Background: Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy has been established as a novel treatment approach for peritoneal sarcomatosis. Despite promising clinical reports, there is still a lack of knowledge regarding optimal drug usage and local effects. Therefore, we intended to establish a murine animal model for further evaluation. Procedure: Alveolar rhabdomyosarcoma cells were xenotransplanted into NOD/LtSz-scid IL2Rγnullmice (n=100). The mice received a continuous intraperitoneal lavage with isotonic saline solution as control- or with cisplatin (30 or 60 mg/m2) as treatment group for 60 minutes at 37 or 42 °C (6 subgroups, each n=16). Tumor spread was documented by an adapted peritoneal cancer index and MRI (n=4). Tumor and tissue samples, harvested at the end of the perfusion, were evaluated regarding morphology, proliferation and apoptosis (H&E-, Ki-67-, Cleaved Caspase 3-staining, TUNEL-assay). Results: Extensive peritoneal sarcomatosis in over 91% of the cases was observed. HIPEC was feasible without acute side effects. Ki-67 staining revealed concentration- or temperature-dependent effects of cisplatin-based HIPEC on the tumors. While Cleaved Caspase-3 showed only sporadic apoptotic effects. TUNEL-assay detected concentration- or temperature-dependent apoptotic effects at the outer tumor surface. MRI scans confirmed the observed tumor dissemination. Conclusion: This is the first animal model for evaluation of HIPEC in pediatric RMS in mice. Cisplatin-based HIPEC had early effects on the proliferation whereas circumscribed apoptotic effects could be detected at the tumor surface. This model allows further insights on the possible efficiency of HIPEC in RMS. Further studies using other drug combinations and treatment will follow.

The paper investigates the exponential stability criterion for an axially moving string system driven by a nonlinear partial differential equation with nonlinear boundary feedback.The control criterion based on a sector condition contains a large class of nonlinearities, which is a negative feedback of the velocity at the right boundary of the moving string. By invoking nonlinear semigroup theory, the well-posedness result of the closed-loop system is verified under the sector criteria. Furthermore, a novel energy like function is constructed to establish the exponential stability of the closed-loop system by using a integral-type multiplier method and the generalized Gronwall-type integral inequality.

We thank Shixiong Wei et al for their interest in our technical paper on Robotic Septal myectomy for HOCM and their letter to the editor. Their technique of using the Computed Tomography Angiography (CTA) along with 3D Printing technology for the better delineation of the anatomy of HOCM has been an evolving way to approach the problem. As they have mentioned in their letter, we used cardiac magnetic resonance imaging (MRI) predominantly for all our patients who undergo septal myectomy. Using 3D printing technology augmenting CTA or MRI can certainly augment the surgical planning in complex patients. In their case report, Wei et al have shaved off most of the subvalvular tissue along with the mitral valve. Removal of the entire mitral valve definitely would have enhanced the exposure to the mid-ventricular cavity and the apex for their thoracoscopic approach. It will be interesting to know whether they tried to repair the valve before replacement. Our technique of Robotic mitral valve repair, septal myectomy, and particularly papillary muscle re-orientation tries to preserve the sub-valvular apparatus even after completely relieving the mid-cavitary obstruction and this may provide better ventricular re-modeling. We congratulate them on providing a successful surgical option to this complex subset of patients using novel evolving technology and meticulous surgical planning.

A document by Shashikant Sholapurkar. Click on the document to view its contents.

Microaxial LVADs are increasingly used for cardiogenic shock treatment. We compared the short-term outcome of patients supported with different microaxial devices for cardiogenic shock. A retrospective propensity score-adjusted analysis was performed in cardiogenic shock patients treated with either the Impella CP (n=64) or the Impella 5.0/5.5 (n=62) at two tertiary cardiac care centers between 1/14 and 12/19. Patients in the Impella CP group were significantly older (69.6±10.7 vs 58.7±11.9 years, p=0.001), more likely in an INTERMACS level 1 (76.6% vs 50%, p=0.003) and post CPR (36% vs 13%, p=0.006). The unadjusted 30-day survival was significantly higher in Impella 5.0/5.5 group (58% vs 36%, p=0.021, odds ratio (OR) for 30-day survival on Impella 5.0/5.5 was 3.68 (95% CI [1.46-9.90], p=0.0072). After adjustment, the 30-day survival was similar for both devices (OR 1.23, 95% CI [0.34-4.18], p=0.744). Lactate levels above 8 mmol/L and preoperative CPR were associated with a significant mortality increase in both cohorts (OR=10.7, 95% CI [3.45-47.34], p<0.001; OR=13.2, 95% CI [4.28-57.89], p<0.001, respectively). Both Impella devices offer a similar effect with regards to survival in cardiogenic shock patients. Preoperative CPR or lactate levels exceeding 8 mmol/L immediately before implantation have a poor prognosis on Impella CP and Impella 5.0/5.5.

Background and Purpose Ca2+ influx via TRPV4 triggers Ca2+ release from the IP3-sensitive internal store to generate repetitive oscillations. While mitochondria are acknowledged regulators of IP3-mediated Ca2+ release, how TRPV4-mediated Ca2+ signals are regulated by mitochondria is unknown. We show that depolarised mitochondria switch TRPV4 signalling from relying on Ca2+-induced Ca2+ release at IP3 receptors, to being independent of Ca2+ influx and instead mediated by ATP release via pannexins. Experimental Approach TRPV4 evoked Ca2+ signals were individually examined in hundreds of cells in the endothelium of rat mesenteric resistance arteries using the indicator Cal520. Key ResultsTRPV4 activation with GSK1016790A(GSK) generated repetitive Ca2+ oscillations that required Ca2+ influx. However, when the mitochondrial membrane potential was depolarised, by the uncoupler CCCP or complex I inhibitor rotenone, TRPV4 activation generated large propagating, multicellular, Ca2+ waves in the absence of external Ca2+. The ATP synthase inhibitor oligomycin did not potentiate TRPV4 mediated Ca2+ signals. GSK-evoked Ca2+ waves, when mitochondria were depolarised, were blocked by the TRPV4 channel blocker HC067047, the SERCA inhibitor cyclopiazonic acid, the phospholipase C (PLC) blocker U73122 and the inositol triphosphate receptor (IP3 R) blocker caffeine. The Ca2+ waves were also inhibited by the extracellular ATP blockers suramin and apyrase and the pannexin blocker probenecid. Conclusion and Implications These results highlight a previously unknown role of mitochondria in shaping TRPV4 mediated Ca2+ signalling by facilitating ATP release. When mitochondria are depolarised, TRPV4-mediated release of ATP via pannexin channels activates plasma membrane purinergic receptors to trigger IP3 evoked Ca2+ release.

Permafrost thaw has been observed in recent decades in the Northern Hemisphere and is expected to accelerate with continued global warming. Predicting the future of permafrost requires proper representation of the interrelated surface/subsurface thermal and hydrologic regimes. Land surface models (LSMs) are well suited for such predictions, as they couple heat and water interactions across soil-vegetation-atmosphere interfaces and can be applied over large scales. LSMs, however, are challenged by the long-term thermal and hydraulic memories of permafrost and the paucity of historical records to represent permafrost dynamics under transient climate conditions. In this study, we address the challenge of model initialization by characterizing the impact of initial climate conditions and initial soil frozen and liquid water contents on the simulation length required to reach equilibrium. Further, we quantify how the uncertainty in model initialization propagates to simulated permafrost dynamics. Modelling experiments are conducted with the Modélisation Environmentale Communautaire – Surface and Hydrology (MESH) framework and its embedded Canadian Land Surface Scheme (CLASS). The study area is in the Liard River basin in the Northwest Territories of Canada with sporadic and discontinuous regions. Results show that uncertainty in model initialization controls various attributes of simulated permafrost, especially the active layer thickness, which could change by 0.5-1.5m depending on the initial condition chosen. The least number of spin-up cycles is achieved with near field capacity condition, but the number of cycles varies depending on the spin-up year climate. We advise an extended spin-up of 200-1000 cycles to ensure proper model initialization under different climatic conditions and initial soil moisture contents.

The keystone species, Pisaster ochraceus, suffered mass mortalities along the northeast Pacific Ocean from Sea Star Wasting Syndrome (SSWS) outbreaks in 2013-2016. SSWS causation is still debated, leading to concerns as to whether outbreaks will continue to impact this species. Considering the apparent link between ocean temperature and SSWS, the future of this species and intertidal communities remains uncertain. Surveys of co-occurring P. ochraceus along the central Oregon coast in 2016 allowed us to address whether variation in disease status showed genetic variation that may be associated with differences in susceptibility to SSWS. We performed restriction site-associated DNA sequencing (2bRAD-seq) to genotype ~72,000 of single nucleotide polymorphism (SNP) loci across apparently normal and wasting sea stars. Locus-specific analyses of differentiation (Fst) between disease-status groups revealed no signal of genetic differences separating the two groups. Using a multivariate approach, we observed weak separation between the groups, but identified 18 SNP loci showing highest discriminatory power between the groups and scanned the genome annotation for linked genes. A total of 34 protein-coding genes were found to be located within 15 kb (measured by linkage disequilibrium decay) of at least one of the 18 SNPs, and 30 of these genes had homologies to annotated protein databases. Our results suggest that likelihood of developing SSWS symptoms does not have a strong genetic basis. The few genomic regions highlighted had only modest levels of differentiation, but the genes associated with these regions may form the basis for functional studies aiming to understand disease progression.

The most effective way to prevent and control infectious disease outbreak is through vaccines. The increasing use of vaccines has elevated the need to establish new manufacturing strategies. One of the major approaches is cell-based production, which creates a need for high cell density to enable higher cell production levels. This has led to development of the technology of cell carriers, including micro and macro cell carriers. To follow the production process, quantifying the number of cells on these carriers is required, as well as the tracking of their viability and proliferation. However, owing to various carriers’ unique structures, tracking the cell’s is challenging using current traditional assays that were originally developed for monolayers of adherent cells. The current “gold standard” method is counting cell nuclei, separating cells from the carrier, staining with crystal violet and visually counting under a microscope. This method is tedious and counts both live and dead cells. A few other techniques were developed but were specific to the carrier type and involved specialized equipment. In this study, we describe a broadly ranging method for counting cells on carriers that was developed and employed as part of the production of a vaccine for use in the SARS-CoV-2 pandemic. The method is based on the Alamar blue dye, a well-known, common marker for cell activity, and was found to be successful in tracking cell adsorption, cell growth and viability on carriers. No separation of the cells from the carriers is needed, nor is any specialized equipment; the method is simple and rapid, and provides comprehensive details necessary for process control of viral vaccine production in cells. This method can be easily implemented in any of a number of cell-based processes and other unique platforms for measuring growth of encapsulated cells.

Hydraulic drive unit (HDU) is a typical actuator, but the characteristic of input delay hinders the application of many advanced control methods in HDU. Firstly, in this paper, a mathematical model of HDU with input delay is established and the parameters are identified. Then, aiming at the input delay problem in HDU, a Smith estimated compensation model predictive control (SECMPC) strategy is proposed. On the one hand, the input delay state equation is employed to be a mathematical pattern for the state observation and predictive model. However, the combination between model predictive control (MPC) and Smith estimated compensation (SEC) is realized, the system state at k+d (d is the time delay coefficient) time is estimated in advance at k time to compensate the delay of the state. And then the prediction model based on input delay state equation is used for model prediction and rolling optimization. Thus the delay system which is unstable is promoted to a stable system without delay, and the effectiveness of SECMPC is proved with the HDU experiment and simulation. The SECMPC have some guiding significance for the control of systems with input delay.

Key points - 3D exoscopy is an emerging visualisation technique designed to improve ergonomics and image quality during surgeries. - We present a novel application of the VITOM® 3D exoscope in cochlear implantation (IDEAL Stage 2a prospective case series). - The system enabled high-quality visualisation during both posterior tympanotomy and electrode insertion. - Both the chief surgeon and the staff members rated the ergonomics of the system highly. - 3D exoscopy is a useful alternative to conventional microscopy, but the two techniques remain to be directly compared in larger studies.

Systemic lupus erythematosus (SLE) is a multisystem disease with a complex etiology which manifests in a multitude of manners. We present a case of lupus nephritis in a patient who developed complications of immunosuppressive treatment with eventual resolution of her nephritis following cure of her Nocardia brain abscess

Background: Standard dose seasonal influenza vaccines often produce modest immunogenic responses in adults ≥65 years old. MF59 is intended to elicit a greater magnitude and increased breadth of immune response. Objective: To determine the effectiveness of seasonal MF59-adjuvanted trivalent/quadrivalent influenza vaccine (aTIV/aQIV) relative to no vaccination or vaccination with standard or high dose egg-based influenza vaccines among people ≥65 years old. Methods: Cochrane methodological standards and PRISMA-P guidelines were followed. Real-world evidence from non-interventional studies published in peer reviewed journals and grey literature from 1997 through to July 15, 2020, including cluster-randomized trials, were eligible. Two reviewers independently extracted data and risk of bias was assessed using the ROBINS-I tool. Results: Twenty-one studies conducted during the 2006/07-2019/20 influenza seasons were included in the qualitative review; 16 in the meta-analyses. Meta-analysis of test-negative studies found that aTIV reduced medical encounters due to lab-confirmed influenza with pooled estimates of 40.7% (95% CI: 21.9, 54.9; I2=0%) for general practitioner visits and 58.5% (40.7, 70.9; I2=52.9%) for hospitalized patients. The pooled estimate of VE from case-control studies was 51.3% (39.1, 61.1; I2=0%) against influenza- or pneumonia-related hospitalization. The pooled estimates for the relative VE of aTIV for the prevention of influenza related medical encounters were 13.9% (4.2, 23.5; I2=95.9%) compared with TIV, 13.7% (3.1, 24.2; I2=98.8%) compared with QIV, and 2.8% (-2.9, 8.5; I2=94.5%) compared with HD TIV. Conclusions: Among adults ≥65 years aTIV demonstrated significant absolute VE, improved relative VE compared to non-adjuvanted standard-dose TIV/QIV, and comparable relative VE to high-dose TIV.

Development of severe hyponatremia after carotid endarterectomy procedure is rare. Several pathophysiological mechanisms related to the carotid endarterectomy procedure may infer an increased risk of developing this complication in specific populations.

This report describes a case of 45 years old male patient who tested positive for COVID-19 presented to the emergency department on March 2021 complaining of fever, cough, runny nose, and shortness of breath. The patient denied any history of nausea or diarrhea who has eventually developed favipiravir-induced nephrotoxicity.

Aims: The purpose of this study was to examine cardiac structure and function in lowlanders at high altitude(HA) to investigate short-term adaptation and long-term cardiac remodeling. Methods: In total of 301 healthy subjects included in this study, short-term exposed (STE) and acclimatized lowlanders (AL) at HA, native Tibetans(NT) and sea level residents(SLR) were comprised of 75,77,69 and 80 participants, respectively. Standard echocardiography was performed on all groups, subjects at HA were examined after return to sea level in <24 hours. Results: SBP and HR did not increase significantly after short-term exposure to HA in STE, but increased after long-term exposure in AL, which could be detected even after returning to the plain. Exposure to HA enlarged right heart, widened pulmonary artery and reduced left ventricular(LV) diastolic function in lowlanders. The degree of diastolic dysfunction was more obvious in AL. LV wall thickness increased even after short-term exposure to HA in lowlanders. Ejection fraction did not change significantly in STE, but decreased in AL. Conclusions: Exposure to HA could enlarged the right heart and decrease the diastolic function of LV in lowlanders. The LV systolic function was preserved after short-term HA exposure, but decreased after long-term HA exposure.

Background: Chemokines are important mediators in immune cell recruitment, contributing to allergy development. However, extensive studies of chemokines in the circulation in relation to the presence and development of allergic diseases remain scarce. Our aim was to investigate associations of circulating allergy-related chemokines with development of asthma and sensitisation cross-sectionally and longitudinally in a population-based cohort. Methods: The chemokines CCL17, CCL22, CXCL10, CXCL11 and CCL18 were measured in plasma samples from children in the Manchester Asthma and Allergy Study. Samples were available from cord blood at birth (n=376), age 1 (n=195) and 8 years (n=334). Cross-sectional and longitudinal association analyses were performed in relation to asthma and allergic sensitisation, as well as allergic phenotype clusters previously derived using machine learning in the same study population. Results: In children with asthma and/or allergic sensitisation, CCL18 levels were consistently elevated at ages 1 and/or 8 years. In a longitudinal model including information on asthma from 4 time-points (ages 5, 8, 11 and 16 years), we observed a significant association between increasing CCL18 levels at age 1 and a higher risk of asthma from early school age to adolescence (OR=2.9, 95% CI 1.1-7.6, p=0.028). We observed similar associations in longitudinal models for allergic sensitisation. Asthma later in life was preceded by increased CXCL10 levels after birth, and decreased CXCL11 levels at birth. Conclusion: Elevated CCL18 levels throughout childhood precede the development of asthma and allergic sensitisation. The Th1-associated chemokines CXCL10 and CXCL11 also associated with development of both outcomes, with differential temporal effects.

Kaposi sarcoma (KS) is an angioproliferative disorder. While KS of the head and neck is common in HIV-positives, it’s rare in HIV-negatives. Our case and the past 24 reported cases of ear KS reviewed here, highlight the importance of considering KS in the differential diagnosis of ear lesions in HIV-negatives.