Application of improved GalNAc conjugation in development of cost-effective siRNA therapies targeting cardiovascular diseases.

N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs.

Proximity to international airports and early transmission of COVID-19 in the United States-An epidemiological assessment of the geographic distribution of 490,000 cases.

BACKGROUND: Identifying hotspots in a pandemic is essential for early containment. In the context of the rapid global dissemination of the Covid-19 pandemic, describing viral infection rates in relation to international air travel early during the pandemic can help inform future public health policy. The objective of this study is to determine whether proximity to an international airport predicted higher infection rates during the early phase of the Covid-19 pandemic in the United States (US). METHODS: In this cross-sectional study, the authors examined the incidence of Covid-19 in areas near US international airports in the first weeks after detection of Covid-19 in all 50 states, using publicly available county-level incidence of Covid-19 data. They performed a multiple regression to determine the relative effects of population density and air traffic in the Counties Containing Airports (CCA) and the number of Covid-19 cases, and determined the odds of Covid-19 in CCA compared to the rest of the state. RESULTS: Multiple regression analysis revealed that air traffic was significantly correlated with Covid-19 cases during the initial phase of pandemic while population density was not significantly correlated. Three weeks into the pandemic, the pooled odds of Covid-19 cases in CCA was 2.66 (95% CI [2.64, 2.68], p < 0.0001). CONCLUSIONS: The counties in the US containing international airports represented initial hotspots for Covid-19 transmission. Early public health containment efforts focused on these areas may help mitigate disease transmission during future similar novel respiratory virus epidemics.

Closing the Gender Gap in Global Surgery: Trends at the Academic Surgical Congress.

INTRODUCTION: Female researchers are underrepresented in academic surgery. While they are increasingly producing original research, they lag male researchers in productivity. This disparity is not well understood within the nascent field of global surgery. The following study examines gender parity in global surgery research presented at the Academic Surgical Congress and within subsequent publications. METHODS: Abstracts presented at the Academic Surgical Congress (ASC) between 2015 and 2019 in "Global Surgery" sessions were reviewed to obtain title, the first author (FA) and senior author (SA). The authors were classified by gender. The Scopus database was queried by two reviewers for abstracts with corresponding publications, citations, and journal impact factors. Statistical analysis was conducted using chi-square analysis and t-tests where appropriate. RESULTS: Of a total of 6635 abstracts, 218 global surgery abstracts over a 5-year period were identified. Of these abstracts, 96 (44%) had female FAs, while 56 (26%) had female SAs. When comparing gender, female (44%) FAs and male (56%) FAs were equally represented. While SAs were significantly less likely to be female (26% versus 74%, P < 0.0001), female senior authorship increased significantly within the study period. Output with respect to publications, citations, and journal impact factors were equal by gender. CONCLUSIONS: This study presents 5 y of gender trends in global surgery scholarly work presented at the ASC. Despite an overall predominance of male senior authors, the paradigm is shifting with a recent trend to gender parity. Male and female authors have equal output and are equally impactful. Findings of gender equity in academic global surgery are encouraging, and further study of other disciplines are warranted.

Development and Preliminary Validation of a Depression Assessment Tool for Maintenance Hemodialysis Patients.

Patients undergoing maintenance hemodialysis (MHD) are subject to a higher-than-usual prevalence of depressive disorders. However, the lack of consensus regarding the best assessment method remains an important problem. Thus, there is a clear need for more effective screening tools and an easily administered, disease-specific self-report measure of depression in MHD patients. After we developed and administered an initial depression inventory for MHD patients (I-DI-MHD), we created the DI-MHD and administered the DI-MHD and the Beck Depression Inventory (BDI) to 354 patients from four hospitals. Reliability, construct validity and receiver operator characteristic curves were assessed. The 17-item DI-MHD instrument displayed good internal consistency (Cronbach's alpha =0.893), provided excellent convergent validity, and correlated with the BDI scale (kappa =0.785, P <0.001). A factor analysis pattern matrix analysis showed that a four-factor model provided the best account of the data. Finally, the DI-MHD cutoff yielded a sensitivity of 0.97 and a specificity of 0.86, which were slightly better than the corresponding values for the BDI. The DI-MHD scale shows reasonable validity and reliability for assessing depression in MHD patients.

Application of contrast-enhanced ultrasonography after radiofrequency ablation for renal cell carcinoma: is it sufficient for assessment of therapeutic response?

PURPOSE: To assess the efficacy of contrast-enhanced ultrasonography (CEUS) with Sonovue in the evaluation of therapeutic response to radiofrequency ablation (RFA) of renal cell carcinoma (RCC). MATERIALS AND METHODS: In a recent 3 years, 63 patients (mean age, 60 years; range 26-81 years) with 64 RCCs were treated by RFA. The lesions had a diameter between 1.8 and 9.8 cm (average diameter, 3.1 cm). The indications for RFA treatment included chronic renal insufficiency (n = 10), presence of solitary kidney (n =3), bilateral renal carcinoma (BRCC) (n =2), advanced age (n =12), significant medical comorbidity (n =29) or refusal of conventional therapy (n =7). Tumors were treated by laparoscopy-assisted (n =41), open surgical (n =18) or percutaneous US guidance (n =4). Follow-up CEUS and contrast-enhanced CT were performed 1 month after treatment to assess the necrotic area. Technical success was defined as elimination of areas that enhanced at imaging within the entire tumor. RESULTS: On the 1-month CEUS and CT imaging after RFA, 62 of 64 tumors (96.9%) were successfully ablated with one session, and residual tumors were found in two RCCs. One of the two tumors was subjected to additional RFA treatment. We could not obtain a complete ablation in the other tumor of a patient with solitary kidney. The diagnostic concordance between the CEUS and 1-month follow-up CT was 100%. Sixty-one patients survived in the follow-up phase which ranged from 2 to 34 months. One patient with solitary kidney died of systemic disease progression and one patient was lost to follow-up. Of the 61 tumors without residual on both CT and CEUS after RFA, four had suspicious findings of recurrence on follow-up CEUS, and two of them were confirmed by subsequent CT examination. With CT as the reference imaging procedure in the assessment of renal tumor ablation, the sensitivity, specificity, positive predictive value, and negative predictive value of CEUS for detecting recurrence during follow-up were 100%, 96.6%, 50%, and 100%. CONCLUSION: Despite its limitation of false-positive value, CEUS is potentially effective in assessing the therapeutic response to RFA of RCC.

[Surface water quality assessment in Miyun reservoir watershed, Beijing in the period 1980-2003].

Single factor water quality identification index was adopted to assess the surface water quality of Miyun reservoir watershed in Beijing using nearly 20 years monitoring data of 4 sites, also the surface water quality pollution sources were analyzed. The results indicated TP had the largest temporal variation at every monitoring site, coefficients of variation were 93.86%, 86.08%, 50.56% and 139.47%, respectively. The following element was Hg, the coefficients of its variation were 86.08%, 25.75%, 56.52% and 47.01%, respectively. While TN, permanganate index, BOD5, Pb and Cr were relatively stable with small coefficient of temporal variation. The permanganate index, BOD5, Pb and Cr did not exceed to the Chinese surface drinking water standard limit in the study period, while Hg had high pollution risk in several years, such as monitoring sites S1 and S3 in 1992, monitoring sites S4 in 1996. The major pollutants of Miyun reservoir watershed in Beijing were TN and TP, and TN had larger pollution risk compared with TP in most years. Comparing to that before the 1990s, the decade average fertilizer, pesticide and agricultural plastic mulch inputs after the 1990s had increased by 46%, 173% and 359%, respectively. The husbandry proportion in agriculture rose from 24.4% to 39.8%, and the average gross industrial production by 424%. The upstream of Miyun reservoir had larger pollution risk than its downstream. In addition, Chaohe watershed contributed more TN and TP to the reservoir than Baihe watershed.