HPV genotyping in clinical samples using long-read single-molecule real-time sequencing.

Human papillomavirus (HPV) genotyping is widely used, particularly in combination with high-risk (HR) HPV tests for cervical cancer screening. We developed a genotyping method using sequences of approximately 800 bp in the E6/E7 region obtained by PacBio single molecule real-time sequencing (SMRT) and evaluated its performance against MY09-11 L1 sequencing and after the APTIMA HPV genotyping assay. The levels of concordance of PacBio E6/E7 SMRT sequencing with MY09-11 L1 sequencing and APTIMA HPV genotyping were 100% and 90.8%, respectively. The sensitivity of PacBio E6/EA7 SMRT was slightly greater than that of L1 sequencing and, as expected, lower than that of HR-HPV tests. In the context of cervical cancer screening, PacBio E6/E7 SMRT is then best used after a positive HPV test. PacBio E6/E7 SMRT genotyping is an attractive alternative for HR and LR-HPV genotyping of clinical samples. PacBio SMRT sequencing provides unbiased genotyping and can detect multiple HPV infections and haplotypes within a genotype.

Human papillomavirus testing using HPV APTIMA® assay and an external cellularity control in self-collected samples.

In cervical cancer screening programs, the detection of high-risk human papillomavirus (HR-HPV) is now widely implemented on physician-collected samples and has expanded to include self-collected samples. The use of a cellularity control (CC) is needed to reduce false-negative HPV results. An external mRNA CC for the HPV APTIMA® assay was assessed for its analytical performance and the results were compared with both cervix cytobrush samples taken by physicians and self-collected vaginal samples from 148 women. The performance of the CC was adjusted to control for the presence of cellular mRNA in the ThinPrep® and Multitest® transport media. This CC is user-friendly but implies to perform two independent assays on PANTHER® automate. Self-collected vaginal sampling gives a lower median CC results (13.2 vs. 16.9 min) but a higher risk of negative CC results (3.3 vs. 0%). The usefulness of the CC for the HR-HPV assay may be optimized by the definition of a threshold for a minimum cell number to be tested to increase confidence in HPV-negative results. The systematic use of an RNA CC increases confidence for HPV RNA assays on self-collected vaginal samples.

The (Co)Production of Difference in the Care of Patients With Cancer From Migrant Backgrounds.

An extensive body of scholarship focuses on cultural diversity in health care, and this has resulted in a plethora of strategies to "manage" cultural difference. This work has often been patient-oriented (i.e., focused on the differences of the person being cared for), rather than relational in character. In this study, we aimed to explore how the difference was relational and coproduced in the accounts of cancer care professionals and patients with cancer who were from migrant backgrounds. Drawing on eight focus groups with 57 cancer care professionals and one-on-one interviews with 43 cancer patients from migrant backgrounds, we explore social relations, including intrusion and feelings of discomfort, moral logics of rights and obligation, and the practice of defaulting to difference. We argue, on the basis of these accounts, for the importance of approaching difference as relational and that this could lead to a more reflexive means for overcoming "differences" in therapeutic settings.

Prevalence and Cost of Care Cascades After Low-Value Preoperative Electrocardiogram for Cataract Surgery in Fee-for-Service Medicare Beneficiaries.

IMPORTANCE: Low-value care is prevalent in the United States, yet little is known about the downstream health care use triggered by low-value services. Measurement of such care cascades is essential to understanding the full consequences of low-value care. OBJECTIVE: To describe cascades (tests, treatments, visits, hospitalizations, and new diagnoses) after a common low-value service, preoperative electrocardiogram (EKG) for patients undergoing cataract surgery. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study using fee-for-service Medicare claims data from beneficiaries aged 66 years or older without known heart disease who were continuously enrolled between April 1, 2013, and September 30, 2015, and underwent cataract surgery between July 1, 2014 and June 30, 2015. Data were analyzed from March 12, 2018, to April 9, 2019. EXPOSURES: Receipt of a preoperative EKG. The comparison group included patients who underwent cataract surgery but did not receive a preoperative EKG. MAIN OUTCOMES AND MEASURES: Cascade event rates and associated spending in the 90 days after preoperative EKG, or in a matched timeframe for the comparison group. Secondary outcomes were patient, physician, and area-level characteristics associated with experiencing a potential cascade. RESULTS: Among 110 183 cataract surgery recipients, 12 408 (11.3%) received a preoperative EKG (65.6% of them were female); of those, 1978 (15.9%) had at least 1 potential cascade event. The comparison group included 97 775 participants (63.1% female). Those who received a preoperative EKG experienced between 5.11 (95% CI, 3.96-6.25) and 10.92 (95% CI, 9.76-12.08) additional events per 100 beneficiaries relative to the comparison group. This included between 2.18 (95% CI, 1.34-3.02) and 7.98 (95% CI, 7.12-8.84) tests, 0.33 (95% CI, 0.19-0.46) treatments, 1.40 (95% CI, 1.18-1.62) new patient cardiology visits, and 1.21 (95% CI, 0.62-1.79) new cardiac diagnoses. Spending for the additional services was up to $565 per Medicare beneficiary (95% CI, $342-$775), or an estimated $35 025 923 annually across all Medicare beneficiaries in addition to the $3 275 712 paid for the preoperative EKGs. Among preoperative EKG recipients, those who were older (adjusted odds ratio [aOR] for patients aged 75 to 84 years vs 66 to 74 years old, 1.42; 95% CI, 1.28-1.57), had more chronic conditions (aOR for each additional Elixhauser condition, 1.18; 95% CI, 1.14-1.22), lived in more cardiologist-dense areas (aOR, 1.05; 95% CI, 1.02-1.09), or had their preoperative EKG performed by a cardiac specialist rather than a primary care physician (aOR, 1.26; 95% CI, 1.10-1.43) were more likely to experience a potential cascade. CONCLUSIONS AND RELEVANCE: Care cascades after preoperative EKG for cataract surgery are infrequent but costly. Policy and practice interventions to reduce low-value services and the cascades that follow could yield substantial savings.

Forgotten patients: ACO attribution omits those with low service use and the dying.

OBJECTIVES: Alternative payment models, such as accountable care organizations, hold provider groups accountable for an assigned patient population, but little is known about unassigned patients. We compared clinical and utilization profiles of patients attributable to a provider group with those of patients not attributable to any provider group. STUDY DESIGN: Cross-sectional study of 2012 Medicare fee-for-service beneficiaries 21 years and older. METHODS: We applied the Medicare Shared Savings Program attribution approach to assign beneficiaries to 2 mutually exclusive categories: attributable or unattributable. We compared attributable and unattributable beneficiaries according to demographics, dual eligibility for Medicaid, nursing home residency, clinical comorbidities, annual service utilization, annual spending, and 1- and 2-year mortality. We estimated multivariate regression models describing correlates of attribution status. RESULTS: Most beneficiaries (88%) were attributable to a provider group. The remaining 12% were unattributable. Beneficiaries unattributable to any provider group were more likely to be younger, male, and from a minority group; to have disability as the basis for enrollment; and to live in high-poverty areas. Unattributable beneficiaries included 3 distinct subgroups: nonusers of care, decedents, and those with healthcare service use but no qualifying evaluation and management visits. Many unattributable Medicare beneficiaries had minimal use of healthcare services, with the exception of a small subgroup of beneficiaries who died within the attribution year. CONCLUSIONS: Attribution approaches that more fully capture unattributable patients with low service use and patients near the end of life should be considered to reward population health efforts and improve end-of-life care.

Neural Foundations of Creativity: A Systematic Review / Fundamentos neurales de la creatividad: una revisión sistemática

Abstract When considering the importance of the human cognitive function of creativity, we often overlook the fact that it is due to human creativity and to the constant search for new sensory stimuli that our world has, throughout the years, been one of innovation in every aspect of our existence -in the sciences, the humanities, and the arts. Almost everything that surrounds us is the result of human creativity, therefore it is not difficult to understand that although neuroscientific research has led to valuable perceptions into the probable underpinnings of this multifaceted ability, the precise neurological substrates that underlie creativity are yet to be determined. Despite the establishment of a strong link between creativity and divergent thinking, other brain networks have been implicated in this mental process. The following review underlines recent studies on the neural foundations of creativity. A comprehensive analysis of the upmost important facts will be presented, with emphasis on concepts, tests, and methods that have been used to study creativity, and how they have outlined a pathway to the key understanding of this unique human ability.

Resumen Al considerar la importancia de la creatividad en la función cognitiva humana, sucede con frecuencia y pasamos por alto el hecho de que es precisamente debido a la creatividad humana que a través de los arios nuestro mundo ha estado en constante innovación en cada aspecto de nuestra existencia: en la ciencia, las humanidades y las artes. Casi todo lo que nos rodea se debe a la creatividad humana; por lo tanto, no es difícil entender que, aunque la investigación neurocientífica ha conducido a percepciones valiosas sobre los fundamentos probables de esta capacidad multifacética, estos estudios no han permitido conclusiones claras y tienen todavía mucho por determinar para comprenderla mejor. A pesar de que se ha establecido un fuerte vínculo entre la creatividad y el pensamiento divergente, científicos han identificado otras redes cerebrales implicadas en este proceso mental. La presente revisión subraya los estudios recientes sobre los fundamentos neuronales de la creatividad. Se presenta un análisis comprensivo con énfasis en los conceptos, las pruebas y los métodos que se han utilizado para estudiar la creatividad y la forma en que han proyectado una vía para la comprensión fundamental de esta capacidad humana única.

Comparison of Cobas® HPV and Anyplex™ II HPV28 assays for detecting and genotyping human papillomavirus.

Persistent infection with high-risk human papillomavirus (HPV-HR) is a recognized cause of cervical cancer. The aim of this study was to compare analytical and clinical performances of the Cobas® HPV and Anyplex™ II HPV28 assays for HPV detection and genotyping. A total of 94 cervical samples were tested. For HPV-HR, the results agreed very well (94.68%), with 100% agreement when detecting CIN2+. The Anyplex™ II HPV28 assay detected more genotypes than the Cobas® HPV Test, but their clinical performances were similar.

No selection of CXCR4-using variants in cell reservoirs of dual-mixed HIV-infected patients on suppressive maraviroc therapy.

We used ultradeep sequencing to investigate the evolution of the frequency of CXCR4-using viruses in the peripheral blood mononuclear cells of 22 patients infected with both CCR5 and CXCR4-using viruses treated with the CCR5 antagonist maraviroc for 24 weeks and a stable antiviral therapy. The mean CXCR4-using virus frequency in peripheral blood mononuclear cells was 59% before maraviroc intensification and 52% after 24 weeks of effective treatment, indicating no selection by maraviroc.

Phenotyping methods for determining HIV tropism and applications in clinical settings.

PURPOSE OF REVIEW: HIV-1 enters CD4-expressing cells via one or both of the chemokine receptors CCR5 and CXCR4. Specific CCR5 antagonists are now in clinical use, but only for CCR5-tropic viruses. Hence, several methods have been developed for assessing HIV-1 tropism in patients who are candidates for CCR5 antagonists. This article reviews current data on phenotypic assays of tropism. RECENT FINDINGS: Phenotypic assays are still used as reference, although genotypic methods have improved. The main advantages of phenotypic assays are their great sensitivity for detecting minor CXCR4-using variants and their capacity to assess non-B subtypes of HIV-1. Clinical trials of maraviroc have, thus, relied on the phenotypic determination of HIV-1 tropism. However, new genotypic approaches that are more sensitive for minor CXCR4-using variants, notably ultra-deep pyrosequencing, are now challenging phenotypic assays. Nevertheless, phenotypic assays are essential for improving genotypic algorithms for determining HIV-1 tropism as well as for assessing the resistance of R5-tropic viruses to CCR5 antagonists. SUMMARY: HIV-1 tropism should be determined before using CCR5 antagonists. Phenotypic recombinant assays are still the benchmark tests for characterizing HIV-1 tropism as their great sensitivity enables them to detect minor CXCR4-using variants of both B and non-B HIV-1 subtypes.

CXCR4-using viruses in plasma and peripheral blood mononuclear cells during primary HIV-1 infection and impact on disease progression.

OBJECTIVE: Cysteine-cysteine receptor 5 (CCR5)-using viruses classically predominate during HIV-1 primary infection but the frequency of cysteine-X-cysteine receptor 4 (CXCR4)-using viruses varies between studies and could be different between plasma and peripheral blood mononuclear cells (PBMCs). Thus, we determined HIV-1 tropism in both these compartments during primary infection and evaluated the impact of CXCR4-using viruses on disease progression. DESIGN: One hundred and thirty-three patients with primary HIV-1 infection were screened for HIV-1 coreceptor usage in plasma and PBMCs using both genotypic and phenotypic methods. The impact of CXCR4-using viruses' transmission on subsequent disease progression was assessed in a case-control study. METHODS: HIV-1 coreceptor usage was determined using a recombinant virus phenotypic entry assay and V3-based genotypic algorithms. We also monitored CD4(+) T-cell count, clinical events and therapeutic intervention. RESULTS: There was 6.4% of CXCR4-using HIV-1 in plasma during primary infection as measured by a phenotypic assay and combined criteria from the 11/25 and net charge genotypic rules. Geno2pheno10 overestimated the prevalence of CXCR4-using viruses (12%). HIV-1 tropism in plasma and PBMCs was 98% concordant. The HIV-1 RNA load and CD4(+) T-cell count during primary infection were not related to virus tropism. Primary infection with CXCR4-using viruses was associated with an accelerated rate of disease progression, estimated by a faster decline of CD4 T-cell count under 350 cells/microl and by a reduced delay in initiating a first antiretroviral treatment. CONCLUSIONS: Plasma or PBMC samples can be used for determining HIV-1 tropism during primary infection. CXCR4-using viruses are rare during primary infection but increase the risk of disease progression.