Association of Cardiovascular Disease in Patients with Mycosis Fungoides and Sézary Syndrome Compared to a Matched Control Cohort.

Mycosis fungoides/Sézary syndrome (MF/SS) produces a low-grade chronic inflammatory state that may be associated with an increased risk of cardiovascular (CV) events, as seen in other chronic, systemic dermatologic diseases. To assess this association, a retrospective, cross-sectional study was designed in which 421 patients with a biopsy-proven diagnosis of MF/SS were compared with a control cohort of 4,210 age-, gender-, and race-matched patients randomly selected from the National Health and Nutritional Evaluation Survey database. The MF/SS cohort had a 14% prevalence of CV events, which was not statistically different from the control population's prevalence of 13%. In the MF/SS cohort, a multivariable logistic regression model showed that older patients (OR = 1.05 for each year of age, 95% confidence interval = 1.02-1.07) and those diagnosed with hypertension (OR = 3.40, 95% confidence interval = 1.71-6.75) had a higher risk of a CV event (P < 0.001). Risk factors such as gender, race, smoking, diabetes, and obesity were not significantly associated with CV events. Findings suggest that in the MF/SS population, advancing age and hypertension are risk factors for CV events, requiring clinical recognition and management. In addition, further research is needed to understand the complex interplay of how chronic inflammation in MF/SS impacts the immune development of CV disease.

Genomic landscape of TP53-mutated myeloid malignancies.

TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional clinical techniques. We performed whole-genome sequencing (WGS) of 42 acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) cases with paired normal tissue to better characterize the genomic landscape of TP53-mutated AML/MDS. WGS accurately determines TP53 allele status, a key prognostic factor, resulting in the reclassification of 12% of cases from monoallelic to multihit. Although aneuploidy and chromothripsis are shared with most TP53-mutated cancers, the specific chromosome abnormalities are distinct to each cancer type, suggesting a dependence on the tissue of origin. ETV6 expression is reduced in nearly all cases of TP53-mutated AML/MDS, either through gene deletion or presumed epigenetic silencing. Within the AML cohort, mutations of NF1 are highly enriched, with deletions of 1 copy of NF1 present in 45% of cases and biallelic mutations in 17%. Telomere content is increased in TP53-mutated AMLs compared with other AML subtypes, and abnormal telomeric sequences were detected in the interstitial regions of chromosomes. These data highlight the unique features of TP53-mutated myeloid malignancies, including the high frequency of chromothripsis and structural variation, the frequent involvement of unique genes (including NF1 and ETV6) as cooperating events, and evidence for altered telomere maintenance.

Genomic landscape of TP53 -mutated myeloid malignancies.

TP53 -mutated myeloid malignancies are most frequently associated with complex cytogenetics. The presence of complex and extensive structural variants complicates detailed genomic analysis by conventional clinical techniques. We performed whole genome sequencing of 42 AML/MDS cases with paired normal tissue to characterize the genomic landscape of TP53 -mutated myeloid malignancies. The vast majority of cases had multi-hit involvement at the TP53 genetic locus (94%), as well as aneuploidy and chromothripsis. Chromosomal patterns of aneuploidy differed significantly from TP53 -mutated cancers arising in other tissues. Recurrent structural variants affected regions that include ETV6 on chr12p, RUNX1 on chr21, and NF1 on chr17q. Most notably for ETV6 , transcript expression was low in cases of TP53 -mutated myeloid malignancies both with and without structural rearrangements involving chromosome 12p. Telomeric content is increased in TP53 -mutated AML/MDS compared other AML subtypes, and telomeric content was detected adjacent to interstitial regions of chromosomes. The genomic landscape of TP53 -mutated myeloid malignancies reveals recurrent structural variants affecting key hematopoietic transcription factors and telomeric repeats that are generally not detected by panel sequencing or conventional cytogenetic analyses. Key Points: WGS comprehensively determines TP53 mutation status, resulting in the reclassification of 12% of cases from mono-allelic to multi-hit Chromothripsis is more frequent than previously appreciated, with a preference for specific chromosomes ETV6 is deleted in 45% of cases, with evidence for epigenetic suppression in non-deleted cases NF1 is mutated in 48% of cases, with multi-hit mutations in 17% of these cases TP53 -mutated AML/MDS is associated with altered telomere content compared with other AMLs.

Mobile usage among degree college students in industrial township of western Maharashtra - "A descriptive study".

Background: With the advent of smartphones, there is an exponential increase in mobile usage and addiction. The statistics pointing toward mobile dependence in adolescents are of paramount importance to assess the prevalence in them and suggest measures accordingly. Aim: To observe the usage and dependence among the degree college students in an industrial township. Materials and Methods: A validated and structured questionnaire was distributed among the students at a women's degree college in western Maharashtra and responses were collected after obtaining consent. Along with sociodemographic details, qualitative and quantitative information regarding mobile usage were collected. Data were cleaned, coded, and analyzed after ensuring the confidentiality of their information using SPSS v26.0. Results: The mean age of the participants was 18.9+/-1.8 years. The mean time spent on mobile was 2.4+/-0.4 hours per day. Mobile dependency was found in 48% of participants. The mean total score was 92. The primary purpose for using the internet was to browse (41%) and social media 36%. The main benefit of using the internet was searching for information urgently (62.5%). A major limitation of using was felt as the internet to be very slow 61 (42.3%). Conclusion: There is a high prevalence of smartphone dependence in college students.

Disseminated Tuberculosis With an Atypical Cutaneous Manifestation in a Hematopoietic Cell Transplant Patient in the Early Posttransplant Period: Case Report and Review of the Literature.

We describe an unusual case of posttransplant tuberculosis reactivation in a man who underwent allogeneic hematopoietic cell transplant. Concomitant with disseminated adenovirus infection, reactivation of tuberculosis manifested as disseminated, nonfollicular pustules on day +49. Skin biopsy was obtained on day +50. Initial histopathologic evaluation did not suggest mycobacterial infection, but tissue stain showed acid-fast organisms, which were subsequently identified as Mycobacterium tuberculosis. Shortly after the cutaneous presentation of tuberculosis, the patient died on day +52. Our case is among a paucity of reports describing tuberculosis reactivation in hematopoietic cell transplant patients in the early posttransplant period. It highlights the difficulty of diagnosing contemporaneous systemic infections, and it presents a rare and atypical cutaneous manifestation of tuberculosis in a hematopoietic cell transplant patient. Our case and review of the literature emphasize the need for further research to elucidate risk factors associated with early posttransplant reactivation of tuberculosis, and the importance of remaining vigilant for active tuberculosis in hematopoietic cell transplant patients with epidemiologic risk factors.

Integrated multi-omics analysis of Huntington disease identifies pathways that modulate protein aggregation.

Huntington disease (HD) is a neurodegenerative disease associated with polyglutamine expansion in the protein huntingtin (HTT). Although the length of the polyglutamine repeat correlates with age at disease onset and severity, psychological, cognitive and behavioral complications point to the existence of disease modifiers. Mitochondrial dysfunction and metabolic deregulation are both associated with the HD but, despite multi-omics characterization of patients and model systems, their mechanisms have remained elusive. Systems analysis of multi-omics data and its validation by using a yeast model could help to elucidate pathways that modulate protein aggregation. Metabolomics analysis of HD patients and of a yeast model of HD was, therefore, carried out. Our analysis showed a considerable overlap of deregulated metabolic pathways. Further, the multi-omics analysis showed deregulated pathways common in human, mice and yeast model systems, and those that are unique to them. The deregulated pathways include metabolic pathways of various amino acids, glutathione metabolism, longevity, autophagy and mitophagy. The addition of certain metabolites as well as gene knockouts targeting the deregulated metabolic and autophagy pathways in the yeast model system showed that these pathways do modulate protein aggregation. Taken together, our results showed that the modulation of deregulated pathways influences protein aggregation in HD, and has implications for progression and prognosis. This article has an associated First Person interview with the first author of the paper.

Proteomic and phosphoproteomic landscapes of acute myeloid leukemia.

We have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow-derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate-dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with posttranscriptionally increased protein abundance and showed that they interact with NPMc but not wild-type NPM1. We identified 2 cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies and confirmed these targets via flow cytometry. Finally, we detected nearly 30 000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. FLT3-TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK and related signaling proteins. PML-RARA-initiated AML samples displayed a unique phosphorylation signature, and TP53-mutant samples showed abundant phosphorylation of serine-183 on TP53 itself. This publicly available database will serve as a foundation for further investigations of protein dysregulation in AML pathogenesis.

Microbial originated surfactants with multiple applications: a comprehensive review.

Microbial synthesized surfactants are used in contaminated soil bioremediation processes and have multiple applications in various industries. These compounds minimize the negative influences in soil via absorption by detoxifying the toxic metals or compounds. Further, applications of biosurfactants are detected in treating chronic diseases or synthetic drugs alternatives in current periods. Various surfactant molecules can provide many benefits due to their diversities in structural and functional groups. These compounds showed a wide array of applications in multiple sectors such as biomedical or pharmaceutical fields. Agricultural, food processing, laundry, or other sectors. Many microbial systems or plant cells are utilized in biosurfactant production as confirmed by biochemical analysis of genome sequencing tools. Biosurfactant compounds can alter drug transport across the cell membrane. Different nature of biosurfactant compounds exhibited their antifungal, antibacterial, antiviral activities, or antiadhesive coating agents used in reduction of many hospital infections. These distinct properties of biosurfactants pushed their broad spectrum applications in biomedical, agriculture sectors and bioremediation tasks. Additionally, many strains of fungi or bacteria are utilized for biosurfactant synthesis involved in the detoxification of soil/other components of the environment. In these reviews, authors explained various biosurfactants molecules and their mode of actions. Also, applications of microbial originated biosurfactants along with their process technologies are described. Future perspectives of biosurfactants and their scope are also critically explained so that this review paper can be used as a showcase for production and application of biosurfactants.

Discrepant serological findings in SARS-CoV-2 PCR-negative hospitalized patients with fever and acute respiratory symptoms during the pandemic.

Coronavirus Disease 2019 (COVID-19) serology has an evolving role in the diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, its use in hospitalized patients with acute respiratory symptoms remains unclear. Hospitalized patients with acute respiratory illness admitted to an isolation ward were recruited. All patients had negative nasopharyngeal swab polymerase chain reaction (PCR) for SARS-CoV-2. Serological studies using four separate assays (cPass: surrogate neutralizing enzyme-linked immunosorbent assay [ELISA]; Elecsys: N-antigen based chemiluminescent assay; SFB: S protein flow-based; epitope peptide-based ELISA) were performed on stored plasma collected from patients during the initial hospital stay, and a convalescent visit 4-12 weeks later. Of the 51 patients studied (aged 54, interquartile range 21-84; 62.7% male), no patients tested positive on the Elecsys or cPass assays. Out of 51 patients, 5 had antibodies detected on B-cell Epitope Assay and 3/51 had antibodies detected on SFB assay. These 8 patients with positive serological test to COVID-19 were more likely to have a high-risk occupation (p = 0.039), bacterial infection (p = 0.028), and neutrophilia (p = 0.013) during their initial hospital admission. Discrepant COVID-19 serological findings were observed among those with recent hospital admissions and bacterial infections. The positive serological findings within our cohort raise important questions about the interpretation of sero-epidemiology during the current pandemic.

Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia.

To better understand clonal and transcriptional adaptations after relapse in patients with acute myeloid leukemia (AML), we collected presentation and relapse samples from six normal karyotype AML cases. We performed enhanced whole-genome sequencing to characterize clonal evolution, and deep-coverage single-cell RNA sequencing on the same samples, which yielded 142,642 high-quality cells for analysis. Identifying expressed mutations in individual cells enabled us to discriminate between normal and AML cells, to identify coordinated changes in the genome and transcriptome, and to identify subclone-specific cell states. We quantified the coevolution of genetic and transcriptional heterogeneity during AML progression, and found that transcriptional changes were significantly correlated with genetic changes. However, transcriptional adaptation sometimes occurred independently, suggesting that clonal evolution does not represent all relevant biological changes. In three cases, we identified cells at diagnosis that likely seeded the relapse. Finally, these data revealed a conserved relapse-enriched leukemic cell state bearing markers of stemness, quiescence, and adhesion. SIGNIFICANCE: These data enabled us to identify a relapse-enriched leukemic cell state with distinct transcriptional properties. Detailed case-by-case analyses elucidated the complex ways in which the AML genome, transcriptome, and immune microenvironment interact to evade chemotherapy. These analyses provide a blueprint for evaluating these factors in larger cohorts.This article is highlighted in the In This Issue feature, p. 1.

Seasonal and annual variations of CO2 and CH4 at Shadnagar, a semi-urban site.

Carbon dioxide (CO2) and methane (CH4) are the most important greenhouse gases (GHGs) due to their significant role in anthropogenic global climate change. The spatio-temporal variations of their concentration are characterized by the terrestrial biosphere, seasonal weather patterns and anthropogenic emissions. Hence, to understand the variability in regional surface GHG fluxes, high precision GHGs measurements were initiated by the National Remote Sensing Center (NRSC) of India. We report continuous CO2 and CH4measurements during 2014 to 2017 for the first time from Shadnagar, a suburban site in India. Annual mean CO2 and CH4 concentrations are 399.56 ± 5.46 ppm and 1.929 ± 0.09 ppm, respectively, for 2017. After the strong El Niño of 2015-2016, an abnormal rise in CO2 growth rate of 5.5 ppm year-1 was observed in 2017 at the study site, compared to 3.03 ppm year-1 at Mauna Loa. Thus, the repercussion of the El Niño effect diminishes the net uptake by the terrestrial biosphere accompanied by increased soil respiration. Seasonal tracer to tracer correlation between CO2 and CH4 was also analyzed to characterize the possible source-sink relationship between the species. We compared CO2 and CH4 concentrations to simulations from an atmospheric chemistry transport model (ACTM). The seasonal phases of CH4 were well captured by the ACTM, whereas the seasonal cycle amplitude of CO2 was underestimated by about 30%.

Planetary albedo decline over Northwest India contributing to near surface warming.

The increase in frequency and severity of heat waves during the pre-monsoon season (March-May) over Northwest India in recent decades is alarming. This study investigates the causative mechanism for warming through the forcing induced by planetary albedo changes over Northwest India, a hotspot for land-cover change. We use satellite-measured planetary albedo (α) and satellite-derived land-use-land-cover (LULC) data to estimate the impact of LULC changes from 2001 to 2018 on α and the associated radiative forcing. Over Northwest India, significant area under native land-cover, viz., barren, shrub and grass-lands, has been converted to cropland. The associated land-cover-induced changes have perturbed the radiation-budget by modifying the absorption of shortwave radiation, thereby contributing to the pronounced reduction of α as observed over this region. The diurnal-mean α has decreased by 0.016 ± 0.001 from 2001 to 2018 during pre-monsoon season which dominates α-decrease during the annual cycle over this region and contributes to the overall decreasing trend over India. Conversion of barren and shrub-lands to cropland is observed to be the greatest contributor to the α-decrease as compared to other land-cover changes. The radiative forcing due to decline in diurnal-mean α over Northwest India from 2001 to 2018 is highest during pre-monsoon at 5.99 ± 0.34 W/m2. This α-induced forcing averaged over the global land surface (0.02 W/m2) is equivalent to the corresponding direct forcing from rise in atmospheric methane concentrations during this period. We find an enhancement in near-surface heating to be associated with change in α; the decreasing trend in α during pre-monsoon has substantially enhanced near-surface extreme effective temperatures by 3.15 ± 2.61 K thus far and may further lead to more extreme heatwaves in future. Further, our findings highlight a decreasing (warming) and increasing (cooling) trend in clear-sky planetary albedo respectively over Northwest India and coastal regions, suggesting that sudden climate change could occur if one forcing dominates over the other.

A small-molecule SUMOylation inhibitor activates antitumor immune responses and potentiates immune therapies in preclinical models.

SUMOylation, the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to protein substrates, has been reported to suppress type I interferon (IFN1) responses. TAK-981, a selective small-molecule inhibitor of SUMOylation, pharmacologically reactivates IFN1 signaling and immune responses against cancers. In vivo treatment of wild-type mice with TAK-981 up-regulated IFN1 gene expression in blood cells and splenocytes. Ex vivo treatment of mouse and human dendritic cells promoted their IFN1-dependent activation, and vaccination studies in mice demonstrated stimulation of antigen cross-presentation and T cell priming in vivo. TAK-981 also directly stimulated T cell activation, driving enhanced T cell sensitivity and response to antigen ex vivo. Consistent with these observations, TAK-981 inhibited growth of syngeneic A20 and MC38 tumors in mice, dependent upon IFN1 signaling and CD8+ T cells, and associated with increased intratumoral T and natural killer cell number and activation. Combination of TAK-981 with anti-PD1 or anti-CTLA4 antibodies improved the survival of mice bearing syngeneic CT26 and MC38 tumors. In conclusion, TAK-981 is a first-in-class SUMOylation inhibitor that promotes antitumor immune responses through activation of IFN1 signaling. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with solid tumors and lymphomas.

Intra-seasonal contrasting trends in clouds due to warming induced circulation changes.

Quantification of long term changes in cloud distribution and properties is critical for the proper assessment of future climate. We show contrasting trends in cloud properties and cloud radiative effects over Northwest Indian Ocean (NWIO) in south Asian summer monsoon. Cloud top height (CTH) decreases in June (- 69 ± 3 myr-1) and July (- 44 ± 3 myr-1), whereas it increases in August (106 ± 2 myr-1) and September (37 ± 1 myr-1). These contrasting trends are investigated to be due to the changes in upper tropospheric winds and atmospheric circulation pattern. Strengthening of upper tropospheric easterlies and changes in vertical wind dampen the vertical development of clouds in June and July. In contrast, weakening of upper tropospheric winds over NWIO and strengthening of updraft favour the vertical growth of clouds in August. Further, changes in horizontal winds at 450-350 hPa and strengthening of Indian Ocean Walker cell favour the westward spread of high level clouds, contributing to the increase in CTH over NWIO in August. Decrease of cloud cover and altitude in June and July and increase of the same in subsequent months would affect the monsoon rainfall over the Indian region. Proper representation of these intra-seasonal contrasting trends of clouds in climate models is important for the better prediction of regional weather.

Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome.

Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3A Overgrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3AR882H mutation. A germline mouse model expressing the homologous Dnmt3aR878H mutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.

Variations in Awareness of Association Between Adverse Pregnancy Outcomes and Cardiovascular Risk by Specialty.

INTRODUCTION: Cardiovascular disease (CVD) remains the leading cause of death among women. Adverse pregnancy outcomes (APOs), including pre-eclampsia (PE), gestational diabetes mellitus (GDM) and pre-term birth (PTB) are associated with future maternal CVD risk. However, data on awareness of the association between APOs and long-term CVD risk among physicians in different specialties are lacking. This study assessed awareness of this association and whether this knowledge varies by specialty. METHODS: An anonymous web-based voluntary survey was sent to physicians in internal medicine (IM), family medicine (FM), obstetrics-gynecology (Ob-Gyn) and cardiology. The questions aimed to assess a physician's knowledge regarding identification of APOs and their association with future CVD risk and knowledge of CVD risk factor screening in women with APOs and future CVD risk. RESULTS: The survey was completed by 53 physicians, of whom 21% were in IM, 26% in FM, 23% in Ob-Gyn and 30% in cardiology. Based on the responses, cardiologists screened most frequently for APOs, with 56% always screening a female patient and 31% often screening. Only half of the IM and FM physicians acknowledged awareness of the association between APOs and CVD risk. Respondents in all specialties recognized PE and GDM as APOs linked to long-term maternal CVD risk, but failed to associate PTB as an APO. The majority of physicians in IM, FM and cardiology also lacked the knowledge of how often to appropriately screen for CVD risk factors associated with APOs. CONCLUSION: Awareness of the association between APO and future maternal CVD risk varies by specialty. A significant percentage of the physicians who responded to the survey did not routinely ask about APOs when assessing CVD risk and failed to identify PTB as a risk factor for APOs. Education on this topic and targeted efforts to improve screening for APOs are needed within all specialties to help reduce CVD morbidity and mortality.

Higher Patient Complexities are Associated with Increased Length of Stay, Complications, and Readmissions After Total Hip Arthroplasty.

INTRODUCTION: There is an increased incidence of complex patients undergoing total hip arthroplasty (THA), which demands a rigorous preoperative, intraoperative, and postoperative assessment. It is important how increases in patient complexity impact a variety of patient outcomes. Therefore, the purpose of our study is to determine if a higher Elixhauser Comorbidity Index (ECI), a measure of patient complexity, is correlated with: 1) longer hospital length of stay; 2) increased 90-day medical complications; 3) higher 90-day readmissions; and 4) greater two-year implant-related complications following primary THA. MATERIALS AND METHODS: Patients undergoing primary THA from January 1, 2004 to December 31, 2015 were queried from the Medicare Standard Analytical Files using the International Classification of Disease, ninth revision (ICD-9) procedure code 81.51. The queried patients (387,831) were filtered by ECI scores of 1 to 5. Patients who have ECI scores of 2 to 5 represented the study cohorts and were matched according to age and sex to patients who have the lowest ECI score (ECI of 1). All cohorts were longitudinally followed to assess and compare hospital length of stay, 90-day medical complications, 90-day readmissions, and two-year implant-related complications. We compared odds-ratios (OR), 95% confidence intervals (95% CI), and p-values using logistic regression analyses and Welch's t-tests. RESULTS: Patients who have ECI scores greater than 1 had higher hospital length of stay (p<0.001), 90-day medical complications (p<0.001), 90-day readmissions (p<0.001), and two-year implant-related complications (p<0.001). Patients who have an ECI score of 2 (1.26, 95% CI: 1.20-1.32), ECI of 3 (1.61, 95% CI: 1.53-1.69), ECI of 4 (2.05, 95% CI: 1.95-2.14), and ECI of 5 (2.32, 95% CI: 2.21-2.43) had an increasing trend for readmissions, with higher ECI scores correlating with greater odds of readmission following primary THA. Two-year implant-related complications also showed a similar increasing trend with greater patient complexity. Patients who had an ECI score of 5 (2.54, 95% CI: 2.39-2.69) had more implant-related complications compared to patients who had an ECI score of 2 (1.39, 95% CI:1.31-1.48). CONCLUSION: The results of this study illustrate that a higher Elixhauser-Comorbidity Index is an independent risk factor for longer hospital length of stay, higher 90-day medical complications, greater 90-day readmissions, and increased two-year implant-related complications following primary THA. This study is important as it further defines and heightens awareness of adverse events for complex patients undergoing this procedure. Future studies can examine if these events can potentially be mitigated through reductions in ECI scores prior to surgery and increased incentives for the healthcare team.

Enhanced Efficacy and Increased Long-Term Toxicity of CNS-Directed, AAV-Based Combination Therapy for Krabbe Disease.

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC) and the progressive accumulation of the toxic metabolite psychosine. We showed previously that central nervous system (CNS)-directed, adeno-associated virus (AAV)2/5-mediated gene therapy synergized with bone marrow transplantation and substrate reduction therapy (SRT) to greatly increase therapeutic efficacy in the murine model of Krabbe disease (Twitcher). However, motor deficits remained largely refractory to treatment. In the current study, we replaced AAV2/5 with an AAV2/9 vector. This single change significantly improved several endpoints primarily associated with motor function. However, nearly all (14/16) of the combination-treated Twitcher mice and all (19/19) of the combination-treated wild-type mice developed hepatocellular carcinoma (HCC). 10 out of 10 tumors analyzed had AAV integrations within the Rian locus. Several animals had additional integrations within or near genes that regulate cell growth or death, are known or potential tumor suppressors, or are associated with poor prognosis in human HCC. Finally, the substrate reduction drug L-cycloserine significantly decreased the level of the pro-apoptotic ceramide 18:0. These data demonstrate the value of AAV-based combination therapy for Krabbe disease. However, they also suggest that other therapies or co-morbidities must be taken into account before AAV-mediated gene therapy is considered for human therapeutic trials.

Repositioning of Drugs to Counter COVID-19 Pandemic - An Insight.

COVID-19 is a pandemic, caused by the novel coronavirus 2 (SARS-CoV-2) which is a severe acute respiratory syndrome. The devastating impact of this novel coronavirus outbreak has necessitated the need for rapid and effective antiviral therapies against SARS-CoV-2 to control the spread of the disease and importantly, alleviate the severe life-threatening symptoms and disorders. Drug repurposing strategy offers an attractive, immediate and realistic approach to tackle this growing pandemic of COVID-19. Due to the similarities with the SARS-CoV-1 virus and phylogenetic relation to the MERS-CoV virus, accelerated screening of approved drugs and the development of repositioning strategies have proved to be critical for the survival of many COVID-19 patients. Numerous scientific investigations from the initial years of the coronavirus outbreak along with upcoming advances of immunotherapy and vaccines, may prove to be beneficial. Currently, several repurposing strategies are under different phases of clinical trials and provide a definitive framework for the development of future therapies for the effective treatment of COVID-19. This review article summarizes the latest developments and trends in drug repurposing strategy for COVID-19 treatment.

Long-Term Morbidity after Endometrial Cancer Surgery: a Comparison of Open vs. Robotic Approach.

This retrospective study is looking into the long-term morbidity after endometrial cancer staging surgery and compares the long-term morbidity of patients who underwent open staging surgery vs. robotic approach. One hundred twenty-nine patients who underwent staging surgery for endometrial cancer from January 2014 until June 2017 were included in the analysis. Morbidities occurring 1 month after surgery-vault complications, incisional hernias, vault dehiscence, and lymphedema-were looked into. There were no statistically significant differences between the long-term complications in both groups (vault infection 5.1% vs. 1.4%, vaginal cuff dehiscence 1.6% vs. 0%, incisional hernia 6.8% vs. 0%, and lymphedema 11.8% vs. 10% in open vs robotic groups respectively). But as far as clinical significance was concerned, patients who underwent robotic staging surgery had a significant decrease in vaginal cuff complications and incisional hernia. Our study shows that robotic-assisted surgery can reduce even long-term morbidity in patients undergoing surgery for endometrial cancer.