Addressing the high cervical cancer rates along the Texas-Mexico border through community outreach, patient navigation, and provider training/telementoring

Objective: Cervical cancer incidence and mortality rates are 68% and 57% higher, respectively, along the Texas-Mexico border compared with the rest of the United States. This is likely due to a combination of low health literacy, limited access to affordable screening, and a lack of trained personnel to perform colposcopy, loop electrosurgical excision procedures (LEEP), and appropriate management of women with pre-invasive disease. The objective of our study was to increase cervical cancer screening, diagnosis, and treatment rates in the Rio Grande Valley (RGV). Method: We initiated a comprehensive program at two health centers and one mobile clinic in the RGV consisting of (1) a public education program designed for community health workers to teach women about cervical cancer screening and HPV vaccination coupled with patient navigation to participating clinics; (2) colposcopy and LEEP training for physicians and advanced-practice providers through locally held hands-on courses and mentoring program; and (3) implementation of Project ECHO (Extension for Community Health Outcomes), a well-established telementoring program using video conferencing to connect academic specialists with community providers for case-based learning. We compared screening, diagnosis, and treatment rates pre- and post-program implementation. Results: From November 2014 to June 2018, local providers screened 19,028 women with Pap ± HPV testing (baseline 12,460, 53% increase); performed colposcopy on 2,644 women with abnormal screening results (baseline 945, 180% increase); and performed 483 LEEP procedures for treatment of cervical dysplasia (baseline 0). Ten women were diagnosed with invasive cancer and navigated to one of the participating gynecologic oncologists for treatment (baseline N/A). Five additional providers in the RGV completed the mentoring program to be certified to perform colposcopy (100% increase from baseline of 5) and two additional providers to perform LEEP (baseline 0). ECHO telementoring video conferences have been held every two weeks for a total 94 sessions (average of 22 participants/session) with 182 patient cases presented and discussed. Conclusion: Our comprehensive approach has led to an increase in the number of women undergoing cervical cancer screening and diagnosis/treatment of dysplasia. If sustained, we anticipate these efforts will decrease cervical cancer rates in the RGV. The program is currently being expanded to additional medically underserved regions of Texas

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers.

BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).RESULTSPCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONSThese results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.FUNDINGInstituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation

Utilization of mechanical power and associations with clinical outcomes in brain injured patients. a secondary analysis of the extubation strategies in neuro-intensive care unit patients and associations with outcome (ENIO) trial

BackgroundThere is insufficient evidence to guide ventilatory targets in acute brain injury (ABI). Recent studies have shown associations between mechanical power (MP) and mortality in critical care populations. We aimed to describe MP in ventilated patients with ABI, and evaluate associations between MP and clinical outcomes.MethodsIn this preplanned, secondary analysis of a prospective, multi-center, observational cohort study (ENIO, NCT03400904), we included adult patients with ABI (Glasgow Coma Scale <= 12 before intubation) who required mechanical ventilation (MV) >= 24 h. Using multivariable log binomial regressions, we separately assessed associations between MP on hospital day (HD)1, HD3, HD7 and clinical outcomes: hospital mortality, need for reintubation, tracheostomy placement, and development of acute respiratory distress syndrome (ARDS).ResultsWe included 1217 patients (mean age 51.2 years [SD 18.1], 66% male, mean body mass index [BMI] 26.3 [SD 5.18]) hospitalized at 62 intensive care units in 18 countries. Hospital mortality was 11% (n = 139), 44% (n = 536) were extubated by HD7 of which 20% (107/536) required reintubation, 28% (n = 340) underwent tracheostomy placement, and 9% (n = 114) developed ARDS. The median MP on HD1, HD3, and HD7 was 11.9 J/min [IQR 9.2-15.1], 13 J/min [IQR 10-17], and 14 J/min [IQR 11-20], respectively. MP was overall higher in patients with ARDS, especially those with higher ARDS severity. After controlling for same-day pressure of arterial oxygen/fraction of inspired oxygen (P/F ratio), BMI, and neurological severity, MP at HD1, HD3, and HD7 was independently associated with hospital mortality, reintubation and tracheostomy placement. The adjusted relative risk (aRR) was greater at higher MP, and strongest for: mortality on HD1 (compared to the HD1 median MP 11.9 J/min, aRR at 17 J/min was 1.22, 95% CI 1.14-1.30) and HD3 (1.38, 95% CI 1.23-1.53), reintubation on HD1 (1.64; 95% CI 1.57-1.72), and tracheostomy on HD7 (1.53; 95%CI 1.18-1.99). MP was associated with the development of moderate-severe ARDS on HD1 (2.07; 95% CI 1.56-2.78) and HD3 (1.76; 95% CI 1.41-2.22).ConclusionsExposure to high MP during the first week of MV is associated with poor clinical outcomes in ABI, independent of P/F ratio and neurological severity. Potential benefits of optimizing ventilator settings to limit MP warrant further investigation

Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure: the DIANA study

Purpose: The DIANA study aimed to evaluate how often antimicrobial de-escalation (ADE) of empirical treatment is performed in the intensive care unit (ICU) and to estimate the effect of ADE on clinical cure on day 7 following treatment initiation. Methods: Adult ICU patients receiving empirical antimicrobial therapy for bacterial infection were studied in a prospective observational study from October 2016 until May 2018. ADE was defined as (1) discontinuation of an antimicrobial in case of empirical combination therapy or (2) replacement of an antimicrobial with the intention to narrow the antimicrobial spectrum, within the first 3 days of therapy. Inverse probability (IP) weighting was used to account for time-varying confounding when estimating the effect of ADE on clinical cure. Results: Overall, 1495 patients from 152 ICUs in 28 countries were studied. Combination therapy was prescribed in 50%, and carbapenems were prescribed in 26% of patients. Empirical therapy underwent ADE, no change and change other than ADE within the first 3 days in 16%, 63% and 22%, respectively. Unadjusted mortality at day 28 was 15.8% in the ADE cohort and 19.4% in patients with no change [p = 0.27; RR 0.83 (95% CI 0.60\u20131.14)]. The IP-weighted relative risk estimate for clinical cure comparing ADE with no-ADE patients (no change or change other than ADE) was 1.37 (95% CI 1.14\u20131.64). Conclusion: ADE was infrequently applied in critically ill-infected patients. The observational effect estimate on clinical cure suggested no deleterious impact of ADE compared to no-ADE. However, residual confounding is likely

MCL-1 is a prognostic indicator and drug target in breast cancer

Analysis of publicly available genomic and gene expression data demonstrates that MCL1 expression is frequently elevated in breast cancer. Distinct from other pro-survival Bcl-2 family members, the short half-life of MCL-1 protein led us to investigate MCL-1 protein expression in a breast cancer tissue microarray and correlate this with clinical data. Here, we report associations between high MCL-1 and poor prognosis in specific subtypes of breast cancer including triple-negative breast cancer, an aggressive form that lacks targeted treatment options. Deletion of MCL-1 in the mammary epithelium of genetically engineered mice revealed an absolute requirement for MCL-1 in breast tumorigenesis. The clinical applicability of these findings was tested through a combination of approaches including knock-down or inhibition of MCL-1 to show triple-negative breast cancer cell line dependence on MCL-1 in vitro and in vivo. Our data demonstrate that high MCL-1 protein expression is associated with poor outcome in breast cancer and support the therapeutic targeting of MCL-1 in this disease

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

An efficient and scalable block parallel algorithm of Neville elimination as a tool for the CMB maps problem

Abstract This paper analyses the performance of several versions of a block parallel algorithm in order to apply Neville elimination in a distributed memory parallel computer. Neville elimination is a procedure to transform a square matrix A into an upper triangular one. This analysis must take into account the algorithm behaviour as far as execution time, efficiency and scalability are concerned. Special attention has been paid to the study of the scalability of the algorithms trying to establish the relationship existing between the size of the block and the performance obtained in this metric. It is important to emphasize the high efficiency achieved in the studied cases and that the experimental results confirm the theoretical approximation. Therefore, we have obtained a high predicting ability tool of analysis. Finally, we will present the elimination of Neville as an efficient tool in detecting point sources in cosmic microwave background maps.© Springer Science+Business Media, LLC 2010This work has been partially supported by the Spanish Research Grants TIN2007-61273, TIN2008-06570-C04-02 and TIN2010-14971, and by Valencia Regional Government Grant PRO-METEO/2009/013. Also, we would like to give special thanks to Professor Francisco Argueso of University of Oviedo for his help.Alonso, P.; Cortina, R.; Ranilla, J.; Vidal Maciá, AM. (2012). An efficient and scalable block parallel algorithm of Neville elimination as a tool for the CMB maps problem. Journal of Mathematical Chemistry. 50(2):345-358. https://doi.org/10.1007/s10910-010-9769-0S345358502Alonso P., Cortina R., Díaz I., Ranilla J.: Analyzing scalability of Neville elimination. J. Math. Chem. 40(1), 49 (2006)Alonso P., Cortina R., Díaz I., Ranilla J.: Scalability of Neville elimination using checkerboard partitioning. Int. J. Comput. Math. 85(3–4), 309 (2008)Alonso P., Cortina R., Díaz I., Ranilla J.: Blocking Neville elimination algorithm for exploiting cache memories. Appl. Math. Comput. 209, 2 (2009)Ando T.: Totally positive matrices. Linear Algebra Appl. 90, 165 (1987)Gasca M., Michelli C.A.: Total Positivity and its Applications. Kluwer, Dordrecht (1996)Gasca M., Peña J.M.: Total positivity and Neville elimination. Linear Algebra Appl. 165, 25 (1992)Gemignani L.: Neville elimination for rank-structured matrices. Linear Algebra Appl. 428(4), 978 (2008)Grama A., Gupta A., Karypis G., Kumar V.: Introduction to Parallel Computing. Pearson Education Limited, London (2003)Lin H., Bao H., Wang G.: Totally positive bases and progressive iteration approximation. Comput. Math. Appl. 50, 575 (2005)Lopez-Caniego M. et al.: Comparison of filters for the detection of point sources in Planck simulations. Mon. Not. Roy. Astron. Soc. 370, 2047 (2006)Peña J.M.: Shape Preserving Representations in Computer Aided–Geometric Design. Nova Science Publishers, New York (1999)Penzias A.A., Wilson R.W.: A measurement of excess antenna temperature at 4080 Mc/s. Astrophys. J. 142, 419 (1965)Prieto M., Montero R.S., Llorente I.M., Tirado F.: A parallel multigrid solver for viscous flows on anisotropic structured grids. Parallel Comput. 29, 907 (2003)Smoot G. et al.: Structure in the COBE differential microwave radiometer first-year maps. Astrophys. J. 396, L1 (1992)Spergel D.N. et al.: First-year Wilkinson microwave anisotropy probe (WMAP) observations: determination of cosmological parameters. Astrophys. J. Suppl. 148, 175 (2003)J.A. Tauber, The Planck mission, in New Cosmological Data and the Values of the Fundamental Parameters. Proceedings of IAU Symposium vol. 201 (2005), p. 86, eds. by A. Lasenby, A. WilkinsonToffolatti L. et al.: Extragalactic source counts and contributions to the anisotropies of the cosmic microwave background: predictions for the Planck Surveyor mission. Mon. Not. Roy. Astron. Soc. 297, 117 (1998