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Implementation of evidence-based interventions (EBIs) can help to increase colorectal cancer screening (CRCS). Potential users of CRCS EBIs are often unclear about the specific features, logic, and core elements of existing EBIs, making it challenging to use or adapt them. We used EBI Mapping, a systematic process developed from Intervention Mapping that identifies an EBI’s components and logic, to characterize existing CRCS EBIs from the National Cancer Institute’s Evidence-Based Cancer Control Programs website. The resulting information can facilitate intervention adoption, adaptation, and/or implementation. Two trained coders independently coded intervention materials to describe intervention components and logic (n = 20). We display CRCS EBI components (potential mechanism of change) using evidence tables and heat maps. All EBIs addressed completion of at least one CRCS behavior (stool-based test, n = 9; stool-based test or another CRCS test, n = 8; colonoscopy, n = 3; colonoscopy or sigmoidoscopy, n = 1). The psychosocial determinants most frequently addressed by these interventions were knowledge (n = 19), attitudes (n = 17), risk perception/perceived susceptibility (n = 16), skills (n = 15), and overcoming barriers (n = 15). Multi-level EBIs (n = 9) attempted to change an average of 2.1 ± 1.1 conditions in the patients’ environment (e.g., accessibility of CRCS); only four EBIs used environmental change agents (e.g., providers, nurses). From the heat maps of EBIs, we describe common theoretical change methods’ (e.g., facilitation) used for addressing determinants (e.g., overcoming barriers). EBI Mapping can help users identify important components of a CRCS EBI’s logic; these proposed mechanisms of action can inform adoption, adaptation, and implementation in new settings, and facilitate scale up of EBIs.

Purpose Our center adopted high-dose-rate brachytherapy with surface applicators (plesiotherapy) in 2008, creating custom molds to treat irregular areas. This study describes the efficacy and safety outcomes after extensive follow-up in the patients. Methods/patients We planned the treatment using two computed tomography (CT) scans: the first to delineate the lesion and the second after placing the thermoplastic mold. Fusing the two CT images enables planning of the target volume and pinpointing, where the catheters are in the mold. Results Seventy patients received plesiotherapy, either exclusively or following excision in patients with risk factors for recurrence. Those receiving plesiotherapy alone showed a complete response rate of 95.8%, and recurrences occurred in 5.7% at a mean follow-up of 96.2 months. Chronic toxicity appeared in 26.6% of patients, but severity was limited to grade 1 or 2. Conclusions High-dose-rate brachytherapy with customized molds yields a high rate of complete response, with long-term recurrence rates in line with similar studies and an acceptable toxicity rate.

Background Emergency Departments (EDs) have served as critical surveillance sites for infectious diseases. We sought to determine the prevalence and temporal trends of acute (by PCR) and convalescent (by antibody [Ab]) SARS-CoV-2 infection during the earliest phase of the pandemic among patients in an urban ED in Baltimore City. Methods We tested remnant blood samples from 3255 unique ED patients, collected between March 16th and May 31st 2020 for SARS-CoV-2 Ab. PCR for acute SARS-CoV-2 infection from nasopharyngeal swabs was obtained on any patients based on clinical suspicion. Hospital records were abstracted and factors associated with SARS-CoV-2 infection were assessed. Results Of 3255 ED patients, 8.2% (95%CI: 7.3%, 9.2%) individuals had evidence of SARS-CoV-2 infection; 155 PCR+, 78 Ab+, and 35 who were both PCR+ and Ab+. Prevalence of disease increased throughout the study period, ranging from 3.2% (95%CI: 1.8%, 5.2%) PCR+ and 0.6% (95%CI: 0.1%, 1.8%) Ab+ in March, to 6.2% (95%CI: 5.1%, 7.4%) PCR+ and 4.2% (95%CI: 3.3%, 5.3%) Ab+ in May. The highest SARS-CoV-2 prevalence was found in Hispanic individuals who made up 8.4% (95%CI: 7.4%, 9.4%) of individuals screened, but 35% (95%CI: 29%, 41%) of infections (PCR and/or Ab+). Demographic and clinical factors independently associated with acute infection included Hispanic ethnicity, loss of smell or taste, subjective fever, cough, muscle ache and fever. Factors independently associated with convalescent infection were Hispanic ethnicity and low oxygen saturation. Conclusions The burden of COVID-19 in Baltimore City increased dramatically over the 11-week study period and was disproportionately higher among Hispanic individuals. ED-based surveillance methods are important for identifying both acute and convalescent SARS-CoV-2 infections and provides important information regarding demographic and clinical correlates of disease in the local community.

We performed optical spectroscopy of the candidates inside the gravitational wave errorboxes (S190408an, S190425z, S190426c, S190510g, S190728q, S190814bv). The spectral classification of 34 transients observed with the 10.4m Gran Telescopio de Canarias prior to 1 Sep 2019 is presented. We ruled out the association of these candidates with gravitational wave events.

BackgroundDespite the availability of multilevel evidence-based interventions for blood pressure management, poor hypertension control is common among community health center patient populations across the state of Texas and the United States. Target:BPTM is a national initiative from the American Heart Association and the American Medical Association to assist healthcare organizations and care teams in improving blood pressure control rates using evidence-based approaches and recognition of organizations who have successfully integrated the program in their practice. Using the Implementation Mapping approach, we identified determinants of Target:BPTM adoption and use and developed implementation strategies to improve program uptake and implementation in Community Health Centers in Texas.MethodsWe used Implementation Mapping (IM) to identify barriers and facilitators influencing the adoption and implementation of the Target:BPTM program and develop strategies to increase program adoption and use. We recruited four clinics across four counties in Texas and assessed barriers and facilitators at the organizational level, including electronic health records and data use. We used this data to inform clinic-specific implementation strategies based on the organization capacity and priorities feedback. We developed an implementation plan and timeline designed to improve the implementation and maintenance of Target:BPTM.ResultsAs part of the needs and capacity assessment, we collected data through interviews with CHC staff, examining gaps in needs and services (e.g., what do clinics need to implement Target:BPTM?), and assets to leverage. We worked with Community Health Centers to a) identify individuals who would be involved in the adoption, implementation, and maintenance of Target:BPTM, b) describe adoption and implementation actions, and c) identify barriers and facilitators influencing adoption and implementation. Together with partners from Community Health Center, we used the IM approach to identify and develop program goals, identify methods and strategies to address barriers, and create an implementation plan. Our strategies included monthly or biweekly meetings to provide technical support, reviewing program goals and timeline to ensure program implementation, progress toward reaching goals, and address quality improvement needs at each clinic site. We developed a Target:BPTM implementation protocol for each clinic based on the needs and capacity assessment, identification of technology use and capacity, and gap analysis. We reviewed Target:BPTM program strategies and self-measured blood pressure protocols tailored to the clinic patient population. We developed a collaborative plan, reviewed funding and capacity for implementation, and provided continuous quality improvement guidance. Ongoing process and impact evaluations using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework are underway.DiscussionThis paper provides an example of using Implementation Mapping to develop strategies to increase the adoption and implementation of evidence-based cardiovascular risk reduction interventions in Community Health Centers. The use of implementation strategies can increase the use of Target:BPTM in Community Health Centers and improve hypertension control.

A series of UiO-66 materials with different functional groups (−H, −NH2, and −NO2) have been evaluated for the adsorption and release of a common ocular drug such as brimonidine tartrate. UiO-66 samples were synthesized under solvothermal conditions and activated by solvent exchange with ethanol. Experimental results suggest that the incorporation of surface functionalities gives rise to the development of structural defects (missing linker defects) but without altering the basic topology of the UiO-66 framework. These defects improve the adsorption performance of the parent metal–organic framework (MOF), while the bulkier functionalities infer slower release kinetics, with the associated benefits for prolonged delivery of brimonidine. Among the evaluated MOFs, defective UiO-66-NO2 can be proposed as the most promising candidate due to the combination of a larger brimonidine volumetric uptake (680 mg/cm3), a prolonged delivery (period of up to 25 days), a small particle size, and a larger instability. Contrariwise, at high concentrations UiO-66-NO2 has higher toxicity toward human retinal pigment epithelium cells (ARPE-19) compared to the pure and NH2-functionalized UiO-66. Authors would like to acknowledge financial support from the Ministerio de Ciencia e Innovación (Project PID2019-108453GB-C21), H2020 (Project MSCA-RISE-2016/NanoMed) and Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital (Project CIPROM/2021/022).

The HIV latent viral reservoir (LVR) remains a major challenge in the effort to find a cure for HIV. There is interest in lymphocyte-depleting agents, used in solid organ and bone marrow transplantation to reduce the LVR. This study evaluated the LVR and T cell receptor repertoire in HIV-infected kidney transplant recipients using intact proviral DNA assay and T cell receptor sequencing in patients receiving lymphocyte-depleting or lymphocyte-nondepleting immunosuppression induction therapy. CD4+ T cells and intact and defective provirus frequencies decreased following lymphocyte-depleting induction therapy but rebounded to near baseline levels within 1 year after induction. In contrast, these biomarkers were relatively stable over time in the lymphocyte-nondepleting group. The lymphocyte-depleting group had early TCRβ repertoire turnover and newly detected and expanded clones compared with the lymphocyte-nondepleting group. No differences were observed in TCRβ clonality and repertoire richness between groups. These findings suggest that, even with significant decreases in the overall size of the circulating LVR, the reservoir can be reconstituted in a relatively short period of time. These results, while from a relatively unique population, suggest that curative strategies aimed at depleting the HIV LVR will need to achieve specific and durable levels of HIV-infected T cell depletion.

SummaryPreclinical studies in myeloid neoplasms have demonstrated efficacy of Bromodomain and Extra-Terminal protein inhibitors (BETi). However, BETi demonstrate poor single agent activity in clinical trials. Several studies suggest that combination with other anti-cancer inhibitors may enhance the efficacy of BETi. To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development. We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce resistance to BETi and sensitize cells to PIMi. Further, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy and credential this using patient-derived xenografts supporting the clinical investigation of this combination.

Using exome sequencing for biomarker discovery and precision medicine requires connecting nucleotide-level variation with functional changes in encoded proteins. However, for functionally annotating the thousands of cancer-associated missense mutations, or variants of uncertain significance (VUS), purifying variant proteins for biochemical and functional analysis is cost-prohibitive and inefficient. We describe parallel functional annotation (PFA) of large numbers of VUS using small cultures and crude extracts in 96-well plates. Using members of a histone methyltransferase family, we demonstrate high-throughput structural and functional annotation of cancer-associated mutations. By combining functional annotation of paralogs, we discovered two phylogenetic and clustering parameters that improve the accuracy of sequence-based functional predictions to over 90%. Our results demonstrate the value of PFA for defining oncogenic/tumor suppressor functions of histone methyltransferases as well as enhancing the accuracy of sequence-based algorithms in predicting the effects of cancer-associated mutations.

Recent empirical studies have found various patterns in the correlations between lifespan inequality and life expectancy in modern human populations. However, it is unclear how general these regularities are. Here we establish three theorems that provide theoretical foundations for such regularities. We show that for populations with a finite maximum lifespan ω , and under certain continuity assumptions, the variance in the age at death is bounded by a function of lifespan that has a maximum and tends to zero as life expectancy tends to zero and ω . We show how the change in said variance is determined by a particular interplay between the coefficient of variation and the mean age in the population. These results lead to three hypotheses—a three-phased pattern of change for the correlation between the variance and life expectancy, a particular shape of the associated variance function, and that survival curve Type is one driver of the pattern. We illustrate those hypotheses empirically via a study of the 10 countries in the Human Mortality Database with the oldest available data. Our results elucidate the emergence of the aforementioned correlation patterns and provide demographically meaningful conditions under which those correlations reverse.

Background Despite the human papillomavirus (HPV) vaccine being a safe, effective cancer prevention method, its uptake is subomptimal in the United States (U.S.). Previous research have found a variety of intervention strategies (environmental and behavioral) in increasing its uptake. The purpose of the study is to systematically review the literature for interventions to promote HPV vaccination from 2015 to 2020. Methods We updated a systemative review of interventions to promote HPV vaccine uptake globally. We ran key word searches in six bibliographic databases. Audiences, design, level of intervention, components and outcomes were abstracted from the full-text articles in Excel databases. Results Of the 79 articles, most were conducted in the U.S. (72.2%) and in clinical (40.5%) or school settings (32.9%), and were directed a single level (76.3%). Related to the intervention type, most were informational (n = 25, 31.6%) or patient-targeted decision support (n = 23, 29.1%). About 24% were multi-level interventions, with 16 (88.9%) combining two levels. Twenty-seven (33.8%) reported the use of theory in intervention development. Of those reporting HPV vaccine outcomes, post-intervention vaccine initiation ranged from 5–99.2%, while series completion ranged from 6.8–93.0%. Facilitators to implementation were use of patient navigators and user-friendly resources, while barriers included costs, time to implement and difficulties of integrating interventions into organizational workflow. Conclusions There is a strong need to expand implementation of HPV-vaccine promotion interventions beyond education alone and at a single level of intervention. Development and evaluation of effective strategies and multi-level interventions may increase the uptake of the HPV vaccine among adolescents and young adults.

BackgroundIt has been challenging to develop agents directly targetingKRASdriver mutations in colorectal cancer (CRC). Recent efforts have focused on developing inhibitors targeting SOS1 as an attractive approach forKRAS-mutant cancers. Here, we aimed to study the translational role of SOS1 in CRC using patient-derived organoids (PDOs).MethodIn this study, we used CRC PDOs as preclinical models to evaluate their sensitivity to SOS1 inhibitor BI3406 and its cellular effects. We utilized large CRC datasets including GENIE cohort, TCGA PanCancer Atlas, and CPTAC-2 cohort to study the significance of molecular alterations of SOS1 in CRC. To identify potential predictive markers, we performed immunohistochemistry (IHC) on CRC tissue for SOS1/2 protein expression and RNA sequencing to identify discriminative gene sets for sensitivity to SOS1 inhibition. The findings were validated by DepMap data forSOS1dependency.ResultCRC PDOs instead of cell lines had differential sensitivities to BI3406. There was a significant correlation between SOS1 and SOS2 mRNA expressions (Spearman’s ρ 0.56, pRAS/RAFmutant CRC (p=0.04). We also found that SOS1/SOS2 protein expression ratio > 1 by IHC (p=0.03) instead ofKRASmutation (p=1) was a better predictive marker to BI3406 sensitivity of CRC PDOs. This was concordant with the significant correlation between SOS1/SOS2 protein expression ratio by mass spectrometry and SOS1 dependency score. RNA-seq and gene set enrichment analysis revealed differentially expressed genes and 7 enriched gene sets involving cholesterol homeostasis, epithelial mesenchymal transition, and TNFα/NFκB signaling in BI3406-resistant CRC PDOs. We further discovered that GTP-bound RAS level underwent rebound at 48 hours upon treatment with BI3406 even in BI3406-sensitive PDOs with no change of KRAS effector genes downstream. Cellular adaptation mechanisms to SOS1 inhibition may involve upregulation of SOS1/2 mRNA and SOS1 protein expressions, which may be overcome by SOS1 knockdown/degradation or synergistic effect of BI3406 with trametinib.ConclusionIn summary, CRC PDOs could serve as better models for translational study of SOS1 in CRC. High SOS1 protein expression was a worse prognostic factor in CRC. High SOS1/SOS2 protein expression ratio predicted sensitivity to SOS1 inhibition and dependency. Our preclinical findings supported further clinical development of SOS1-targeting agents in CRC.

This prospective cohort study aimed to assess whether and to what extent different quantitative pupillometry (QP) metrics are associated with different intoxicant drug classes as well as investigate the potential benefit of QP as a tool in the rapid assessment of clinically intoxicated patients in the emergency department (ED).Between February 25, 2019 and April 24, 2021, 325 patients were enrolled in the EDs of the Hospital of the University of Pennsylvania (HUP) and Penn Presbyterian Medical Center (PPMC). Patients deemed clinically intoxicated or in withdrawal by an attending emergency physician were considered for eligibility. Patients 18 years old, with a chief complaint indicative of head trauma or stroke or without a urine drug screen (UDS) positive for drugs of abuse were excluded. QP data were also collected from a cohort of 82 healthy control subjects.Neurological Pupil index (NPi) values did not vary significantly between control and study groups nor between study group patients with a UDS positive for opioids. With exception of latency of constriction, all other QP metrics for the study group were depressed relative to controls (This work demonstrated the feasibility of QP measurement in the ED, finding that NPi remains unaffected by clinical intoxication and therefore can potentially be used for ED patient evaluation without risk of confounding by key intoxicants of abuse. Future work will evaluate the value of QP as a means of rapid and reproducible neurological assessment to identify various pathologies.

Background Cardiac ageing is associated to heart failure with preserved ejection fraction (HF-pEF) and increased senescence, hypertrophy and diastolic dysfunction. No treatments have yet proved to reduce HF-pEF morbidity and mortality. Cardiosphere-derived cells (CDCs) and their secreted extracellular vesicles (CDC-EVs) have demonstrated efficacy in old animals with cardiac dysfunction, but variability of effect and lack of adequate potency tests remain as challenges. Purpose To explore in vitro predictors of cardiac protective potency of CDC-EVs, focusing on the chronological age of the CDC-donors, CDC-senescence, and their in vitro anti-senescent and pro-angiogenic effect. Methods CDCs derived from 34 patients (age range 0–81 years old, both sexes) were characterized in terms of senescence, proliferative and migration capacities, VEGF secretion, expression of specific surface markers and cardiosphere size. CDC-EVs were purified and their in vitro anti-senescent potential (at genetic, secretory and cellular level over cardiac stromal cells) and their pro-angiogenic potential (ability to induce tube formation over endothelial cells) quantified. According to the performance in each of these tests, potency was scored and CDC-EVs were classified as potent (P-EVs) and non-potent (NP-EVs). The effect of P-EVs and NP-EVs were then tested in vivo in rats with induced cardiac aging. SD-rats received 3-months of daily intraperitoneal injections (IP) of saline (healthy control) or D-galactose. Rats in the D-Gal group were randomly allocated to receive IP saline (sham control, n=12), P-EVs (n=7) or NP-EVs (n=6) and followed-up for one month. Results Chronological age of the donor or expression of surface markers did not relate to most CDC properties nor to their in vitro potency. CDC senescence did relate to other CDC bioactive properties, but this was insufficient to predict CDC-EV anti-senescence and pro-angiogenic in vitro potency. In vivo, EV classified as P-EVs, but not NP-EVs, prevented D-gal induced hypertrophy (2.4 vs. 2.9 mg/gr, p=0.05). This finding was in parallel to the levels of galactosidase-beta 1 expression in cardiac tissue, which were increased in sham vs. P-EVs (1.22 vs. 0.73, p=0.03) but levels in NP-EVs were not significantly different to the sham group (0.86, p=0.1). P-EVs tended to reduce TGFB1 expression, while NP-EVs significantly increased cardiac fibrosis and reduced cardiac perfusion. At systemic level, while P-EVs significantly improved glucose metabolism and tended to drive total antioxidant capacity and hair growth to a healthier profile, NP-EVs did not significantly improve any of the explored parameters and significantly increased total antioxidant capacity. Conclusions After further validation, the matrix potency assay proposed here, scoring the anti-senescent and pro-angiogenic in vitro effect of CDC-EVs could be used to predict EV suitability as an allogenic product in the treatment of cardiac ageing. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III, Ministerio de Ciencia e Innovaciόn, Spain: PI16/01123; PI19/00161; Red de Terapia Celular, Tercel, (RD16.0011.0029) and CIBERCV (CB16.11.00292)

Introduction The bolus thermodilution-derived index of microcirculatory resistance (IMR) has emerged over years as the standard of reference to invasively define coronary microvascular dysfunction (CMD). However, the technique still presents some limitations, mainly related to the fact that manual injection of saline bolus accounts for some variance in the measurements. Continuous intracoronary thermodilution has been recently introduced as a tool to directly quantify absolute coronary flow and microvascular resistance both at rest and during hyperemia and has shown to be safe and operator independent. Microvascular resistance reserve (MRR), derived from continuous thermodilution, has been validated as novel index specific for microcirculation and independent from myocardial mass. Purpose To compare head-to-head the intra-observer repeatability of bolus and continuous thermodilution for assessing microvascular function. Methods Patients undergoing coronary angiography in the absence of obstructive coronary artery disease were prospectively enrolled. Bolus and continuous intracoronary thermodilution measurements were performed in duplicates in the left anterior descending artery (LAD). Patients were randomly assigned in a 1:1 ratio to undergo first bolus thermodilution or first continuous thermodilution assessment. Results A total of 102 patients were enrolled. Average FFR was 0.86±0.06. Coronary Flow Reserve (CFR) calculated with continuous thermodilution (CFRthermo) was significantly lower than bolus thermodilution-derived CFR (CFRbolus) (2.63±0.65 and 3.29±1.17, respectively, p Conclusion Continuous intracoronary thermodilution has a higher repeatability than bolus thermodilution in the assessment of CMD. Funding Acknowledgement Type of funding sources: None.

A novel multidrug resistance conjugative 177,859-bp IncC plasmid pJEF1-OXA-181 coharboring the carbapenemase-coding

IntroductionThis paper explores leadership attributes important for practice change in community health centers (CHCs) and assesses attributes' fit with the Full-Range Leadership Theory (FRLT).MethodsWe conducted four focus groups and 15 in-depth interviews with 48 CHC leaders from several U.S. states using a modified appreciative inquiry approach. Thematic analysis was used to review transcripts for leadership concepts and code with a priori FRLT-derived and inductive codes.ResultsCHC leaders most often noted attributes associated with transformational leadership as essential for practice change. Important attributes included emphasizing a collective sense of mission and a compelling, achievable vision; expressing enthusiasm about what needs to be done; and appealing to employees' analytical reasoning and challenging others to think creatively to problem solve. Few expressions of leadership fit with the transactional typology, though some did mention active vigilance to ensure standards are met, clarifying role and task requirements, and rewarding followers. Passive-avoidant attributes were rarely mentioned.ConclusionsOur results enhance understanding of leadership attributes supportive of successful practice change in CHCs.

The Matsigenka people living traditional lifestyles in remote areas of the Amazon rely on a fish-based diet that exposes them to methylmercury (MeHg) at levels that have been associated with decreased IQ scores. In this study, the association between Hg levels and working memory was explored using the framework of the Multicomponent Model. Working memory tasks were modified to fit the culture and language of the Matsigenka when needed and included measures for verbal storage (Word Span) visuospatial storage (Corsi Block Task) and a measure of executive functions, the Self-Ordered Pointing Task (SOPT). An innovation of the Trail Making Tests A & B (TMT A & B) was pilot tested as another potential measure of executive functions. The mean hair Hg levels of 30 participants, ages 12 to 55 years, from three different communities (Maizal, Cacaotal and Yomibato) was 7.0 ppm (sd = 2.40), well above the World Health Organization (WHO) limit for hair of 2.0 ppm and ranged from 1.8 to 14.2 ppm, with 98% of a broader sample of 152 individuals exceeding the WHO limit. Hair Hg levels showed significant associations with cognitive performance, but the degree varied in magnitude according to the type of task. Hg levels were negatively associated with executive functioning performance (SOPT errors), while Hg levels and years of education predicted visuospatial performance (Corsi Block accuracy). Education was the only predictor of Word Span accuracy. The results show that Hg exposure is negatively associated with working memory performance when there is an increased reliance on executive functioning. Based on our findings and the review of the experimental research, we suggest that the SOPT and the Corsi Block have the potential to be alternatives to general intelligence tests when studying remote groups with extensive cultural differences.

Background Organ transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV-positive donors is critical for safety. Methods We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) test results within the HIV Organ Policy Equity (HOPE) Act in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262, NCT03500315, and NCT03734393). We compared clinical characteristics in HIV-positive versus FP donors. We measured CD4 T cells, HIV viral load (VL), drug resistance mutations (DRMs), coreceptor tropism, and serum antiretroviral therapy (ART) detection, using mass spectrometry in HIV-positive donors. Results Between March 2016 and March 2020, 92 donors (58 HIV positive, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidneys and 46 livers). Each year the number of donors increased. The prevalence of hepatitis B (16% vs 0%), syphilis (16% vs 0%), and cytomegalovirus (CMV; 91% vs 58%) was higher in HIV-positive versus FP donors; the prevalences of hepatitis C viremia were similar (2% vs 6%). Most HIV-positive donors (71%) had a known HIV diagnosis, of whom 90% were prescribed ART and 68% had a VL Conclusion The use of HIV-positive donor organs is increasing. HIV DRMs are common, yet resistance that would compromise integrase strand transfer inhibitor–based regimens is rare, which is reassuring regarding safety.

Ovarian cancer (OC) represents a serious health problem worldwide. In Mexico, most OC patients are detected at late stages, consequently making OC one of the leading causes of death in women after reaching puberty. Personalized medicine (PM) provides an individualized therapeutic opportunity for treating each patient relying on “omic” tools to match the correct drug with the specific pathogenic genomic signature. PM can help predict the best therapeutic option for each affected woman suffering from OC. In recent years, Mexico has made contributions to the PM of OC; however, it still has a long way to go for its full implementation in the country’s health system. World J Oncol. 2021;12(4):85-92 doi: https://doi.org/10.14740/wjon1383

Colorectal cancer (CRC) cells have low or absent tumor cell PD-L1 expression that we previously demonstrated can confer chemotherapy resistance. Here, we demonstrate that PD-L1 depletion enhances JNK activity resulting in increased BimThr116 phosphorylation and its sequestration by MCL-1 and BCL-2. Activated JNK signaling in PD-L1-depeted cells was due to reduced mRNA stability of the CYLD deubiquitinase. PD-L1 was found to compete with the ribonuclease EXOSC10 for binding to CYLD mRNA. Thus, loss of PD-L1 promoted binding and degradation of CYLD mRNA by EXOSC10 which enhanced JNK activity. An irreversible JNK inhibitor (JNK-IN-8) reduced BimThr116 phosphorylation and unsequestered Bim from MCL-1 and BCL-2 to promote apoptosis. In cells lacking PD-L1, treatment with JNK-IN-8, an MCL-1 antagonist (AZD5991), or their combination promoted apoptosis and reduced long-term clonogenic survival by anticancer drugs. Similar effects of the JNK inhibitor on cell viability were observed in CRC organoids with suppression of PD-L1. These data indicate that JNK inhibition may represent a promising strategy to overcome drug resistance in CRC cells with low or absent PD-L1 expression.

Objective: To investigate factors associated with cognitive impairment (CI) in institutionalized Mexican older adults. Material and methods: Cross-sectional study of residents of three long-term care facilities in the metropolitan area of Monterrey, Mexico. A medical history, Mini-Mental State Examination (MMSE), Barthel index, geriatric depression scale, and a nutritional screening were performed. CI was defined as MMSE ≤24. Results: Of 280 octogenarian residents (72.1% females) 61.1 % had a MMSE ≤24. Older age (OR=1.047), functional dependence (OR=10.309), malnutrition (OR=2.202), urinary incontinence (OR=2.588), and history of fracture (OR=1.764) were directly associated to CI. While higher education level (OR=0.583) and the use of antihypertensives (OR=0.521), antihistamines (OR=0.322), antiprostatic hypertrophy (OR=0.219), and lipid-lowering drugs (OR=0.575) were inversely associated. Conclusions: The evaluation of cognitive performance and its associated factors is essential for institutionalized patients in order to implement a management program aimed at reducing the progression of CI and its possible complications.

Many in the U.S. are not up to date with cancer screening. This systematic review examined the effectiveness of interventions engaging community health workers to increase breast, cervical, and colorectal cancer screening.Authors identified relevant publications from previous Community Guide systematic reviews of interventions to increase cancer screening (1966 through 2013) and from an update search (January 2014-November 2021). Studies written in English and published in peer-reviewed journals were included if they assessed interventions implemented in high-income countries; reported screening for breast, cervical, or colorectal cancer; and engaged community health workers to implement part or all of the interventions. Community health workers needed to come from or have close knowledge of the intervention community.The review included 76 studies. Interventions engaging community health workers increased screening use for breast (median increase=11.5 percentage points, interquartile interval=5.5‒23.5), cervical (median increase=12.8 percentage points, interquartile interval=6.4‒21.0), and colorectal cancers (median increase=10.5 percentage points, interquartile interval=4.5‒17.5). Interventions were effective whether community health workers worked alone or as part of a team. Interventions increased cancer screening independent of race or ethnicity, income, or insurance status.Interventions engaging community health workers are recommended by the Community Preventive Services Task Force to increase cancer screening. These interventions are typically implemented in communities where people are underserved to improve health and can enhance health equity. Further training and financial support for community health workers should be considered to increase cancer screening uptake.

Fibroblast to myofibroblast conversion is a major driver of tissue remodeling in organ fibrosis. Several distinct lineages of fibroblasts support homeostatic tissue niche functions, yet, specific activation states and phenotypic trajectories of fibroblasts during injury and repair have remained unclear. Here, we combined spatial transcriptomics, longitudinal single-cell RNA-seq and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. We discovered a transitional fibroblast state characterized by high Sfrp1 expression, derived from both Tcf21-Cre lineage positive and negative cells. Sfrp1+ cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1+ transitional fibroblasts and Cthrc1+ myofibroblasts. Tgfβ1 downregulated Sfrp1 in non-invasive transitional cells and induced their switch to an invasive Cthrc1+ myofibroblast identity. Finally, using loss of function studies we showed that autocrine Sfrp1 directly inhibits fibroblast invasion by regulating the RhoA pathway. In summary, our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies Sfrp1 as an autocrine inhibitor of fibroblast invasion during early stages of fibrogenesis.

Supply chain management has existed for thousands of years. Technology started evolving with the industrial revolution and yet, paper-based bills of lading are still widely used in the international trade today. This chapter explores what problems exist in today’s supply chains, and whether blockchain technology can help solve them. The problems are categorized into three categories: The origin of the raw material or the product is not obvious; trust issues can exist between seller and buyer; and the supply chain execution is inefficient. A brief explanation of blockchain technology follows as the second part, with a focus on the technology that is useful for this purpose of this article. The two parts come together in the third part, showing how blockchain technology can solve the problems. Finally, a critical view is taken to show the limitations of blockchain technology as a problem solver.

Study question Which are the transcriptional signatures of chromosome instability (CIN) on the human pre-implantation embryo biology at single-cell level? Summary answer CIN-perturbed cells show gene expression dosage effects as well as signatures of developmental delay and cell competition within the developing human embryo. What is known already According to studies analysing whole human embryos at single-cell resolution, as much as 90% of the Day3-4 and up to 100% of the Day6-12 carry one or more cells with mitotic abnormalities. Intriguingly, embryonic CIN does not necessarily preclude normal offspring, since ∼30% of mosaic blastocysts detected by preimplantation genetic testing for aneuploidy (PGT-A) can result in healthy live births. A model of post-implantation human development revealed cell selection mechanisms that deplete aneuploid cells from the germ layers. However, single-cell multi-omics approaches have not yet been applied to resolve the transcriptional signatures of CIN in human embryos. Study design, size, duration Cryopreserved human embryos donated for research were dissociated into single cells between Day1-7 post-fertilization. Cells were processed by scG&T-seq generating 295 genomes and 576 transcriptomes. This data was integrated with published single-cell RNA-seq data, totalling 2105 single-cell transcriptomes from 172 embryos. Inference of cells' DNA copy number (CN) from gene expression was benchmarked using G&T-seq data and used for cells lacking DNA-seq data. Participants/materials, setting, methods Effects of aneuploidies on gene expression, regulatory programs, lineage specification and developmental progression rates were studied by integrative analysis on single-cell whole genome copy number and whole transcriptome data. Main results and the role of chance On the genomic level, we observed frequent acquired numerical and structural chromosomal aberrations. Deletions were more frequent than duplications and were equally spread across pre-implantation stages and cell lineages. Although 88% of the embryos contained aneuploid cells, 63% still contained euploid cells. On the transcriptome level, we disclosed 248 active transcription factors (TFs), including key regulators of cell identity, that constitute 10 major gene regulatory modules driving pre-implantation development. By integrating single-cell DNA-plus-RNA information, we unveil that changes in genes’ CN directly result in transcriptional changes in the same direction, and we disclose aberrant gene regulation. Moreover, we observed cell competition instigating well before ICM/TE cell lineages specification. Common transcriptomic signatures within CIN-perturbed cells were identified. Interestingly, in TE, cell competition signatures co-existed with up-regulation of pro-proliferative and implantation-related genes. Limitations, reasons for caution Our study is based on single-cell whole genome expression data from disaggregated IVF pre-implantation embryos. Wider implications of the findings Our analyses suggest that while unfit CIN-perturbed cells might be eliminated by cell competition mechanisms, these might be tolerated and potentially beneficial in TE. Thus, encouraging the transfer of mosaic embryos after PGT-A. Besides, we provide a unique comprehensive data resource for future work. Trial registration number not applicable

BACKGROUND: Anal cancer incidence has increased in Western countries in recent decades and currently there are no consensus screening guidelines. Home-based self-sampling kits might facilitate screening for anal precancer/cancer but could require travel through postal mail where they may experience extreme temperatures or long transport times. OBJECTIVE: To determine the effect of the environment on specimen adequacy for HPV genotyping of a mailed home-based self-sampling anal cancer screening kit. STUDY DESIGN: The Prevent Anal Cancer (PAC) Study in Milwaukee, Wisconsin recruited men who have sex with men (MSM) and transgender persons 25 years of age and older. Participants were randomized to receive a mailed self-sampling kit or attend a clinic for screening. Kits were insulated with foam and included a device to record temperature every twenty minutes. Samples were returned via mail and underwent HPV genotyping using the SPF(10)-LiPA(25) assay which also detected human RNase P to determine specimen adequacy by qPCR. For the first 93 kits, logistic regression assessed associations between specimen inadequacy and temperature, freeze-thaw cycle, presence of fecal matter, and number of days in an uncontrolled environment. RESULTS: Most specimens (92.5%) were adequate for HPV genotyping. Specimen inadequacy was not associated with temperature, freeze-thaw cycle, or transit time. Fecal matter was present more often in inadequate (71.4%) compared to adequate specimens (16.3%) (p = .004). CONCLUSIONS: These real-world data from mailed home-based anal self-sampling kits found that environmental conditions did not affect specimen adequacy. While over 90% of specimens were adequate, presence of fecal matter predicted specimen inadequacy.