Geographic variability in rural patient internet connectivity when accessing telehealth services from home: A retrospective analysis during the COVID-19 pandemic.

PURPOSE: Telehealth at home (TAH) is a means of providing patient care that is increasingly utilized by health care organizations. It is crucial to identify factors, such as internet accessibility, that might impact the ability of patients to make use of such services. METHODS: A retrospective analysis was conducted using real-time data from audio-visual telehealth encounters conducted using the Cisco Webex Meetings platform from April 22, 2020 to May 26, 2020, and originating from a single rural health care system in the state of Wisconsin. Quality scores were determined for each encounter, and comparative call qualities were mapped to demonstrate zones of poor and unacceptable quality throughout the service area. FINDINGS: Of 3,962 encounters meeting the study criteria, 746 (18.8%) had poor or unacceptable quality, with 116 of poor or unacceptable encounters failing to connect, and greater than 1 in 20 encounters (5.8%) requiring conversion to a telephone-only visit. Geographic mapping of encounters with poor to unacceptable quality highlights numerous locations throughout the service area that suffer from connectivity issues. CONCLUSIONS: In our study, there is wide and unpredictable variability in the quality of TAH encounters throughout the service area, which impacts the ability of patients living in rural areas to access timely and effective care. Our study supports the need for further infrastructure changes to improve internet connection quality in rural areas, with implications that extend beyond the current COVID-19 pandemic.

Drug Repurposing Prediction for Immune-Mediated Cutaneous Diseases using a Word-Embedding-Based Machine Learning Approach.

Immune-mediated diseases affect more than 20% of the population, and many autoimmune diseases affect the skin. Drug repurposing (or repositioning) is a cost-effective approach for finding drugs that can be used to treat diseases for which they are currently not prescribed. We implemented an efficient bioinformatics approach using word embedding to summarize drug information from more than 20 million articles and applied machine learning to model the drug-disease relationship. We trained our drug repurposing approach separately on nine cutaneous diseases (including psoriasis, atopic dermatitis, and alopecia areata) and eight other immune-mediated diseases and obtained a mean area under the receiver operating characteristic of 0.93 in cross-validation. Focusing in particular on psoriasis, a chronic inflammatory condition of skin that affects more than 100 million people worldwide, we were able to confirm drugs that are known to be effective for psoriasis and to identify potential candidates used to treat other diseases. Furthermore, the targets of drug candidates predicted by our approach were significantly enriched among genes differentially expressed in psoriatic lesional skin from a large-scale RNA sequencing cohort. Although our algorithm cannot be used to determine clinical efficacy, our work provides an approach for suggesting drugs for repurposing to immune-mediated cutaneous diseases.

Restrictive versus liberal red blood cell transfusion for cardiac surgery: a systematic review and meta-analysis of randomized controlled trials.

Patients undergoing cardiac surgery are among the most common recipients of allogeneic red blood cell (RBC) transfusions. However, whether restrictive RBC transfusion strategies for cardiac surgery achieve a similar clinical outcome in comparison with liberal strategies remains unclear. We searched electronic databases from inception to December 2017 for randomized controlled trials (RCTs). We calculated the risk ratios (RRs) and weighted-mean difference (MD) using a random-effects model. We included 9 RCTs with a total of 9005 patients. There was no significant difference in mortality between groups [RR 1.03; 95% confidence interval (CI) 0.74-1.45; P = 0.86]. In addition, there were no significant differences between groups in the clinical outcomes of infections (RR 1.09; 95% CI 0.94-1.26; P = 0.26), stroke (RR 0.98; 95% CI 0.72-1.35; P = 0.91), respiratory morbidity (RR 1.05; 95% CI 0.89-1.24; P = 0.58), renal morbidity (RR 1.02; 95% CI 0.94-1.09; P = 0.68), myocardial infarction (RR 1.00; 95% CI 0.80-1.24; P = 0.99), cardiac arrhythmia (RR 1.05; 95% CI 0.88-1.26; P = 0.56), gastrointestinal morbidity (RR 1.93; 95% CI 0.81-4.63; P = 0.14), or reoperation (RR 0.90; 95% CI 0.67-1.20; P = 0.46). There was a significant difference in the intensive care unit length of stay (h) (MD 4.29; 95% CI 2.19-6.39, P < 0.01) favoring the liberal group. However, there was no significant difference in the hospital length of stay (days) (MD 0.15; 95% CI - 0.18 to 0.48; P = 0.38). In conclusion, this meta-analysis showed that restrictive strategies for RBC transfusion are as safe as liberal strategies in patients undergoing cardiac surgery with regards to short-term clinical outcomes.

Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation.

Acute promyelocytic leukemia is an aggressive malignancy characterized by the accumulation of promyelocytes in the bone marrow. PML/RARA is the primary abnormality implicated in this pathology, but the mechanisms by which this chimeric fusion protein initiates disease are incompletely understood. Identifying PML/RARA targets in vivo is critical for comprehending the road to pathogenesis. Utilizing a novel sorting strategy, we isolated highly purified promyelocyte populations from normal and young preleukemic animals, carried out microarray and methylation profiling analyses, and compared the results from the two groups of animals. Surprisingly, in the absence of secondary lesions, PML/RARA had an overall limited impact on both the transcriptome and methylome. Of interest, we did identify down-regulation of secondary and tertiary granule genes as the first step engaging the myeloid maturation block. Although initially not sufficient to arrest terminal granulopoiesis in vivo, such alterations set the stage for the later, complete differentiation block seen in leukemia. Further, gene set enrichment analysis revealed that PML/RARA promyelocytes exhibit a subtle increase in expression of cell cycle genes, and we show that this leads to both increased proliferation of these cells and expansion of the promyelocyte compartment. Importantly, this proliferation signature was absent from the poorly leukemogenic p50/RARA fusion model, implying a critical role for PML in the altered cell-cycle kinetics and ability to initiate leukemia. Thus, our findings challenge the predominant model in the field and we propose that PML/RARA initiates leukemia by subtly shifting cell fate decisions within the promyelocyte compartment.

Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia.

Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in genes encoding epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable, with few means to predict which patients will benefit. Here, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients who were responsive or resistant to decitabine (DAC) in order to develop a molecular means of predicting response at diagnosis. While somatic mutations did not differentiate responders from nonresponders, we identified 167 differentially methylated regions (DMRs) of DNA at baseline that distinguished responders from nonresponders using next-generation sequencing. These DMRs were primarily localized to nonpromoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. Transcriptional analysis revealed differences in gene expression at diagnosis between responders and nonresponders. In responders, the upregulated genes included those that are associated with the cell cycle, potentially contributing to effective DAC incorporation. Treatment with CXCL4 and CXCL7, which were overexpressed in nonresponders, blocked DAC effects in isolated normal CD34+ and primary CMML cells, suggesting that their upregulation contributes to primary DAC resistance.

Different effects of valproic acid on photoreceptor loss in Rd1 and Rd10 retinal degeneration mice.

PURPOSE: The histone-deacetylase inhibitor activity of valproic acid (VPA) was discovered after VPA's adoption as an anticonvulsant. This generated speculation for VPA's potential to increase the expression of neuroprotective genes. Clinical trials for retinitis pigmentosa (RP) are currently active, testing VPA's potential to reduce photoreceptor loss; however, we lack information regarding the effects of VPA on available mammalian models of retinal degeneration, nor do we know if retinal gene expression is perturbed by VPA in a predictable way. Thus, we examined the effects of systemic VPA on neurotrophic factor and Nrl-related gene expression in the mouse retina and compared VPA's effects on the rate of photoreceptor loss in two strains of mice, Pde6b(rd1/rd1) and Pde6b(rd10/rd10) . METHODS: The expression of Bdnf, Gdnf, Cntf, and Fgf2 was measured by quantitative PCR after single and multiple doses of VPA (intraperitoneal) in wild-type and Pde6b(rd1/rd1) mice. Pde6b(rd1/rd1) mice were treated with daily doses of VPA during the period of rapid photoreceptor loss. Pde6b(rd10/rd10) mice were also treated with systemic VPA to compare in a partial loss-of-function model. Retinal morphology was assessed by virtual microscopy or spectral-domain optical coherence tomography (SD-OCT). Full-field and focal electroretinography (ERG) analysis were employed with Pde6b(rd10/rd10) mice to measure retinal function. RESULTS: In wild-type postnatal mice, a single VPA dose increased the expression of Bdnf and Gdnf in the neural retina after 18 h, while the expression of Cntf was reduced by 70%. Daily dosing of wild-type mice from postnatal day P17 to P28 resulted in smaller increases in Bdnf and Gdnf expression, normal Cntf expression, and reduced Fgf2 expression (25%). Nrl gene expression was decreased by 50%, while Crx gene expression was not affected. Rod-specific expression of Mef2c and Nr2e3 was decreased substantially by VPA treatment, while Rhodopsin and Pde6b gene expression was normal at P28. Daily injections with VPA (P9-P21) dramatically slowed the loss of rod photoreceptors in Pde6b(rd1/rd1) mice. At age P21, VPA-treated mice had several extra rows of rod photoreceptor nuclei compared to PBS-injected littermates. Dosing started later (P14) or dosing every second day also rescued photoreceptors. In contrast, systemic VPA treatment of Pde6b(rd10/rd10) mice (P17-P28) reduced visual function that correlated with a slight increase in photoreceptor loss. Treating Pde6b(rd10/rd10) mice earlier (P9-P21) also failed to rescue photoreceptors. Treating wild-type mice earlier (P9-P21) reduced the number of photoreceptors in VPA-treated mice by 20% compared to PBS-treated animals. CONCLUSIONS: A single systemic dose of VPA can change retinal neurotrophic factor and rod-specific gene expression in the immature retina. Daily VPA treatment from P17 to P28 can also alter gene expression in the mature neural retina. While daily treatment with VPA could significantly reduce photoreceptor loss in the rd1 model, VPA treatment slightly accelerated photoreceptor loss in the rd10 model. The apparent rescue of photoreceptors in the rd1 model was not the result of producing more photoreceptors before degeneration. In fact, daily systemic VPA was toxic to wild-type photoreceptors when started at P9. However, the effective treatment period for Pde6b(rd1/rd1) mice (P9-P21) has significant overlap with the photoreceptor maturation period, which complicates the use of the rd1 model for testing of VPA's efficacy. In contrast, VPA treatment started after P17 did not cause photoreceptor loss in wild-type mice. Thus, the acceleration of photoreceptor loss in the rd10 model may be more relevant where both photoreceptor loss and VPA treatment (P17-P28) started when the central retina was mature.

Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy and is characterized by recurring structural genetic alterations. Previous studies of DNA methylation suggest epigenetic alterations may also be important, but an integrated genome-wide analysis of genetic and epigenetic alterations in ALL has not been performed. We analyzed 137 B-lineage and 30 T-lineage childhood ALL cases using microarray analysis of DNA copy number alterations and gene expression, and genome-wide cytosine methylation profiling using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. We found that the different genetic subtypes of ALL are characterized by distinct DNA methylation signatures that exhibit significant correlation with gene expression profiles. We also identified an epigenetic signature common to all cases, with correlation to gene expression in 65% of these genes, suggesting that a core set of epigenetically deregulated genes is central to the initiation or maintenance of lymphoid transformation. Finally, we identified aberrant methylation in multiple genes also targeted by recurring DNA copy number alterations in ALL, suggesting that these genes are inactivated far more frequently than suggested by structural genomic analyses alone. Together, these results demonstrate subtype- and disease-specific alterations in cytosine methylation in ALL that influence transcriptional activity, and are likely to exert a key role in leukemogenesis.