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Background: Multiple myeloma (MM) is the second most common hematologic malignancy, with 34,470 estimated new cases in 2022. High-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) remains a standard treatment for MM even in the era of novel therapies. This is usually performed in hospital-based settings, either in the inpatient or outpatient units. Advanced Care at Home (ACH) represents a virtual hybrid hospital-at-home program that combines a virtual provider-staffed command center with a vendor-mediated supply chain capable of delivering high-acuity care in the comfort of the patients' own homes. In our program, we used the existing ACH platform to deliver post-HCT care for recipients of auto-HCT., Patients and Methods: Four patients (female = 2, 50%) with MM, with a median age of 60 (range, 40-74) years, were admitted to the inpatient Blood and Marrow Transplant (BMT) unit. The conditioning regimen consisted of melphalan 200 mg/m 2 , administered on day -2. All patients received stem cell infusion (day 0) in the inpatient setting, with a median dose of 3.64 (range, 2.92-8.22) × 10 6 /kg CD34 cells., Results: Patients were discharged to their homes after completing the infusion on day 0 or day +1 at the latest. Post-infusion care was provided by the ACH team in coordination with the BMT team. The median time intervals to absolute neutrophil count and platelet engraftment were 12 (range, 11-13) and 11 (range, 9-16) days, respectively. All patients were successfully discharged from the ACH program at a median of day +14 (range, day +14 to day +15)., Conclusions: Our results highlight the feasibility of delivering post-HCT care for auto-HCT recipients in the home setting and confirm the generalizability of this approach.

Background: Acute uncomplicated cystitis is one of the most common diagnoses for which antibiotic treatment is prescribed in the outpatient setting. Despite the availability of national guidelines, there remains a wide pattern in prescriber choices for therapy. Recent data portray a picture of consistently longer durations than recommended prescribed in outpatient settings., Objective: The objective was to evaluate the effect of a system-based intervention on adherence to guideline-recommended durations of therapy for uncomplicated cystitis in the outpatient setting., Methods: This quasi-experimental study included women aged 18-64 years who were seen at five family medicine clinics at an academic medical centre and were prescribed targeted antibiotics for uncomplicated cystitis (nitrofurantoin monohydrate/macrocrystals 100 mg, trimethoprim-sulfamethoxazole 160/800 mg or ciprofloxacin 250 mg). The intervention involved revising or adding pre-filled, but modifiable, default prescribing instructions in the electronic health record (EHR) for the targeted antibiotics. We evaluated adherence to guideline-recommended duration of therapy as well as days of therapy (DOT) before and after the intervention., Results: A total of 787 pre-intervention and 862 post-intervention cases were included. Adherence to recommended duration of therapy increased from 29.4% to 76.3% (P < 0.01). The average DOT decreased by 23% from 6.6 to 5.1 (P < 0.01)., Conclusion: A stewardship intervention consisting of revising/adding default prescribing instructions to targeted antimicrobials in an EHR was associated with increased adherence to recommended durations of therapy for uncomplicated cystitis and reduction of unnecessary antibiotic exposure. More studies are needed to confirm effectiveness across multiple medical record platforms., (Published by Oxford University Press 2019.)

Children can be exposed to arsenic through play areas which may have contaminated fill material from historic land use. The objective of the current study was to evaluate the risk to children who play and/or spend time at baseball fields with soils shown to have arsenic above background levels. Arsenic in soils at the study sites located in Miami, FL, USA showed distinct distributions between infield, outfield, and areas adjacent to the fields. Using best estimates of exposure factors for children baseball scenarios, results show that non-cancer risks depend most heavily upon the age of the person and the arsenic exposure level. For extreme exposure scenarios evaluated in this study, children from 1 to 2 years were at highest risk for non-cancer effects (Hazard Quotient, HQ > 2.4), and risks were higher for children exhibiting pica (HQ > 9.7) which shows the importance of testing fill for land use where children may play. At the study sites, concentration levels of arsenic resulted in a range of computed cancer risks that differed by a factor of 10. In these sites, the child's play position also affected risk. Outfield players, with a lifetime exposure to these arsenic levels, could have 10 times more increased chance of experiencing cancers associated with arsenic (i.e., lung, bladder, skin) in comparison to infielders. The distinct concentration distributions observed between these portions of the baseball fields emphasize the need to delineate contaminated areas in public property where citizens may spend more free time. This study also showed a need for more tools to improve the risk estimates for child play activities. For instance, more refined measurements of exposure factors for intake (e.g., inhalation rates under rigorous play activities, hand to mouth rates), exposure frequency (i.e., time spent in various activities) and other exposure factors (e.g., soil particulate emission rates at baseball play fields) can help pinpoint risk on baseball fields where arsenic levels may be a concern., Competing Interests: The authors declare no conflict of interest.

Unlabelled: Adenovirus E4-ORF3 and E1B-55K converge in subverting critical overlapping cellular pathways to facilitate virus replication. Here, we show that E1B-55K and E4-ORF3 induce sumoylation and the assembly of SUMO2/3 viral genome replication domains. Using a conjugation-deficient SUMO2 construct, we demonstrate that SUMO2/3 is recruited to E2A viral genome replication domains through noncovalent interactions. E1B-55K and E4-ORF3 have critical functions in inactivating MRN and ATM to facilitate viral genome replication. We show that ATM kinase inhibitors rescue ΔE1B-55K/ΔE4-ORF3 viral genome replication and that the assembly of E2A domains recruits SUMO2/3 independently of E1B-55K and E4-ORF3. However, the morphology and organization of SUMO2/3-associated E2A domains is strikingly different from that in wild-type Ad5-infected cells. These data reveal that E1B-55K and E4-ORF3 specify the nuclear compartmentalization and structure of SUMO2/3-associated E2A domains, which could have important functions in viral replication. We show that E4-ORF3 specifically targets and sequesters the cellular E3 SUMO ligase PIAS3 but not PIAS1, PIAS2, or PIAS4. The assembly of E4-ORF3 into a multivalent nuclear matrix is required to target PIAS3. In contrast to MRN, PIAS3 is targeted by E4-ORF3 proteins from disparate adenovirus subgroups. Our studies reveal that PIAS3 is a novel and evolutionarily conserved target of E4-ORF3 in human adenovirus infections. Furthermore, we reveal that viral proteins not only disrupt but also usurp SUMO2/3 to transform the nucleus and assemble novel genomic domains that could facilitate pathological viral replication., Importance: SUMO is a key posttranslational modification that modulates the function, localization, and assembly of protein complexes. In the ever-escalating host-pathogen arms race, viruses have evolved strategies to subvert sumoylation. Adenovirus is a small DNA tumor virus that is a global human pathogen and key biomedical agent in basic research and therapy. We show that adenovirus infection induces global changes in SUMO localization and conjugation. Using virus and SUMO mutants, we demonstrate that E1B-55K and E4-ORF3 disrupt and usurp SUMO2/3 interactions to transform the nucleus and assemble highly structured and compartmentalized viral genome domains. We reveal that the cellular E3 SUMO ligase PIAS3 is a novel and conserved target of E4-ORF3 proteins from disparate adenovirus subgroups. The induction of sumoylation and SUMO2/3 viral replication domains by early viral proteins could play an important role in determining the outcome of viral infection., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.

African American Men are 65% more likely to develop prostate cancer and are twice as likely to die of prostate cancer, than are Caucasian American Males. The explanation for this glaring health disparity is still unknown; although a number of different plausible factors have been offered including genetic susceptibility and gene-environment interactions. We favor the hypothesis that altered gene expression plays a major role in the disparity observed in prostate cancer incidence and mortality between African American and Caucasian American Males. To discover genes or gene expression pattern(s) unique to African American or to Caucasian American Males that explain the observed prostate cancer health disparity in African American males, we conducted a micro array pilot project study that used prostate tumors with a Gleason score of 6. We compared gene expression profiling in tumors from African-American Males to prostate tumors in Caucasian American Males. A comparison of case-matched ratios revealed at least 67 statistically significant genes that met filtering criteria of at least +/- 4.0 fold change and p < 0.0001. Gene ontology terms prevalent in African American prostate tumor/normal ratios relative to Caucasian American prostate tumor/normal ratios included interleukins, progesterone signaling, Chromatin-mediated maintenance and myeloid dendritic cell proliferation. Functional in vitro assays are underway to determine roles that selected genes in these onotologies play in contributing to prostate cancer development and health disparity.

Fanconi anemia (FA) is a recessive genome instability syndrome characterized by heightened cellular sensitivity to DNA damage, aplastic anemia and cancer susceptibility. Leukemias and squamous cell carcinomas (SCCs) are the most predominant FA-associated cancers, with the latter exhibiting markedly early disease onset and aggressiveness. Although studies of hematopoietic cells derived from FA patients have provided much insight into bone marrow deficiencies and leukemogenesis, molecular transforming events in FA-deficient keratinocytes, which are the cell type of origin for SCC, are poorly understood. We describe here the growth and molecular properties of FANCA-deficient versus FANCA-corrected HPV E6/E7 immortalized keratinocytes in monolayer and organotypic epithelial raft culture. In response to DNA damage, FANCA-deficient patient-derived keratinocyte cultures displayed a G2/M phase arrest, senescence and apoptosis. Organotypic raft cultures exhibited DNA repair-associated defects with more 53BP1 foci and TdT-mediated dNTP nick end labeling-positive cells over their corrected counterparts. Interestingly, together with reduced rates of DNA damage, FA correction resulted in a marked decrease in epithelial thickness and the presence of fewer cell layers. The observed FANCA-mediated suppression of hyperplasia correlated with the detection of fewer cells transiting through the cell cycle in the absence of gross differentiation abnormalities or apoptotic differences. Importantly, the knockdown of either FANCA or FANCD2 in HPV-positive keratinocytes was sufficient for increasing epithelial hyperplasia. Our findings support a new role for FA pathways in the maintenance of differentiation-dependent cell cycle exit, with the implication that FA deficiencies may contribute to the high risk of FA patients for developing HPV-associated SCC.