neurodegenerative disease.

An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates.

Lin28 is an evolutionarily conserved RNA-binding protein that inhibits processing of pre-let-7 microRNAs (miRNAs) and regulates translation of mRNAs that control developmental timing, pluripotency, metabolism, and tumorigenesis. The RNA features that mediate Lin28 binding to the terminal loops of let-7 pre-miRNAs and to Lin28-responsive elements (LREs) in mRNAs are not well defined. Here we show that Lin28 target datasets are enriched for RNA sequences predicted to contain stable planar structures of 4 guanines known as G-quartets (G4s). The imino NMR spectra of pre-let-7 loops and LREs contain resonances characteristic of G4 hydrogen bonds. These sequences bind to a G4-binding fluorescent dye, N-methyl-mesoporphyrin IX (NMM). Mutations and truncations in the RNA sequence that prevent G4 formation also prevent Lin28 binding. The addition of Lin28 to a pre-let-7 loop or an LRE reduces G4 resonance intensity and NMM binding, suggesting that Lin28 may function to remodel G4s. Further, we show that NMM inhibits Lin28 binding. Incubation of a human embryonal carcinoma cell line with NMM reduces its stem cell traits. In particular it increases mature let-7 levels, decreases OCT4, HMGA1, CCNB1, CDK4, and Lin28A protein, decreases sphere formation, and inhibits colony formation. Our results suggest a previously unknown structural feature of Lin28 targets and a new strategy for manipulating Lin28 function.

Multifocal FIGO Stage IA1 Squamous Carcinoma of the Cervix: Criteria for Identification, Staging, and its Good Clinical Outcome.

Multifocal squamous cervical carcinomas account for up to 25% of IA1 tumors identified on excisional biopsy, yet there are no uniformly accepted histopathologic criteria for defining and staging these lesions. Here, we use a strict case definition and meticulous specimen processing from colposcopist to pathologist to identify and follow-up 25 cases of multifocal IA1 cervical squamous carcinomas identified in excisional biopsies. We stage these tumors using the dimensions of the largest focus and a minimum of 2 mm between each foci to define multifocality. The cases are followed up for a median of 7 yr with no episodes of tumor recurrence or metastasis. We also show that the prevalence of residual preinvasive (20%) and invasive disease (5%) on repeat excision/surgery are comparable to data available for unifocal IA1 cases. Our study supports the hypothesis that multifocal lesions should be staged according to largest individual focus of invasion and we emphasize the importance of meticulous specimen handling to appropriately identify multifocal tumors. In addition, our analysis suggests that outcomes are comparable to unifocal lesions and supports the hypothesis that they may be managed in a similar manner.

Genomic analysis of the emergence of 20th century epidemic dysentery.

BACKGROUND: Shigella dysenteriae type 1 (Sd1) causes recurrent epidemics of dysentery associated with high mortality in many regions of the world. Sd1 infects humans at very low infectious doses (10 CFU), and treatment is complicated by the rapid emergence of antibiotic resistant Sd1 strains. Sd1 is only detected in the context of human infections, and the circumstances under which epidemics emerge and regress remain unknown. RESULTS: Phylogenomic analyses of 56 isolates collected worldwide over the past 60 years indicate that the Sd1 clone responsible for the recent pandemics emerged at the turn of the 20th century, and that the two world wars likely played a pivotal role for its dissemination. Several lineages remain ubiquitous and their phylogeny indicates several recent intercontinental transfers. Our comparative genomics analysis reveals that isolates responsible for separate outbreaks, though closely related to one another, have independently accumulated antibiotic resistance genes, suggesting that there is little or no selection to retain these genes in-between outbreaks. The genomes appear to be subjected to genetic drift that affects a number of functions currently used by diagnostic tools to identify Sd1, which could lead to the potential failure of such tools. CONCLUSIONS: Taken together, the Sd1 population structure and pattern of evolution suggest a recent emergence and a possible human carrier state that could play an important role in the epidemic pattern of infections of this human-specific pathogen. This analysis highlights the important role of whole-genome sequencing in studying pathogens for which epidemiological or laboratory investigations are particularly challenging.

Digital PCR strategies in the development and analysis of molecular biomarkers for personalized medicine.

The efficient delivery of personalized medicine is a key goal of healthcare over the next decade. It is likely that PCR strategies will play an important role in the delivery of this goal. Digital PCR has certain advantages over more traditional PCR protocols. In this article we will discuss the current status of digital PCR, highlighting its advantages and focusing on how it can be utilized in biomarker development and analysis, including the use of individualized biomarkers. We will explore recent developments in this field including examples of how digital PCR may integrate with next generation sequencing to deliver truly personalized medicine.

Worker assessments of organizational practices and psychosocial work environment are associated with musculoskeletal injuries in hospital patient care workers.

BACKGROUND: Hospital patient care (PC) workers have high rates of workplace injuries, particularly musculoskeletal injuries. Despite a wide spectrum of documented health hazards, little is known about the association between psychosocial factors at work and OSHA-recordable musculoskeletal injuries. METHODS: PC-workers (n = 1,572, 79%) completed surveys assessing a number of organizational, psychosocial and psychological variables. Associations between the survey responses and injury records were tested using bivariate and multivariate analyses. RESULTS: A 5% of the PC-workers had at least one OSHA-recordable musculoskeletal injury over the year, and the injuries were significantly associated with: organizational factors (lower people-oriented culture), psychosocial factors (lower supervisor support), and structural factors (job title: being a patient care assistant). CONCLUSIONS: The results show support for a multifactorial understanding of musculoskeletal injuries in hospital PC-workers. An increased focus on the various dimensions associated with injury reports, particularly the organizational and psychosocial factors, could contribute to more efficient interventions and programs.

HIV DNA is heavily uracilated, which protects it from autointegration.

Human immune cells infected by HIV naturally contain high uracil content, and HIV reverse transcriptase (RT) does not distinguish between dUTP and dTTP. Many DNA viruses and retroviruses encode a dUTPase or uracil-DNA glycosylase (UNG) to counteract uracil incorporation. However, although HIV virions are thought to contain cellular UNG2, replication of HIV produced in cells lacking UNG activity does not appear to be impaired. Here we show that HIV reverse transcripts generated in primary human immune cells are heavily uracilated (>500 uracils per 10 kb HIV genome). We find that HIV DNA uracilation, rather than being dangerous, may promote the early phase of the viral life cycle. Shortly after reverse transcription, the ends of the HIV DNA are activated by the viral integrase (IN) in preparation for chromosomal insertion. However, the activated ends can attack the viral DNA itself in a suicidal side pathway, called autointegration. We find here that uracilation of target DNA inhibits the strand transfer of HIV DNA ends by IN, thereby inhibiting autointegration and facilitating chromosomal integration and viral replication. When uracilation is increased by incubating uracil-poor cells in the presence of increasing concentrations of dUTP or by infecting with virus that contains the cytosine deaminase APOBEC3G (A3G), the proportion of reverse transcripts that undergo suicidal autointegration decreases. Thus, HIV tolerates, or even benefits from, nonmutagenic uracil incorporation during reverse transcription in human immune cells.