The serious drawbacks of conventional pancreatic ductal adenocarcinoma (PDAC) therapy like nonspecific toxicity and high resistance to chemo and radiation therapy, prompted the development and application of countless siRNA-based therapeutics. Significant technological success has been achieved in this area; however, the major challenges to siRNA-based therapeutics becoming a new paradigm in the pancreatic cancer therapy stem from enzymatic digestion, off-target effects, difficulty to enter cells, induction of innate immune responses, and renal clearance. Recent advances in drug delivery systems hold great promise for improving siRNA-based therapeutics and developing a new class of drugs, nano-siRNA drugs. However, a number of fundamental questions, regarding toxicity, immunostimulation, and poor knowledge of nano-bio interactions, need to be addressed before clinical translation. In this review, we provide recent achievements in designing and development of various non-viral delivery vehicles for pancreatic cancer therapy. More importantly, co-delivery of conventional anticancer drugs with siRNA as a new revolutionary pancreatic cancer combinational therapy is completely discussed.

The Jordan River Basin, and its seven sub-catchments of the Central Wasatch Mountains immediately east of Salt Lake City, UT, are home to an array of research infrastructrure that collectively form the Wasatch Environmental Observatory (WEO). Each sub-catchment is comprised of a wildland to urban land use gradient that spans an elevation range of over 2000 m in a linear distance of ~25km. Geology varies across the sub-catchments, ranging from granitic, intrusive to mixed sedimentary rocks in uplands that drain to the alluvial or colluvial sediments of the former Lake Bonneville. Vegetation varies by elevation, aspect, distance to stream channels, and land use.  The sharp elevation gradient results in a range of precipitation from 700 to 1200 mm/yr (roughly 2/3 as snow) and mean annual temperature from 3.5 o to 6.8o C. Spring snowmelt dominates annual discharge. Although climate is relatively similar across the catchments, annual water yield varies spatially by more than a factor of 3, ranging from 0.18 to 0.63. With historical strengths in ecohydrology, water supply, and social-ecological research, current infrastructure supports both basic and applied research in meteorology, climate, atmospheric chemistry, hydrology, ecology, biogeochemistry, resource management, sustainable systems, and urban redesign. Climate and discharge data span over a century for the seven sub-catchments of the larger basin. These data sets, combined with multiple decades of hydrochemistry, isotopes, ecological data sets, social survey data sets, and high-resolution LiDAR topography and vegetation structure, provide a baseline for long-term data collected by NEON, public agencies, and individual research projects. The combination of long-term data with active state of the art observing facilities allows WEO to serve as a unique natural laboratory for addressing research questions facing rapidly growing, seasonally snow-covered, semi-arid regions worldwide and an excellent facility for providing student education and research training.

It has been long believed that ischemic mitral regurgitation is secondary to left ventricular remodelling and the mitral per se remains unaffected. This proviso has recently been challenged and the mitral valve has been described as a structure that responds and adapts to challenges and attempts to correct the mitral regurgitation. The response of mitral valves in this setting can be incomplete or can even be mal-adapted. The ability of the mitral valve to respond in this manner has been described as “mitral plasticity”. Endothelial to Mesenchymal transition and Valvular Interstitial Cells are key to this mitral plasticity and function through a complex array of signalling pathways. Identification and manipulation of these pathways may provide a possibility to correct the incomplete or mal-adapted mitral valve responses. Surgical treatment can also be tailored based on whether the valve has maladapted or has undergone incomplete adaptation.

It is not well understood why some healthy vaginal microbiomes are dominated by Lactobacillus and some are not. This review outlines factors which impact the vaginal microbiome and may explain this phenomenon. Specifically, hygiene practices, diet, sexual partners and practices, gender affirming treatments, stress, and social determinants are discussed. The goal of this review is to discuss key endogenous and exogenous factors that clinical experts and research scientists should consider when evaluating the vaginal microbiome in health and disease.

A total of 130 patients who underwent robotic mitral valve surgery and conventional mitral valve surgery with full sternotomy between 2014 and 2020 were included in our study. All patients were divided into two groups; Group I, with 64 patients who underwent robotic mitral valve replacement, and Group II, with 66 patients with conventional full sternotomy. General demographic data (age, gender, body weights, etc.), comorbidities (hypertension, diabetes mellitus, chronic obstructive pulmonary disease, peripheral artery disease, hyperlipidemia, etc.), intraoperative variables (cardiopulmonary bypass times, cross-clamp times) postoperative ventilation times, drainage amounts, transfusion amount, inotropic need, revision, arrhythmia, intensive care and hospital stay times and mortality were analyzed retrospectively. According to conventional methods, robotic mitral valve replacement is an effective and reliable method, since total perfusion and cross clamp times are longer, drainage amount and blood transfusion need are less, ventilation time, intensive care and hospital stay time are shorter. Compared to conventional methods, robotic surgery is an increasingly widespread successful treatment option because of its early mobilization, rapid recovery, better cosmetic outcome and improving quality of life.

Objectives:Surgical management of aortic arch hypoplasia with associated intra-cardiac anomalies is a challenge in newborns.We reviewed the characteristics and outcomes of neonates and infants who underwent pulmonary artery banding concomitant to arch repair and single-stage total repair at our institution. Methods:Medical records of 60 patients undergoing aortic arch reconstruction for aortic arch hypoplasia between 2014 to 2019 were retrospectively reviewed.Twenty-five patients were female (41.6%), and the age of the patients ranged from 4 to 120 days (median 19.5 days).The patients were divided into two groups;Group 1 (23 patients) underwent pulmonary artery banding concomitant to arch repair, Group 2 (37 patients) underwent single-stage total repair in addition to arch repair.All arch repair procedures consisted of an extended (to the midportion of the ascending aorta)patch aortoplasty. Results:Postoperative early mortality occurred in 12 patients, 8 in Group 1(34.8%), and 4 in Group 2 (10.8%).There was an early survival advantage in group 2 (p=0.019).Recoarctation was occurred in 13 cases (21.6%), and 11 (18.3%) of them required reintervention (balloon angioplasty:7, re-operation:4).On univariate analysis, risk factors associated with death were pulmonary artery banding (HR,0.44;CI,0.09-2;p=0.019),prematurity (HR,4,67;CI,1.34-16.18;p=<0.001),preoperative mechanical ventilation support requirement (HR,0.048;CI, 0.52-6.39;p=0.048),and functional single ventricle (HR,0.43;CI,0.1-1.86;p=0.006).The mean duration of follow-up was 21.9±15.1 months, and there was no late death in each group. Conclusion:Single-stage repair of aortic arch hypoplasia with intracardiac pathologies has better results than palliation, according to survival rates and postoperative results.The use of patch augmentation technique in aortic arch hypoplasia is valid and associated with an acceptable incidence of recurrent arch obstruction.

Background. Irreversible bilateral sensorineural hearing loss is a common side effect of platinum compounds. Because of extended overall survival period of children, a prolonged hearing surveillance and management of hearing impairments are emerging concerns for pediatric oncology. Methods. In this retrospective observational study we enrolled 38 children out of 116 treated at our institution by chemotherapy (cisplatin and/or carboplatin) with or without irradiation between 2007–2014, and submitted to hearing monitoring before every cycle of chemotherapy and that completed a 5 years long-term follow-up. Chemotherapy regimens, demographic findings, cumulative doses and cranial irradiation were compared. Results. At the end of 5-years follow-up ototoxicity was significantly increased compared to that at observed the end of chemotherapy (52.5% vs 39.5%, p<0.001). A late onset of hearing loss was experienced in 13.1% of children while in 26.3% progressive hearing loss was measured. Deafness at the end of chemotherapy and irradiation was significant prognostic factor for late ototoxicity outcomes (Odds Ratio 7.2 – CI:1.67–31.1 – p<0.01 and 5.25 – CI:1.26–21.86 – p<0.01 respectively). No significant differences were found between cisplatin and combined treatment (i.e. cisplatin shifted to carboplatin during monitoring for the onset of ototoxicity) and ototoxicity was not associated with platinum compounds cumulative dose (p>0.05). 13.1% of children needed hearing aids at the end of follow-up. Conclusions. Our study confirms the effectiveness of long-term follow-up in identifying late onset/progressive hearing loss after platinum compound chemotherapy and allows us to avoid the harmful effects of hearing deprivation with hearing aid intervention.

Within the last 25 years, high-resolution CT scans have revealed pulmonary micronodules (nodules < 10 mm) not previously seen. For osteosarcoma (OST), staging criteria, prognosis estimates, and surgical recommendations have not yet changed to reflect this reality, however, the frequent identification of micronodules on presentation leaves clinicians in a difficult position regarding the need to biopsy, resect, or follow the lesions and whether to consider the patient metastatic or non-metastatic. We retrospectively collected data on all newly diagnosed OST patients, age less than 50, treated at Rush University Hospital over 25 years without pulmonary nodules > 10mm to study the relationship between size and location of micronodules discovered at the time of diagnosis and its relationship to 5 year overall survival. Kaplan-Meier curves comparing 5 year overall survival of patients with their largest nodules on presentation at each size interval showed there was no difference in 5 year overall survival in patients with any size nodule < 5 mm compared to patients with no nodules. In addition, our study showed a survival advantage for those who presented with 0 or 1 nodule (90%) compared to ≥ 2 nodules (53%). Additionally, patients who develop nodules after presentation but within a year of diagnosis with any number of new micronodules had a lower 5 year overall survival (93% vs 63%). Our data suggest surgery may not be necessary for singular nodules < 5 mm identified on presentation, and that these patients behave more like “localized” patients than metastatic patients.

A document by Atish Bakane. Click on the document to view its contents.

Aims: The recently described SARS-CoV-2 has led to a pandemia which has severe consequences for the global community. Hydroxychloroquine has been repurposed for the treatment of COVID-19 but conflicting information on its efficacy and safety has since emerged. Our group designed a trial on the use of high-dose hydroxychloroquine in a high-risk ambulatory population with mild COVID-19 (NCT04351620) and summarizes herein the clinical data of hydroxychloroquine in COVID-19. Methods: Single-arm and single-center study evaluating the tolerability of high-dose hydroxychloroquine, 600 mg twice daily for 5 days, in patients with mild COVID-19 and risk factors for clinical decompensation and hospitalization. Secondary objectives included maintenance of ambulatory status, defervescence, and symptom relief. Results: Over a six-week period, 59 patients met eligibility criteria out of 314 contacted (18.7%). Out of these 59 potentially eligible patients, 44 (74.5%) patients declined to be screened further due to concerns about its risks and unproven efficacy, referencing media accounts and politization of the medication. Out of the 9 patients consented, 2 did not complete the therapy plan, 1 due to headaches, 1 did not follow up. Two of the 7 patients who completed the study continued to have fevers, one was admitted for pneumonia. Study was terminated early due to recruitment difficulties. Conclusions: The trial met pre-defined primary outcome of tolerability, but sample size was too small to allow further interpretation. The political climate and media coverage might have negatively impacted patient recruitment, which has ultimately led to its early interruption.

A document by Roman Komorovsky. Click on the document to view its contents.

A steroid- and cyclosporine A- resistant case of Pfeiffer-Weber-Christian disease (PWCD) was remitted completely with sequential treatment with Histobulin and IVIG. The multiple food allergies and the atopic dermatitis of this PWCD patient were also improved with Histobulin treatment. The upper respiratory infections were improved by Histobulin therapy also.

An amino acid supplement containing 700 mg of cystine and 280 mg of theanine was administered to 4 patients during the treatment of SARS-CoV-2 virus infection. Negative reactions on polymerase chain reaction (PCR) testing were promptly obtained. Oral ingestion of cysteine and theanine (C/T) may promote SARS-CoV-2 virus elimination.

Background: Multipoint pacing (MPP) in cardiac resynchronization therapy (CRT) activates the left ventricle from two locations, thereby shortening the QRS duration and enabling better resynchronization; however, compared with conventional CRT, MPP reduces battery longevity. On the other hand, electrocardiogram-based optimization using the fusion-optimized intervals (FOI) method achieves more significant reverse remodeling than nominal CRT programming. Our study aimed to determine whether MPP could attain better resynchronization than single-point pacing (SPP) optimized by FOI. Methods: This prospective study included 32 consecutive patients who successfully received CRT devices with MPP capabilities. After implantation, the QRS duration was measured during intrinsic rhythm and with three pacing configurations: MPP, SPP-FOI, and MPP-FOI. In 14 patients, biventricular activation times (by electrocardiographic imaging, ECGI) were obtained during intrinsic rhythm and for each pacing configuration to validate the findings. Device battery longevity was estimated at the 45-day follow-up. Results: The SPP-FOI method achieved greater QRS shortening than MPP (-56±16 vs. -42±17 ms, P<0.001). Adding MPP to the best FOI programming did not result in further shortening (MPP-FOI: - 58±14 ms, P=0.69). Furthermore, the biventricular activation time according to ECGI was also shorter with SPP-FOI than with MPP. The estimated battery longevity was longer with SPP than with MPP (8.1±2.3 vs. 6.3±2.0 years, P=0.03). Conclusions: SPP optimized by FOI resulted in better resynchronization and longer battery duration than MPP.

A 42-year-old woman with tricuspid atresia who underwent a Fontan surgery (atrio-pulmonary connection) was admitted to our hospital due to symptomatic ventricular tachycardia. A defibrillation lead was implanted in a distal site of a coronary vein since there was no usual entry to the ventricle. Ventricular pacing was impossible due to the high threshold, however, good sensing was obtained. Three years later, she felt palpitations and a subsequent shock therapy while climbing stairs. The cardioverter data showed that an appropriate cardioversion therapy successfully converted ventricular tachycardia to normal rhythm.

Dear Editor,We reviewed the article entitled: “Analysis of reflux as the etiology of laryngeal dysplasia progression through a matched case-control study ”.1 The authors did not find differences in the level of pepsin, enterokinase and bilirubin in laryngeal dysplasia (LD) of patients with malignant transformationversus those without transformation. The involvement of reflux in the development of LD and laryngeal cancers is an important topic and the realization of such a study is important. However, we wish to draw attention to many points.First, it is difficult to know if the included patients with tissue pepsin really suffered from reflux. The detection of pepsin into the tissue means that patients had some pharyngeal reflux events the day before the surgery but cannot confirm the diagnosis. The sensitivity of pepsin detection in laryngeal tissue depends on the technique and the material (antibodies), reaching 75 to 85% depending on the type of reflux (acid versus nonacid).2 Moreover, we have no detailed information about the immunostaining technique, limiting the reproducibility of the protocol. The presence of pepsin into the tissue does not ensure the reflux diagnosis. Thus, for example, it has been showed that the back flow of gastric content and the deposit of pepsin into the tissue are influenced by the meals preceding the sample collection, making the pepsin tissue a poorly reliable marker of reflux.3 To improve the sensitivity, authors1 could have performed hypopharyngeal-esophageal pH-impedance monitoring, which is the only way to confirm the diagnosis.4Second, the LD malignant transformation involves many factors such as tobacco history, environmental factors, genetic, or immune response.5 The authors did not provide information about the tobacco history (pack-year data) of groups, which is an important data to consider the risk of malignant transformation. Even many years after the tobacco cessation, it is conceivable that patients with long/more severe history of tobacco consumption may have more cell mucosa DNA impairments and a higher risk to develop cancer.Third, the focus on pepsin as the only enzyme associated with malignant transformation limits the understanding of transformation mechanisms. More than 50% of patients had mixed or nonacid reflux,4 in which the activity of pepsin is decreased regarding the alkaline pH of refluxate. To reliably investigate the involvement of reflux in the malignant transformation, authors have to consider the entire content of refluxate, including bile salts and trypsin.4 Furthermore, bile salts may be involved in laryngopharyngeal malignant transformation.6In future studies, reflux has to be diagnosed at the LD diagnosis time and physicians have to follow the reflux clinical course over the time. More than 50% of reflux patients had chronic course,4which leads to a potential higher risk to develop cell DNA damage and lesions. Thus, cross-sectional study design is probably not adequate to study a disease association involving chronic and repeated exposure.Acknowledgments: No.

Background: Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation is a major cause of postoperative morbidity and mortality. Despite the availability of multiple imaging parameters, none of these parameters had adequate predictive accuracy for post-LVAD RVF. Aim: To study whether right ventricular pressure-dimension index (PDI), which is a novel echocardiographic index that combines both morphologic and functional aspects of the right ventricle, is predictive of post-LVAD RVF and survival. Methods: 49 cases that underwent elective LVAD implantation were retrospectively analyzed using data from an institutional registry. PDI was calculated by dividing systolic pulmonary artery pressure to the square of the right ventricular minor diameter. Cases were categorized according to tertiles. Results: Patients within the highest PDI tertile (PDI>3.62 mmHg/cm2) had significantly higher short-term mortality (42.8%) and combined short-term mortality and definitive RVF (50%) compared to other tertiles (p<0.05 for both, log-rank p for survival to 15th day 0.014), but mortality was similar across tertiles in the long-term follow up. PDI was an independent predictor of short-term mortality (HR:1.05–26.49, p=0.031) and short-term composite of mortality and definitive RVF (HR:1.37–38.87, p=0.027). Conclusions: Increased PDI is a marker of an overburdened right ventricle. Heart failure patients with a high PDI is at risk for short-term mortality following LVAD implantation.

Coronavirus-2019 (COVID-19) pandemic is a global health challenge where pregnant women are potentially more vulnerable to respiratory infections. We describe the successful management of a case a 35 years old pregnant woman, G3, P1, with a history of caesarian section who tested positive for COVID-19 and required critical care support

The patient in this case can walk alone and take care of himself. Therefore through surgical separation and removal of the cloudy lens, the establishment of a visual pathway can help improve the children's vision and improve their quality of life.

Traditional Indian medicine practice (Ayurveda) emphasized the role of “panchgavya” five products from Bos indicus for human welfare. Ayurveda classics, “Sushruta Samhita,” “Ashtanga Sangraha,” alluded to the therapeutic potential of pristine cow urine (CU) as drug or drug ingredients. Compelling evidence is exhibiting the innumerable medicinal properties of CU; accordingly, this elixir can directly treat complex ailments such as leprosy, tuberculosis, and fever. Also, the classics narrated many formulations that have utilized CU for the preparation of drugs, supplemented to enhance the potency. This practice is more empirical, and only a few experimental evidence is supporting the claim are known. The associated mechanisms are poorly understood and so rendered its appeal to the limited mass. The study aims to investigate bio-enhancer like properties of CU towards network pharmacology. For that, 25 medicines having anti-bacterial, anti-fungal, anti-viral, enzyme inhibitors, and anti-inflammatory actions selected as a reference. Network analysis for twenty chemotypes found in CU was carried out. First, through enrichment analysis, the KEGG and GO terms were obtained. Second, we performed protein-protein interaction studies to screen more targets. Towards this, the drug-protein and CU- protein interactions networks built separately and processed.

Grey Crowned Crane Balearica regulorum is described as an icon of Africa’s wetlands and grasslands and is listed as Endangered on the IUCN Red List of Threatened species. Conservation efforts are partially hindered by lack of information on factors influencing breeding productivity, such as nest-site selection. Factors influencing nest-site selection were investigated at Lake Ol’ Bolossat, a 43.3 km2 wetland located in the central Kenya from 30 paired nests. Generalized Linear Mixed-Effects Models were used to analyse the relationship between factors influencing nest-site selection by cranes and variables that were predicted to have a compelling influence on nest-site selection besides i) food and nesting materials availability i.e. the offshore distance of the nest and water depth, and ii) nest concealment and susceptibility to predation i.e. vegetation height and grazing intensity. Results show that variables which had a significant influence on nest-site selection were: water depth (p=0.005), the offshore distance from the nest (p=0.037), and vegetation height (p=0.035). Cranes located their nests in water points above 50 cm deep, vegetation height of 60-90 cm, and preferably 100 m offshore. A minimum of 103 territorial pairs, both breeding and non-breeding cranes, were recorded. The middle section of the lake had the highest number (52), while north and south had 32 and 19 pairs respectively. The mean distance between any two pairs was 302.53±17.02 (SE) meters. This study sheds some light on the understanding of characteristics of Grey Crowned Crane’s nesting sites that will facilitate manipulation and management of breeding sites. Lake Ol’ Bolossat is consequently a critical breeding site with a substantial role in the species’ population recovery and survival. A wetland management option that aims at achieving sustainable use of lake’s resources by local communities without compromising needs of wildlife is highly commended.

Aims Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural protein 5A inhibitor for the treatment of chronic HCV genotype 1 infection. The objective of this analysis was to develop a population pharmacokinetic model of yimitasvir in Chinese healthy volunteers and HCV infection patients. Methods The model was performed using data from 219 subjects across 6 studies. Nonlinear mixed effects models were developed using Phoenix NLME software. The covariates were evaluated using a stepwise forward inclusion (P < 0.01) and then a backward exclusion procedure (P < 0.001). Results A two-compartment model with sequential zero-first order absorption and first-order elimination reasonably described yimitasvir pharmacokinetics (PK). The apparent oral clearance and central volume of distribution were 13.8 l h-1 and 188 l, respectively. The bioavailability (F) of yimitasvir decreased 12.9% for each 100 mg dose increase. Food was found to affect absorption rate (Ka) and F. High-fat meal decreased Ka and F by 90.9% and 38.5%, respectively. Gender and alanine aminotransferase were identified as significant covariates on apparent oral clearance. Female subjects had lower clearance than male subjects. Zero-order absorption duration was longer in healthy volunteers (2.17 h) than that in patients (1.43 h). Conclusions The population pharmacokinetic model described yimitasvir PK profile well. Food decreased Ka and F significantly, so it was recommended to take yimitasvir at least 2 h before or after a meal. Other significant covariates were not clinically important.

Purpose: Our previous studies have confirmed that the catecholamine norepinephrine (NE) promoted the corneal infection and progression of Pseudomonas aeruginosa (P. aeruginosa) keratitis. Here we explored the effects of adrenoceptor (AR) blockers on the severity of P. aeruginosa keratitis in mice. Methods: A total of 630 C57BL/6 mice were used and ocularly inoculated with P. aeruginosa (ATCC 19660). Six AR blockers were topically administrated 6 h before or combined with Tobrex 12 h after bacterial inoculation. Clinical scores, neutrophil infiltration and neutrophil extracellular traps (NETs), proinflammatory factors and bacterial virulence factors expression, bacterial load and biofilm formation were evaluated in vivo. The growth inhibitory and bactericidal activity of ICI118551 was measured in vitro. Results: Among various blockers, the selective β2-AR blocker ICI118551 showed the most significant improvement in disease severity. Prophylactic administration of ICI118551 attenuated the clinical scores, neutrophil infiltration, NETs formation, proinflammatory factors expression of infected corneas, accompanied with the reduction of bacterial load, virulence factors expression, and biofilm formation. When adjunctive treatment with Tobrex, ICI118551 exhibited apparent therapeutic effects with the reduced severity after 12 h of bacterial inoculation. Moreover, ICI118551 inhibited bacterial growth and possessed bactericidal activity in vitro. In addition, ICI118551 had no significant influence on ocular barrier function and intraocular pressure. Conclusions: The selective β2-AR blocker ICI118551 attenuated the severity of P. aeruginosa keratitis in mice, which may represent the potential prophylactic and therapeutic approach to control the P. aeruginosa corneal infection.

The role of editors or a team of editors has two important tasks: deciding a paper for review or not, and writing editorials for disseminating messages to the world.