Costs of Providing Preexposure Prophylaxis for HIV Prevention at Community Health Centers in the United States.

OBJECTIVE: Preexposure prophylaxis (PrEP) is recommended for people at risk of acquiring HIV. We assessed billable costs associated with PrEP delivery at community health centers. METHODS: The Sustainable Health Center Implementation PrEP Pilot (SHIPP) study is an observational cohort of people receiving daily oral PrEP at participating federally qualified health centers and other community health centers. We assessed health care utilization and billable costs of providing PrEP at 2 health centers, 1 in Chicago, Illinois, and 1 in Washington, DC, from 2014 to 2018. The health centers followed the clinical practice guidelines for PrEP provision, including regular visits with health care providers and ongoing laboratory monitoring. Using clinic billing records and Current Procedural Terminology (CPT) coding, we retrospectively extracted data on the frequency and costs (in 2017 US dollars) of PrEP clinic visits and laboratory screening, for each patient, for 12 months since first PrEP prescription. RESULTS: The average annual number of PrEP clinic visits and associated laboratory screens per patient was 5.1 visits and 25.2 screens in Chicago (n = 482 patients) and 5.4 visits and 24.8 screens in Washington, DC (n = 56 patients). The average annual PrEP billable cost per patient was $583 for clinic visits and $1070 for laboratory screens in Chicago and $923 for clinic visits and $1018 for laboratory screens in Washington, DC. The average annual total cost per patient was $1653 (95% CI, $1639-$1668) in Chicago and $1941 (95% CI, $1811-$2071) in Washington, DC. CONCLUSIONS: Our analysis, which provides PrEP billable cost estimates based on empirical data, may help inform health care providers who are considering implementing this HIV prevention strategy.

Maize varietal replacement in Eastern and Southern Africa: Bottlenecks, drivers and strategies for improvement.

Seed security is vital for food security. Rapid-cycle, climate-adaptive breeding programs and seed systems that deliver new, elite varieties to farmers to replace obsolete ones can greatly improve the productivity of maize-based cropping systems in sub-Saharan Africa (SSA). Despite the importance and benefits of accelerated varietal turnover to climate change adaptation and food security, the rate of maize varietal replacement in SSA is slow. This review outlines the major bottlenecks, drivers, risks, and benefits of active replacement of maize varieties in eastern and southern Africa (ESA) and highlights strategies that are critical to varietal turnover. Although there is an upsurge of new seed companies in ESA and introduction of new varieties with better genetics in the market, some established seed companies continue to sell old (over 15-year-old) varieties. Several recently developed maize hybrids in ESA have shown significant genetic gains under farmers' conditions. Empirical evidence also shows that timely replacement of old products results in better business success as it helps seed companies maintain or improve market share and brand relevance. Therefore, proactive management of product life cycles by seed companies benefits both the farmers and businesses alike, contributing to improved food security and adaptation to the changing climate.

Elite rhetoric can undermine democratic norms.

Democratic stability depends on citizens on the losing side accepting election outcomes. Can rhetoric by political leaders undermine this norm? Using a panel survey experiment, we evaluate the effects of exposure to multiple statements from former president Donald Trump attacking the legitimacy of the 2020 US presidential election. Although exposure to these statements does not measurably affect general support for political violence or belief in democracy, it erodes trust and confidence in elections and increases belief that the election is rigged among people who approve of Trump's job performance. These results suggest that rhetoric from political elites can undermine respect for critical democratic norms among their supporters.

Ultrasound Evaluation of Gastric Emptying Time in Healthy Term Neonates after Formula Feeding.

BACKGROUND: The current American Society of Anesthesiologists fasting guideline for formula-fed infants in the periprocedural setting is 6 h. Prolonged fasting in very young infants is associated with an increased risk for hypoglycemia and dehydration as well as patient discomfort and patient/parental dissatisfaction. This study aimed to determine the time to gastric emptying in healthy neonates after formula feeding by serially evaluating the gastric antrum with ultrasound. The authors hypothesized that gastric emptying times in formula-fed neonates are significantly shorter than the current 6 h fasting recommendation. METHODS: After institutional review board approval and written informed parental consent, ultrasound examination was performed in healthy full-term neonates before and after formula feeding at 15-min intervals until return to baseline. Ultrasound images of the gastric antrum were measured to obtain cross-sectional areas, which were then used to estimate gastric antral volumes. RESULTS: Forty-six of 48 recruited neonates were included in the final analysis. Gastric emptying times ranged from 45 to 150 min and averaged 92.9 min (95% CI, 80.2 to 105.7 min; 99% CI, 76.0 to 109.8 min) in the overall study group. No significant differences were found in times to gastric emptying between male and female neonates (male: mean, 93.3 [95% CI, 82.4 to 104.2 min]; female: mean, 92.6 [95% CI, 82.0 to 103.2 min]; P = 0.930) or those delivered by vaginal versus cesarean routes (vaginal: mean, 93.9 [95% CI, 81.7 to 106.1 min]; cesarean: mean, 92.2 [95% CI, 82.5 to 101.9 min]; P = 0.819). CONCLUSIONS: These results demonstrate that gastric emptying times are substantially less than the current fasting guideline of 6 h for formula-fed, healthy term neonates.

Executive functions in children with heart disease: a systematic review and meta-analysis.

CONTEXT: People with CHD are at increased risk for executive functioning deficits. Meta-analyses of these measures in CHD patients compared to healthy controls have not been reported. OBJECTIVE: To examine differences in executive functions in individuals with CHD compared to healthy controls. DATA SOURCES: We performed a systematic review of publications from 1 January, 1986 to 15 June, 2020 indexed in PubMed, CINAHL, EMBASE, PsycInfo, Web of Science, and the Cochrane Library. STUDY SELECTION: Inclusion criteria were (1) studies containing at least one executive function measure; (2) participants were over the age of three. DATA EXTRACTION: Data extraction and quality assessment were performed independently by two authors. We used a shifting unit-of-analysis approach and pooled data using a random effects model. RESULTS: The search yielded 61,217 results. Twenty-eight studies met criteria. A total of 7789 people with CHD were compared with 8187 healthy controls. We found the following standardised mean differences: -0.628 (-0.726, -0.531) for cognitive flexibility and set shifting, -0.469 (-0.606, -0.333) for inhibition, -0.369 (-0.466, -0.273) for working memory, -0.334 (-0.546, -0.121) for planning/problem solving, -0.361 (-0.576, -0.147) for summary measures, and -0.444 (-0.614, -0.274) for reporter-based measures (p < 0.001). LIMITATIONS: Our analysis consisted of cross-sectional and observational studies. We could not quantify the effect of collinearity. CONCLUSIONS: Individuals with CHD appear to have at least moderate deficits in executive functions. Given the growing population of people with CHD, more attention should be devoted to identifying executive dysfunction in this vulnerable group.

Non-Hodgkin Lymphomas: Malignancies Arising from Mature B Cells.

Non-Hodgkin lymphomas (NHLs) are a diverse group of entities, both clinically and molecularly. Here, we review the evolution of classification schemes in B-cell lymphoma, noting the now standard WHO classification system that is based on immune cell-of-origin and molecular phenotypes. We review how lymphomas arise throughout the B-cell development process as well as the molecular and clinical features of prominent B-cell lymphomas. We provide an overview of the major progress that has occurred over the past decade in terms of our molecular understanding of these diseases. We discuss treatment options available and focus on a number of the diverse research tools that have been employed to improve our understanding of these diseases. We discuss the problem of heterogeneity in lymphomas and anticipate that the near future will bring significant advances that provide a measurable impact on NHL outcomes.

Associations Between Social Support and Social Media Use Among Young Adult Cisgender MSM and Transgender Women Living With HIV.

Social media platforms offer the opportunity to develop online social networks. Use of these platforms has been particularly attractive to younger sexual and gender minority individuals as well as those living with HIV. This cross-sectional study examined the perceived level of social support and associations with social media use among youth and young adult cisgender men who have sex with men (MSM) and transgender (trans) women living with HIV and examined these associations by gender identity. The study drew from baseline data collected from 612 cisgender MSM and 162 trans women enrolling in one of 10 demonstration sites that were part of a Health Resources and Services Administration Special Projects of National Significance initiative. The individual projects were designed to evaluate the potential for social media/mobile technology-based interventions to improve retention in care and HIV health outcomes. The data used in this study came from baseline surveys completed when participants enrolled in a site between October 2016 and May 2018. Results demonstrated that a significantly greater proportion of MSM than trans women participants reported the use of social media platforms (e.g., Facebook: MSM = 86%, trans women = 62%; Instagram: MSM = 65%, trans women = 35%). Furthermore, increased social media use improved perceptions of social support only among MSM participants (direct adjusted OR = 1.49) and not trans women participants (gender identity interaction term adjusted OR = 0.64). These results revealed that MSM participants perceived greater social benefit from the use of social media platforms than trans women, which could be a result of generalized online transphobia experienced by trans women. More nuanced data on various social media platforms, that is, anonymous versus profile-based, and group differences, are needed to better understand how social media platforms can be best utilized to optimize health care outcomes among sexual and gender minority youth and young adults living with HIV.

Geranylgeranyl generosity: a new prenyl-transferase gives a fat to a SNARE protein.

Protein prenylation, a well-defined protein consensus motifs direct modification by one of three prenyl-transferases, has been an area of fairly settled science for 20 or 30 years. Protein prenylation, the specific prenyl modification (farnesyl or geranylgeranyl), as well as the prenyl-transferases involved can be inferred by protein sequence. Two new papers now upset this settled wisdom with the discovery of a fourth prenyl-transferase, namely geranylgeranyl-transferase-III (GGTase-III) (Kuchay et al, 2019; Shirakawa et al, 2020).

Redefining the Trauma Triage Matrix: The Role of Emergent Interventions.

BACKGROUND: A tiered trauma team activation (TTA) system aims to allocate resources proportional to the patient's need based upon injury burden. The current metrics used to evaluate appropriateness of TTA are the trauma triage matrix (TTM), need for trauma intervention (NFTI), and secondary triage assessment tool (STAT). MATERIALS AND METHODS: In this retrospective study, we compared the effectiveness of the need for an emergent intervention within 6 h (NEI-6) with existing definitions. Data from the Michigan Trauma Quality Improvement Program was utilized. The dataset contains information from 31 level 1 and 2 trauma centers from 2011 to 2017. Inclusion criteria were: adult patients (≥16 y) and ISS ≥5. RESULTS: 73,818 patients were included in the study. Thirty percentage of trauma patients met criteria for STAT, 21% for NFTI, 20% for TTM, and 13% for NEI-6. NEI-6 was associated with the lowest rate of undertriage at 6.5% (STAT 22.3%, NFTI 14.0%, TTM 14.3%). NEI-6 best predicted undertriage mortality, early mortality, in-hospital mortality, and late (>60 h) mortality. Most patients who met criteria for TTM (58%), NFTI (51%), and STAT (62%) did not require emergent intervention. All four methods had similar rates of early mortality for patients who did not meet criteria (0.3%-0.5%). CONCLUSIONS: NEI-6 performs better than TTM, NFTI, and STAT in terms of undertriage, mortality and need for resource utilization. Other methods resulted in significantly more full TTAs than NEI-6 without identifying patients at risk for early mortality. NEI-6 represents a novel tool to determine trauma activation appropriateness.

Asymmetric synthesis of cyclopentanones through dual Lewis acid-catalysed [3+2]-cycloaddition of donor-acceptor cyclopropanes with ketenes.

When InBr3-EtAlCl2 (15-30 mol%) was used as a dual Lewis acid system to promote the formal [3+2]-cycloaddition of enantioenriched donor-acceptor cyclopropanes with ketenes, cyclopentanones were formed in good to excellent yields (84-99%, 18 examples), and with excellent transfer of chirality (15 examples, 90% ee to >99% ee).

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

Post-mortem molecular profiling of three psychiatric disorders.

BACKGROUND: Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate important regulators of pathogenesis and provide new therapeutic targets. METHODS: We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens from three groups of 24 patients each diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, and from 24 control subjects. We identified differentially expressed genes and validated the results in an independent cohort. Anterior cingulate cortex samples were also subjected to metabolomic analysis. ChIP-seq data were used to characterize binding of the transcription factor EGR1. RESULTS: We compared molecular signatures across the three brain regions and disorders in the transcriptomes of post-mortem human brain samples. The most significant disease-related differences were in the anterior cingulate cortex of schizophrenia samples compared to controls. Transcriptional changes were assessed in an independent cohort, revealing the transcription factor EGR1 as significantly down-regulated in both cohorts and as a potential regulator of broader transcription changes observed in schizophrenia patients. Additionally, broad down-regulation of genes specific to neurons and concordant up-regulation of genes specific to astrocytes was observed in schizophrenia and bipolar disorder patients relative to controls. Metabolomic profiling identified disruption of GABA levels in schizophrenia patients. CONCLUSIONS: We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions. We highlight a high-confidence set of independently validated genes differentially expressed between schizophrenia and control patients in the anterior cingulate cortex and integrate transcriptional changes with untargeted metabolite profiling.

Targeting the Ras palmitoylation/depalmitoylation cycle in cancer.

The Ras proteins are well-known drivers of many cancers and thus represent attractive targets for the development of anticancer therapeutics. Inhibitors that disrupt the association of the Ras proteins with membranes by blocking the addition of the farnesyl lipid moiety to the Ras C-terminus failed in clinical trials. Here, we explore the possibility of targeting a second lipid modification, S-acylation, commonly referred to as palmitoylation, as a strategy to disrupt the membrane interaction of specific Ras isoforms. We review the enzymes involved in adding and removing palmitate from Ras and discuss their potential roles in regulating Ras tumorigenesis. In addition, we examine other proteins that affect Ras protein localization and may serve as future drug targets.

Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2.

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.

Genome-wide DNA methylation measurements in prostate tissues uncovers novel prostate cancer diagnostic biomarkers and transcription factor binding patterns.

BACKGROUND: Current diagnostic tools for prostate cancer lack specificity and sensitivity for detecting very early lesions. DNA methylation is a stable genomic modification that is detectable in peripheral patient fluids such as urine and blood plasma that could serve as a non-invasive diagnostic biomarker for prostate cancer. METHODS: We measured genome-wide DNA methylation patterns in 73 clinically annotated fresh-frozen prostate cancers and 63 benign-adjacent prostate tissues using the Illumina Infinium HumanMethylation450 BeadChip array. We overlaid the most significantly differentially methylated sites in the genome with transcription factor binding sites measured by the Encyclopedia of DNA Elements consortium. We used logistic regression and receiver operating characteristic curves to assess the performance of candidate diagnostic models. RESULTS: We identified methylation patterns that have a high predictive power for distinguishing malignant prostate tissue from benign-adjacent prostate tissue, and these methylation signatures were validated using data from The Cancer Genome Atlas Project. Furthermore, by overlaying ENCODE transcription factor binding data, we observed an enrichment of enhancer of zeste homolog 2 binding in gene regulatory regions with higher DNA methylation in malignant prostate tissues. CONCLUSIONS: DNA methylation patterns are greatly altered in prostate cancer tissue in comparison to benign-adjacent tissue. We have discovered patterns of DNA methylation marks that can distinguish prostate cancers with high specificity and sensitivity in multiple patient tissue cohorts, and we have identified transcription factors binding in these differentially methylated regions that may play important roles in prostate cancer development.

The Genetic Basis of Hepatosplenic T-cell Lymphoma.

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets.Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR.See related commentary by Yoshida and Weinstock, p. 352This article is highlighted in the In This Issue feature, p. 339.

Statistical Methodology of the National Immunization Survey, 2005-2014.

The National Immunization Survey (NIS) family of surveys includes NIS-Child, which monitors vaccination coverage for the U.S. population of children aged 19-35 months; NIS- Teen, which monitors vaccination coverage for the U.S. population of adolescents aged 13-17; and NIS-Flu, which monitors influenza vaccination coverage for the U.S. population of children aged 6 months through 17 years. This report describes the methods used in this family of surveys during the 2005-2014 period.

Resting Heart Rate Variability Among Professional Baseball Starting Pitchers.

Cornell, DJ, Paxson, JL, Caplinger, RA, Seligman, JR, Davis, NA, and Ebersole, KT. Resting heart rate variability among professional baseball starting pitchers. J Strength Cond Res 31(3): 575-581, 2017-The purpose of this study was to examine the changes in resting heart rate variability (HRV) across a 5-day pitching rotation schedule among professional baseball starting pitchers. The HRV data were collected daily among 8 Single-A level professional baseball starting pitchers (mean ± SD, age = 21.9 ± 1.3 years; height = 185.4 ± 3.6 cm; weight = 85.2 ± 7.5 kg) throughout the entire baseball season with the participant quietly lying supine for 10 minutes. The HRV was quantified by calculating the natural log of the square root of the mean sum of the squared differences (lnRMSSD) during the middle 5 minutes of each R-R series data file. A split-plot repeated-measures analysis of variance was used to examine the influence of pitching rotation day on resting lnRMSSD. A statistically significant main effect of rotation day was identified (F4,706 = 3.139, p = 0.029). Follow-up pairwise analyses indicated that resting lnRMSSD on day 2 was significantly (p ≤ 0.05) lower than all other rotation days. In addition, a statistically significant main effect of pitcher was also identified (F7,706 = 83.388, p < 0.001). These results suggest that professional baseball starting pitchers display altered autonomic nervous system function 1 day after completing a normally scheduled start, as day 2 resting HRV was significantly lower than all other rotation days. In addition, the season average resting lnRMSSD varied among participants, implying that single-subject analysis of resting measures of HRV may be more appropriate when monitoring cumulative workload among this cohort population of athletes.

In-Game Heart Rate Responses Among Professional Baseball Starting Pitchers.

Cornell, DJ, Paxson, JL, Caplinger, RA, Seligman, JR, Davis, NA, Flees, RJ, and Ebersole, KT. In-game heart rate responses among professional baseball starting pitchers. J Strength Cond Res 31(1): 24-29, 2017-The purpose of the current study was to characterize the in-game heart rate (HR) responses of baseball pitching. In-game HR was recorded from 16 professional baseball starting pitchers (mean ± SD, age = 22.1 ± 1.3 years; height = 187.9 ± 4.4 cm; weight = 90.5 ± 9.5 kg) for a total of 682 innings (home = 381, away = 301). All analyzed HR data were then normalized to each pitcher's age-predicted maximal HR (%HRmax). The group mean ± SD in-game %HRmax among all pitchers was 84.8 ± 3.9%, suggesting that baseball pitching is predominantly an anaerobic task. A split-plot mixed-model repeated measures analysis of variance identified a significant interaction effect between inning and game location (p = 0.042). Follow-up simple effects indicated that the in-game %HRmax was significantly different across innings, but only during home starts (p < 0.001). Specifically, pairwise analyses indicated that the in-game %HRmax during home starts were significantly (p ≤ 0.05) higher in the first and second innings than in all other innings. In addition, follow-up simple effects indicated that the in-game %HRmax was significantly (p = 0.017) higher during home starts than away starts in the first inning (87.3 ± 3.6% vs. 85.8 vs. 3.8%, respectively). Thus, it is possible that inning-dependent psychological factors may have contributed to the observed changes in in-game physiological intensity across innings and that these factors are specific to game location. Consequently, strength and conditioning practitioners should prescribe high-intensity exercises when developing conditioning programs for professional baseball starting pitchers.