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Survivors of critical illness, including those with COVID-19, are likely to experience post-intensive care syndrome (PICS). PICS involves a constellation of physical, cognitive, and mental health problems that can occur following hospitalization in an intensive care unit (ICU). This focused review describes the impact of PICS on an individual’s function, societal participation, and family. Specific evidence-based screening tools for in-home identification of the deficits associated with PICS are recommended. Recognition of PICS through early screening by home health care providers is crucial in order to assemble the physical rehabilitation, mental health, and community resources needed to mitigate the long-term effects of COVID-19 and other critical illnesses. This review concludes with further PICS resources for community-based providers to enhance their knowledge and expertise and to prepare them for caring for COVID-19 and other critical illness survivors.

Abdominal pain can arise from numerous sources, including those extra‐abdominal. It is important to obtain additional imaging in the setting of clinical suspicion for malignancy.

DNA methylation is a stable epigenetic modification that contributes to the spatiotemporal regulation of gene expression. The manner in which DNA methylation contributes to transcriptional control is dependent on the biological context, including physiological state and the properties of the DNA itself. Classically, dense promoter DNA methylation is associated with transcriptional repression. However, growing evidence suggests that this association may not always hold true, and promoter hypermethylation now also appears to be associated with high transcriptional activity. Furthermore, in a selection of contexts, increasing levels of promoter methylation correlate directly with increased gene expression. These findings postulate a context-dependent model whereby epigenetic contributions to transcriptional regulation occur in a more complex and dynamic manner. We present current evidence documenting promoter hypermethylation and high levels of gene expression, offer insights into the possible mechanisms by which this occurs, and discuss the potential implications for both research and clinical applications.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

Background: PRMT5 is an epigenetic enzyme that catalyzes symmetric dimethylation of arginine substrates (SDMA), regulating multiple cell processes. The PRMT5-MTAP collateral vulnerability describes the accumulation of the metabolite methylthioadenosine (MTA) in tumor cells (as a result of the deletion of the MTAP gene), which acts as a natural endogenous partial inhibitor of PRMT5. This provides an opportunity to selectively inhibit PRMT5 in MTAP deleted tumors, which occurs in ~15% of all cancers. First generation PRMT5 inhibitors, which cannot discriminate between MTAP-proficient normal cells and MTAP-deficient tumor cells, have a narrow therapeutic index which may limit clinical efficacy due to on-target toxicity. MTAP-selective PRMT5 inhibitors spare MTAP-proficient normal cells, improving therapeutic index and clinical efficacy. We have developed a novel MTAP-selective PRMT5 inhibitor, AZ-PRMT5i-1, that selectively targets MTAP-deficient tumors and spares MTAP-proficient tissue. Methods: In vitro activity of AZ-PRMT5i-1 was profiled using six MTAP isogenic cell lines, as well as in a panel of 300 cancer cell lines. In vivo efficacy was assessed using three MTAP deleted models and hematological toxicity was addressed using a 3D human bone marrow model. Results: Using a MTAP CRISPR KO isogenic pair we demonstrate potent inhibition of SDMA in MTAP-null tumors with a 54-fold margin over the MTAP wildtype (WT) counterpart. MTAP differential activity was maintained in proliferation assays across a number of MTAP isogenic cell lines and in a panel of 300 cancer cell lines. AZ-PRMT5i-1 demonstrates strong dose dependent efficacy across MTAP deleted xenograft and PDX models of gastric and lung origin, where greater than 80% of tumor growth inhibition was detected, with no apparent toxicity. In addition, corresponding dose-dependent inhibition of SDMA is observed in the treated tumors. In an in vitro 28-day 3D human bone marrow model, AZ-PRMT5i-1 has reduced toxicity in erythroid and megakaryocyte cell lineages, compared to a first generation PRMT5 inhibitor. Conclusion: Overall, these studies demonstrate that AZ-PRMT5i-1 is a potent PRMT5 inhibitor demonstrating MTAP selectivity and anti-tumor activity in in vitro and in vivo pre-clinical models. Citation Format: James T. Lynch, Shaun Moore, Ivan Del Barco Barrantes, Lauren Bradshaw, Chris Chambers, Ted Hong, Sophie Cooke, Jelena Urosevic, Mercedes Vazquez-Chantada, James M. Smith, Anna Cronin, Benedicte Recolin, Sonja Gill, Susan Critchlow, Ho Man Chan, Emma Dean. AZ-PRMT5i-1: A potent MTAP-selective PRMT5 inhibitor with pharmacodynamic and monotherapy anti-tumor activity in MTAP-deleted tumours [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6272.

Topical on-demand forms for HIV pre-exposure prophylaxis (PrEP) may be a desirable alternative for people that prefer not to use daily PrEP. CONRAD has developed inserts containing tenofovir alafenamide (TAF) and elvitegravir (EVG) for on-demand vaginal or rectal pericoital use. We assessed the pharmacokinetics (PK) and pre-exposure efficacy of rectally applied TAF/EVG inserts in macaques.PK was assessed in 12 pigtailed macaques. Tenofovir (TFV) and EVG levels were assayed in rectal biopsies and secretions, and tenofovir-diphosphate (TFV-DP) levels in biopsies and peripheral blood mononuclear cells (PBMC). Drug biodistribution was evaluated in 10 animals at necropsy 4 h post-dosing. For efficacy assessments, one or two TAF/EVG inserts were administered to macaques (n = 6) 4 h before repeated rectal SHIV162p3 challenges.One TAF/EVG insert resulted in rapid and high EVG and TFV-DP in rectal tissue 4 h after application. Adding a second insert led to a 10-fold increase in EVG and TFV-DP in rectal tissue. Efficacy of one and two TAF/EVG inserts were 72.6% (CI 24.5%-92.6%) and 93.1% (CI 73.3%-99.2%), respectively.Although high TFV-DP and EVG levels were observed with one rectal TAF/EVG insert, it only conferred partial protection from rectal SHIV challenges. Adding a second insert led to an increase in TFV and EVG in rectal tissues resulting in higher (90%) efficacy. These results highlight the high efficacy of TAF/EVG inserts as topical on-demand rectal PrEP, as well as the need for appropriate drug coverage in the deep rectum and colon to achieve high protection.The work related to animal studies was funded by CDC intramural funds and an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002). The work related to the insert formulation was funded by U.S. PEPFAR through USAID under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School. The findings and conclusions of this manuscript are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention (CDC), USAID, President's Emergency Plan for AIDS Relief (PEPFAR), Eastern Virginia Medical School (EVMS), or the US government.

Decision aids can promote shared decision making and behavior change and may be effective in helping patients quit smoking. Patients are increasingly using e-cigarettes for smoking cessation; however, little is known about the impact of including e-cigarette information in smoking cessation decision aids. Our objective was to assess the feasibility and acceptability of a smoking cessation decision aid including e-cigarette information. This study was conducted at one family medicine clinic in the United States. We used a pre-post design. In Phase I, the decision aid presented information about approved cessation methods. In Phase II, current e-cigarette users and patients with no intention of quitting received additional information on switching to e-cigarettes. We assessed the impact of the decision aids on quit attempts and abstinence, confidence and readiness to quit, confidence and readiness to switch to e-cigarettes, and patient satisfaction. We enrolled 60 patients in each phase (N = 120). Patients reported higher confidence and readiness to quit after viewing the decision aids and consulting with their physician (p 0.01). Patients reported the decision aid helped prepare them to make a decision about quitting smoking and expressed satisfaction with the decision aid and clinician consultation. We did not observe an impact of including e-cigarette information. Smoking cessation decision aids are acceptable to patients and may promote behavior change. Future studies should explore the impact of providing patients e-cigarette information using larger sample sizes and rigorous designs. Further research is needed to identify strategies to promote shared decision-making regarding e-cigarettes.

DNA methylation is a key epigenetic modification implicated in the pathogenesis of numerous human diseases, including cancer development and metastasis. Gene promoter methylation changes are widely associated with transcriptional deregulation and disease progression. The advent of CRISPR-based technologies has provided a powerful toolkit for locus-specific manipulation of the epigenome. Here, we describe a comprehensive global workflow for the design and application of a dCas9-SunTag-based tool for editing a DNA methylation locus in human melanoma cells, alongside protocols for downstream techniques used to evaluate subsequent methylation and gene expression changes in methylation-edited cells. Using transient system delivery, we demonstrate both highly efficacious methylation and demethylation of the EBF3 promoter, a putative epigenetic driver of melanoma metastasis, achieving up to 304.00% gain of methylation and 99.99% relative demethylation, respectively. Further, we employ a novel, targeted screening approach to confirm minimal off-target activity and high on-target specificity of our editing sys-tem within our target locus.

Phosphatidyl inositol (4,5)-bisphosphate (PI(4,5)P

Dysregulation of the epigenome is associated with the onset and progression of several diseases, including cancer, autoimmune, cardiovascular, and neurological disorders. Members from the three families of epigenetic proteins (readers, writers, and erasers) have been shown to be druggable using small-molecule inhibitors. Increasing knowledge of the role of epigenetics in disease and the reversibility of these modifications explain why pharmacological intervention is an attractive strategy for tackling epigenetic-based disease. In this review, we provide an overview of epigenetics drug targets, focus on approaches used for initial hit identification, and describe the subsequent role of structure-guided chemistry optimisation of initial hits to clinical candidates. We also highlight current challenges and future potential for epigenetics-based therapies.

BACKGROUND: Recent clinical trials suggest that e-cigarettes may be more effective for smoking cessation than traditional cessation aids, yet primary care physician (PCP) practices regarding e-cigarette recommendations for smokers have not been studied in-depth. OBJECTIVE: To identify factors influencing PCP recommendation of e-cigarettes for smoking cessation. DESIGN: Discrete choice experiment and survey. PARTICIPANTS: Florida PCPs. MEASURES: The survey included a discrete choice experiment in which PCPs indicated whether they would recommend e-cigarettes for each of 8 hypothetical patient profiles with the following contrasting characteristics: e-cigarette use, interest in approved cessation methods, smoking intensity, prior experience with approved cessation medications, quit intention, age, and comorbidity. Responses were summarized using descriptive statistics and standardized scores (SS). KEY RESULTS: The sample (n = 216) was predominately male (76%), white (66%), and non-Hispanic (78%), and most respondents had held their medical degree for 20+ years (77%). The response rate was 28.7%. Most PCPs thought e-cigarettes were at least somewhat effective for smoking cessation (66%) and lowering disease risk (65%); 31% perceived e-cigarettes to be equally/more effective than traditional cessation aids. PCPs were split regarding whether e-cigarettes were less (50%) or equally harmful (38%) as cigarettes. Yet, few were very confident in their ability to counsel patients on e-cigarettes risks (27%) or benefits (15%). PCPs recommended e-cigarettes in 27% of patient profiles they evaluated. The most important factors influencing the decision to recommend or not recommend e-cigarette were patients’ prior use of nicotine replacement therapy with (SS = 0.22, 95% CI = 0.17–0.27) and without use of other medications for cessation (SS = 0.18, 95% CI = 0.13–0.23), and being middle age (50 years old) with chronic obstructive pulmonary disease (SS = 0.16, 95% CI = 0.10–0.23). CONCLUSIONS: Considering the increased patient use of e-cigarettes and increasing use for cessation, this study highlights the need for guidelines and education to aid PCPs’ counseling of patients about e-cigarette use. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06615-w.

In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.

The testimony above comes from the CLANN report, an evidence gathering and advocacy project that facilitated survivor participation in the Republic of Ireland’s ongoing Commission of Investigation into Mother and Baby Homes and Certain Related Matters. We open this special issue of Éire-Ireland, entitled Toward Transitional Justice in Ireland? Addressing Legacies of Harm, with survivors’ voices in order to acknowledge that the volume is concerned with the experience of hundreds of thousands of individuals who were born or grew up in Ireland, and of their families across multiple generations, who have been too frequently ignored. As academics and members of the Justice for Magdalenes Research (JFMR) advocacy group, for the past decade we have endeavored to place the motto of survivors, “nothing about us, without us,” at the center of our research and activism on the subject of Ireland’s class, race, disability, and gender-based abuses, so evident in Irish carceral institutions. 2021-01-27 JG: PDF replaced with published version at publisher's request

More than 4 million adults survive a stay in the intensive care unit each year, with many experiencing new or worsening physical disability, mental health problems, and/or cognitive impairments, known as post-intensive care syndrome (PICS). Given the prevalence and magnitude of physical impairments after critical illness, many survivors, including those recovering from COVID-19, could benefit from physical therapist services after hospital discharge. However, due to the relatively recent recognition and characterization of PICS, there may be limited awareness and understanding of PICS among physical therapists practicing in home health care and community-based settings. This lack of awareness may lead to inappropriate and/or inadequate rehabilitation service provision. While this perspective article provides information relevant to all physical therapists, it is aimed toward those providing rehabilitation services outside of the acute and postacute inpatient settings. This article reports the prevalence and clinical presentation of PICS and provides recommendations for physical examination and outcomes measures, plan of care, and intervention strategies. The importance of providing patient and family education, coordinating community resources including referring to other health care team members, and community-based rehabilitation service options is emphasized. Finally, this perspective article discusses current challenges for optimizing outcomes for people with PICS and suggests future directions for research and practice.

Background Comprehensive assessments of the frequency and associated doses from radiologic and nuclear medicine procedures are rarely conducted. The use of these procedures and the population-based radiation dose increased remarkably from 1980 to 2006. Purpose To determine the change in per capita radiation exposure in the United States from 2006 to 2016. Materials and Methods The U.S. National Council on Radiation Protection and Measurements conducted a retrospective assessment for 2016 and compared the results to previously published data for the year 2006. Effective dose values for procedures were obtained from the literature, and frequency data were obtained from commercial, governmental, and professional society data. Results In the United States in 2006, an estimated 377 million diagnostic and interventional radiologic examinations were performed. This value remained essentially the same for 2016 even though the U.S. population had increased by about 24 million people. The number of CT scans performed increased from 67 million to 84 million, but the number of other procedures (eg, diagnostic fluoroscopy) and nuclear medicine procedures decreased from 17 million to 13.5 million. The number of dental radiographic and dental CT examinations performed was estimated to be about 320 million in 2016. Using the tissue-weighting factors from Publication 60 of the International Commission on Radiological Protection, the U.S. annual individual (per capita) effective dose from diagnostic and interventional medical procedures was estimated to have been 2.9 mSv in 2006 and 2.3 mSv in 2016, with the collective doses being 885 000 and 755 000 person-sievert, respectively. Conclusion The trend from 1980 to 2006 of increasing dose from medical radiation has reversed. Estimated 2016 total collective effective dose and radiation dose per capita dose are lower than in 2006. © RSNA, 2020 See also the editorial by Einstein in this issue.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRAS

While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.

Background Post–intensive care syndrome (PICS) is a constellation of new or worsening impairments in physical, mental, or cognitive abilities or a combination of these in individuals who have survived critical illness requiring intensive care. Purpose The 2 purposes of this systematic review were to identify the scope and magnitude of physical problems associated with PICS during the first year after critical illness and to use the World Health Organization's International Classification of Functioning, Disability and Health (ICF) framework to elucidate impairments of body functions and structures, activity limitations, and participation restrictions associated with PICS. Data Sources Ovid MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, CINAHL Plus with Full Text (EBSCO), Web of Science, and Embase were searched from inception until March 7, 2017. Study Selection Two reviewers screened titles, abstracts, and full text to independently determine study eligibility based on inclusion and exclusion criteria. Data Extraction Study methodological quality was assessed using the Newcastle–Ottawa Scale. Data describing study methods, design, and participant outcomes were extracted. Data Synthesis Fifteen studies were eligible for review. Within the first year following critical illness, people who had received intensive care experienced impairments in all 3 domains of the ICF (body functions and structures, activity limitations, and participation restrictions). These impairments included decreased pulmonary function, reduced strength of respiratory and limb muscles, reduced 6-minute walk test distance, reduced ability to perform activities of daily living and instrumental activities of daily living, and reduced ability to return to driving and paid employment. Limitations The inclusion of only 15 observational studies in this review may limit the generalizability of the findings. Conclusions During the first year following critical illness, individuals with PICS experienced physical impairments in all 3 domains of the ICF.

This study evaluated effects of differing gel volumes on pharmacokinetics (PK). IQB4012, a gel containing the non-nucleoside reverse transcriptase inhibitor IQP-0528 and tenofovir (TFV), was applied to the pigtailed macaque vagina and rectum. Vaginal gel volumes (1% loading of both drugs) were 0.5 or 1.5 ml; following wash-out, 1 or 4 ml of gel were then applied rectally. Blood, vaginal, and rectal fluids were collected at 0, 2, 4, and 24 h. Vaginal and rectal tissue biopsies were collected at 4 and 24 h. There were no statistically significant differences in concentrations for either drug between gel volumes within compartments at matched time points. After vaginal gel application, median IQP-0528 concentrations were ~ 10(4)–10(5) ng/g, 10(5)–10(6) ng/ml, and 10(3)–10(5) ng/ml in vaginal tissues, vaginal fluids, and rectal fluids, respectively (over 24 h). Median vaginal TFV concentrations were 1–2 logs lower than IQP-0528 levels at matched time points. After rectal gel application, median IQP-0528 and TFV concentrations in rectal fluids were ~ 10(3)–10(5) ng/ml and ~ 10(2)–10(3) ng/ml, respectively. Concentrations of both drugs sampled in rectal tissues were low (~ 10(1)–10(3) ng/g). For 1 ml gel, half of sampled rectal tissues had undetectable concentrations of either drug, and over half of sampled rectal fluids had undetectable TFV concentrations. These results indicate differences in drug delivery between the vaginal and rectal compartments, and that smaller vaginal gel volumes may not significantly compromise microbicide PK and prophylactic potential. However, effects of rectal gel volume on PK for both drugs were less definitive.