Cumulative Activity Research Articles

Influence of NaCl and pH on lysostaphin catalytic activity, cell binding, and bacteriolytic activity.

Peptidoglycan-degrading enzymes are a group of proteins intensively studied as novel antibacterials, with some of them having reached pre-clinical and clinical stages of research. Many peptidoglycan-degrading enzymes have modular organization and consist of a catalytic and a cell wall binding domain. This property has been exploited in enzyme engineering efforts, and many new peptidoglycan-degrading enzymes were generated through domain exchange. However, rational combination of domains from different enzymes is still challenging since relative contribution of every domain to the cumulative bacteriolytic activity is not yet clearly understood. In this work, we investigated the influence of ionic strength and pH on the catalytic efficiency and cell binding of peptidoglycan-degrading enzyme lysostaphin and how this influence is reflected in the lysostaphin bacteriolytic activity. Contrary to generally accepted view, lysostaphin domains are not completely independent and their combination within one protein leads to increased bacteriolytic activity with increasing NaCl concentration, despite both catalysis and cell binding being inhibited by NaCl. This effect is likely mediated by changes in conformation of bacterial cell wall peptidoglycan rather than the physical inter-domain interaction. KEY POINTS: • NaCl enhances bacteriolytic activity of lysostaphin but not of its catalytic domain. • Catalytic activity and cell binding of lysostaphin are inhibited by NaCl. • Peptidoglycan conformation likely affects lysostaphin bacteriolytic activity.

Do older surgeons have safer hands? A retrospective cohort study

BackgroundFor complex surgical procedures a volume-outcome relationship can often be demonstrated implicating multiple factors at a unit and surgeon specific level. This study aims to investigate this phenomenon in lung transplantation over a 30-year period with particular reference to surgeon age and experience, cumulative unit activity and time/day of transplant.MethodsProspective databases identified adult patients undergoing isolated lung transplantation at a single UK centre between June 1987 and October 2017. Mortality data was acquired from NHS Spine. Individual surgeon demographics were obtained from the General Medical Council. Student t-test, Pearson’s Chi-squared, Logistic Regression, and Kaplan–Meier Survival analyses were performed using Analyse-it package for MicrosoftExcel and STATA/IC.Results954 transplants (55.9% male, age 44.4 ± 13.8 years, 67.9% bilateral lung) were performed, with a median survival to follow-up of 4.37 years. There was no difference in survival by recipient gender (p = 0.661), between individual surgeons (p = 0.224), or between weekday/weekend procedures (p = 0.327).Increasing centre experience with lung transplantation (OR1.001, 95%CI: 1.000–1.001, p = 0.03) and successive calendar years (OR1.028, 95%CI: 1.005–1.052, p = 0.017) was associated with improved 5-year survival.Advancing surgeon age at the time of transplant (mean, 48.8 ± 6.6 years) was associated with improved 30-day survival (OR1.062, 95%CI: 1.019 to1.106, p = 0.003), which persisted 5 years post-transplant (OR1.043, 95%CI: 1.014–1.073, p = 0.003).Individual surgeon experience, measured by the number of previous lung transplants performed, showed a trend towards improved outcomes at 30 days (p = 0.0413) with no difference in 5-year survival (p = 0.192).ConclusionsOur study demonstrates a relationship between unit volume, increasing surgeon age and survival after lung transplantation. A transplant volume: outcome relationship was not seen for individual surgeons.

ACL Research Retreat IX Summary Statement: The Pediatric Athlete, March 17-19, 2022; High Point, North Carolina.

ACL Research Retreat IX Summary Statement: The Pediatric Athlete, March 17-19, 2022; High Point, North Carolina.

Collinsella is associated with cumulative inflammatory burden in an established rheumatoid arthritis cohort

ObjectiveTo analyze the gut microbiota of patients with rheumatoid arthritis (RA) according to disease activity. MethodsAn observational cross-sectional study of 110 patients with RA and 110 age- and sex-matched controls was performed. Patients were classified according to the disease activity (DAS28 ≥3.2 or DAS28 <3.2). Clinical and epidemiological variables were included. The gut microbiota was analyzed using 16S rRNA sequencing and bioinformatics analysis based on QIIME and PICRUSt. A multivariate analysis was performed to identify factors associated with inflammatory activity. ResultsThe mean DAS28 indicated remission/low inflammatory activity in 71 patients (64.5 %) and moderate/high activity in 39 (35.5 %) during follow-up. Alpha and beta diversity analysis revealed differences in gut microbiota between the 3 study groups. In the moderate/high activity RA, we observed a significant change in the abundance of genera compared with the other groups. The abundance of Collinsella and Bifidobacterium was increased in RA patients compared with controls. The metabolic profile of gut microbiota was characterized by differences in pathways related to Biosynthesis, Generation of Precursor Metabolites/Energy, and Degradation/Utilization/Assimilation between the 3 groups. The factors associated with cumulative inflammatory activity in RA were age (OR [95 % CI], 1.065 [1.002–1.131]), obesity (OR [95% CI], 3.829 [1.064–8.785]), HAQ score (OR [95% CI], 2.729 [1.240–5.009]), and expansion of the genus Collinsella (OR [95% CI], 3.000 [1.754–9.940]). ConclusionsThe composition of gut microbiota differed between patients with RA and moderate/high activity, patients with remission/low activity, and controls. The genus Collinsella, age, obesity, and physical function were associated with cumulative inflammatory burden in RA.

Autoimmune Thyroid Disease in Primary Sjögren's Syndrome: Real-life Screening Practice and Clinical Outcomes.

Notwithstanding the frequent coexistence of autoimmune thyroid disease (ATD) and primary Sjögren's Syndrome (SS), it is still unknown how often this association is studied along with its clinical impact. This study aimed to describe real-world screening practices for ATD in patients with SS and evaluate clinical outcomes of patients with both diagnoses using validated activity and chronicity indexes. It is a retrospective study of 223 patients with SS attending a tertiary referral center. Patients were under rheumatology surveillance and might have attended other clinics, including internal medicine and/or endocrinology. We registered glandular and extraglandular features, serology and scored the activity (ESSDAI) and the accrual damage (SSDDI) indexes. We also identified any thyroid function tests (TFT) performed, anti-thyroid antibodies, images, and histological thyroid examinations. A single endocrinologist reviewed all data. One hundred forty-nine patients had at least one set of TFT. Younger age was associated with a lack of screening (OR 0.98, 95 % CI 0.95-0.99, p=0.01). Sixty-nine patients had thyroid disease, with the most common diagnosis being ATD (n=24). Patients with ATD had a lower prevalence of Ro/SSA and anti-La/SSB antibodies but similar cumulative SS activity and damage scores. At least one-third of our patients were not screened for thyroid disease, with these patients being the youngest. Thyroid disorders were found in about 40 % of patients with SS, with ATD being the most common. Having SS/ATD did not confer more disease activity or damage accrual. These results highlight the importance of making treating physicians aware of screening for thyroid disease in this population.

Dosimetry assessment of theranostic Auger-emitting radionuclides in a micron-sized multicellular cluster model: A Monte Carlo study using Geant4-DNA simulations

The present work is aimed at improving the multicellular dosimetry of several Auger radionuclides of interest for targeted cancer therapy, including 99mTc, 111In, 123I, 125I, and 201Tl. For this purpose, using the Geant4-DNA Monte Carlo code, a cluster of 13 similar spherical cells with a hexagonal packed arrangement was modeled, and the mean absorbed doses per unit cumulated activity (S-values) were calculated by considering two target←source configurations, cell←cell and nucleus←nucleus. The obtained ratios of cross-dose to self-dose S-value in terms of the distance between the source and target regions were evaluated and also compared to those estimated by the Medical Internal Radiation Dose (MIRD) method. Besides, the contribution of the Coster-Kronig, Auger and internal conversion electrons to the S-values was provided for each radionuclide. According to the results, it can be concluded that in contrast to self-absorption, the cross-absorption due to the Auger-emitters has not a significant role in the total energy deposition within a cell in the cluster.

Effects of high-activity radioactive iodine treatment on renal function in patients with differentiated thyroid carcinoma - retrospective study.

It is not clear whether high-activity radioactive iodine (¹³¹I) treatment will affect renal function. This study aimed to investigate the effects of high-activity ¹³¹I treatment on the clinical metrics of renal function in patients with differentiated thyroid carcinoma (DTC). 262 DTC patients with abnormal baseline renal function (group A) and 262 DTC patients with normal baseline renal function (group B) who received 131I therapy were analysed. Each group was further divided into three subgroups based on the cumulative activity of 131I: subgroup 1 if the cumulative activity was less than 11.1 GBq; subgroup 2 if the cumulative activity was between 11.1 GBq and 18.5 GBq; and subgroup 3 if the cumulative activity was more than 18.5 GBq. The clinical metrics of renal function including serum creatinine (SCr), blood urea nitrogen (BUN) and estimated glomerular filtration rate (eGFR) were measured and compared before initial 131I treatment and 5 years later. There was no significant difference of the demographics between the two groups. In group A, SCr and BUN levels were elevated in 186 and 113 patients, respectively, and eGFR was decreased in 108 patients before the initial ¹³¹I therapy. SCr and BUN levels were found to be increased in all subgroups 5 years after the initial ¹³¹I therapy; furthermore, eGFR was found to be decreased in all subgroups after ¹³¹I therapy, and the difference was statistically significant (p < 0.05). A gender bias was not observed in the changing trends of SCr and BUN levels and eGFR. In group B, no significant difference in the mean levels of SCr, BUN, and eGFR was observed in the 3 subgroups (p > 0.05), regardless of gender, before the initial ¹³¹I therapy and 5 years later. A total of 5, 2, and 2 patients presented with abnormal renal function after ¹³¹I treatment in subgroups 1, 2, and 3, respectively. No statistically significant difference was observed in the incidence of renal dysfunction among the 3 subgroups (p = 0.423). Our findings suggest that the nephrotoxicity of high-activity ¹³¹I therapy, regardless of gender, is very low in patients with DTC with normal renal function; however, high-activity ¹³¹I therapy may exacerbate the loss of renal function in those with renal dysfunction.

Long-Term Outcomes of Submaximal Activities of Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in Neuroendocrine Tumor Patients.

In the literature, up to 45% of neuroendocrine tumor (NET) patients who are treated with 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) do not receive the intended cumulative activity of 29.6 GBq (800 mCi). The aim of this study was to analyze the efficacy of submaximal activities of PRRT in patients who discontinued treatment for non-disease-related reasons. Methods: We retrospectively included patients with well-differentiated and advanced NETs who underwent PRRT from 2000 until 2019 and did not receive 29.6 GBq of 177Lu-DOTATATE. For comparison, we selected control NET patients who received the intended cumulative activity of 29.6 GBq of 177Lu-DOTATATE between 2000 and 2012. Primary outcomes were progression-free survival (PFS) and tumor response, and the secondary outcome was overall survival (OS). Results: In total, 243 patients received 3.7-27.8 GBq. In 130 patients, the submaximal activity was unrelated to disease (e.g., bone marrow and renal toxicity in 48% and maximal renal absorbed dose in 23%), and they were included. Patients receiving a reduced activity had more bone metastases, a lower body mass index and albumin level, a higher alkaline phosphatase level, and fewer grade 1 tumors than the 350 patients included in the control group. The disease control rate in the reduced-activity group was 85%, compared with 93% for the control group (P = 0.011). The median PFS (95% CI) was 23 mo (range, 21-26 mo) for the reduced-activity group and 31 mo (range, 27-35 mo) for the control group (P = 0.001), and the median OS (95% CI) was 34 mo (range, 28-40 mo) and 60 mo (range, 53-67 mo), respectively (P < 0.0001). With adjustment for relevant confounders in the multivariable Cox regression analyses, cumulative activity was an independent predictor of both PFS and OS. Conclusion: In NET patients treated with a cumulative activity of less than 29.6 GBq of 177Lu-DOTATATE, PRRT was less efficacious in tumor response and survival than in patients who received 29.6 GBq.

Breast cancer survivors’ physical activity and experiences while transitioning to a virtual cardiovascular rehabilitation program during a pandemic (COVID-19)

Breast cancer accounts for 25% of all cancers among Canadian females. Despite successes of decreased mortality, adverse treatment effects, such as cardiotoxicity, contribute to a sedentary lifestyle and decreased quality of life. Physical activity (PA) is a possible therapy for the late effects; however, COVID-19 restricted access to in-person cardiovascular rehabilitation (CR) programs. The purposes are as follows: (1) compare PA of breast cancer survivors’ in-person CR to virtual CR following a transition during COVID-19 and (2) compare the PA of the pandemic cohort to a matched cohort who had completed the program in 2018/2019; (3) explore survivors’ experiences of transitioning to and engaging in virtual CR. Mixed methods included analysis of CR PA data from a pandemic cohort (n = 18) and a 2018/2019 cohort (n = 18) and semi-structured focus group interviews with the pandemic cohort (n = 9) in the context of the PRECEDE-PROCEED model. After the transition, there were no significant differences in mean activity duration, frequency, and cumulative activity (expressed as MET-minutes) (p > 0.05). However, variation of PA duration doubled following the transition from in-person to virtual (p = 0.029), while for the 2018/2019 cohort, variation remained unchanged. Focus groups revealed that women valued their CR experiences pre-COVID-19 and had feelings of anxiety during the transition. Perceived factors affecting participation were environmental, personal, and behavioural. Recommendations for virtual programs were to increase comradery, technology, and professional guidance. PA experiences during a transition to virtual care prompted by a pandemic vary among breast cancer survivors. Targeting individualised strategies and exercise prescriptions are important for improving PA programs and patient outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00520-022-07142-y.

Prognostic value of dysnatremia for survival in neuroendocrine neoplasm patients.

Hyponatremia and hypernatremia are common electrolyte abnormalities in patients with malignancy and have been independently associated with worse survival outcomes. To date, there are no data on the impact of dysnatremia on survival outcomes in patients with neuroendocrine neoplasms (NENs). This study involves retrospective cohort analysis from a tertiary care center of NEN patients treated with peptide receptor radionuclide therapy (PRRT) with a cumulative activity of at least 3.7 GBq 177Lu-DOTATATE between the years 2000 and 2015. Comparison of overall survival of patients with the occurrence of hyponatremia (serum sodium < 135 mmol/L) or hypernatremia (serum sodium > 145 mmol/L) before starting or during PRRT was perfomed. A total of 649 patients were included. Hyponatremia occurred in 57 patients during the observation period and was associated with a shorter median overall survival (95% CI) of 25 months (14-36) compared to 55 months (48-61) of the 512 normonatremic patients (P < 0.001), adjusted hazard ratio (HR): 1.48 (95% CI: 1.04-2.12). Overall survival time was reduced regardless of whether hyponatremia was present at baseline or during PRRT. In contrast, hypernatremia occurred in 80 patients and was associated with a longer median overall survival (95% CI) of 94 months (47-140) compared with the 512 normonatremic patients (P = 0.018), adjusted HR: 0.61 (95% CI: 0.40-0.92). This association was driven by the patients with hypernatremia during PRRT. No association between dysnatremia and progression-free survival after PRRT was observed. The occurrence of hypo- or hypernatremia in PRRT-treated NET patients is associated with opposing outcomes with regard to overall survival. Sodium levels might have a prognostic role in these patients.

Validation of Monte Carlo 131 I radiopharmaceutical dosimetry workflow using a 3D-printed anthropomorphic head and neck phantom.

PurposeApproximately 50% of head and neck cancer (HNC) patients will experience loco‐regional disease recurrence following initial courses of therapy. Retreatment with external beam radiotherapy (EBRT) is technically challenging and may be associated with a significant risk of irreversible damage to normal tissues. Radiopharmaceutical therapy (RPT) is a potential method to treat recurrent HNC in conjunction with EBRT. Phantoms are used to calibrate and add quantification to nuclear medicine images, and anthropomorphic phantoms can account for both the geometrical and material composition of the head and neck. In this study, we present the creation of an anthropomorphic, head and neck, nuclear medicine phantom, and its characterization for the validation of a Monte Carlo, SPECT image‐based, 131I RPT dosimetry workflow.Methods3D‐printing techniques were used to create the anthropomorphic phantom from a patient CT dataset. Three 131I SPECT/CT imaging studies were performed using a homogeneous, Jaszczak, and an anthropomorphic phantom to quantify the SPECT images using a GE Optima NM/CT 640 with a high energy general purpose collimator. The impact of collimator detector response (CDR) modeling and volume‐based partial volume corrections (PVCs) upon the absorbed dose was calculated using an image‐based, Geant4 Monte Carlo RPT dosimetry workflow and compared against a ground truth scenario. Finally, uncertainties were quantified in accordance with recent EANM guidelines.ResultsThe 3D‐printed anthropomorphic phantom was an accurate re‐creation of patient anatomy including bone. The extrapolated Jaszczak recovery coefficients were greater than that of the 3D‐printed insert (∼22.8 ml) for both the CDR and non‐CDR cases (with CDR: 0.536 vs. 0.493, non‐CDR: 0.445 vs. 0.426, respectively). Utilizing Jaszczak phantom PVCs, the absorbed dose was underpredicted by 0.7% and 4.9% without and with CDR, respectively. Utilizing anthropomorphic phantom recovery coefficient overpredicted the absorbed dose by 3% both with and without CDR. All dosimetry scenarios that incorporated PVC were within the calculated uncertainty of the activity. The uncertainties in the cumulative activity ranged from 23.6% to 106.4% for Jaszczak spheres ranging in volume from 0.5 to 16 ml.ConclusionThe accuracy of Monte Carlo‐based dosimetry for 131I RPT in HNC was validated with an anthropomorphic phantom. In this study, it was found that Jaszczak‐based PVCs were sufficient. Future applications of the phantom could involve 3D printing and characterizing patient‐specific volumes for more personalized RPT dosimetry estimates.

Source Characteristics and Along‐Strike Variations of Shallow Very Low Frequency Earthquake Swarms on the Nankai Trough Shallow Plate Boundary

AbstractWe detected shallow very low frequency earthquakes (VLFEs) off the Cape Muroto and Kii Channel in the Nankai subduction zone and estimated their moment rate functions. Combining the new and previously estimated catalogs, we obtained the comprehensive catalog of shallow VLFE moment rate functions along the Nankai Trough. We defined the shallow VLFE swarms and investigated the scaling relationships of their cumulative moments, activity area, and durations in each region. Detected swarms were considered candidates for shallow slow slip events. A similar scaling relationship was observed between the cumulative moments and activity areas, irrespective of regions. It indicates similar stress drops in each region. However, the relationship between the cumulative moments and durations varied. This difference was explained by the along‐strike variations in the faulting conditions of shallow slow earthquakes, such as material or hydrological properties.

Estimation of Cumulative Activity of 177Lu-Cetuximab from a Single Diagnostic 64Cu-Cetuximab Scan.

Background: This study aimed at investigating whether a single diagnostic 64Cu-cetuximab scan might predict therapeutic 177Lu-cetuximab cumulative activity in a preclinical study. Methods: The framework of the reversible Patlak-Blasberg analysis was used to derive two independent equations of 177Lu-cetuximab cumulative activity that involve the tumor-to-blood standard uptake value ratio (i.e., the SUR) assessed at peak-time of either decay-uncorrected or decay-corrected activity concentration of trapped 64Cu-cetuximab, respectively. Applied to published data in TE-8 tumor-bearing mice, the two peak times and corresponding SUR values were assessed. Two estimates of 177Lu-cetuximab cumulative activity were then computed for comparison with two previously published values obtained from different methods. Results: The two estimates of 177Lu-cetuximab cumulative activity, computed at 14 and 59 h postinjection, were consistent with the previously published values: 4.7 × 1012 and 5.5 × 1012 versus 4.1 × 1012 and 5.3 × 1012 disintegrations/g. Conclusion: Two independent equations are proposed for estimating 177Lu-cetuximab cumulative activity from an initial diagnostic 64Cu-cetuximab scan, when acquired at two relevant injection acquisition times, respectively. Applied to published tumor-bearing mouse data, the 64Cu-cetuximab SUR assessed at either 14 or 59 h postinjection turns out to be key metrics.

Longitudinal Associations Between Cumulative Physical Activity and Change in Structure and Function of the Left Side of the Heart: The Tromsø Study 2007-2016.

BackgroundCurrent knowledge about the relationship between physical activity (PA) and cardiac remodeling is mainly derived from cross-sectional studies of athletes, and there is a knowledge gap of this association in the general adult and elderly population. Therefore, we aimed to explore the longitudinal association between cumulative PA and change in cardiac structure and function in a general adult and elderly population.MethodsThis longitudinal study includes 594 participants from the sixth (Tromsø6, 2007–08) and seventh (Tromsø7, 2015–16) survey of the Tromsø Study. Cardiac structure and function were assessed by echocardiography at two time points, and PA was self-reported by questionnaire at both time points. PA volume was expressed as cumulative PA (Low, Moderate, and Hard) and the association with left atrial (LA) and left ventricular (LV) structure and function was assessed using ANCOVA.ResultsOverall, LA diameter index (LADi) increased significantly more in Hard compared to Moderate PA (+0.08 cm/m2, 95% CI 0.01–0.15, p = 0.020) from Tromsø6 to Tromsø7. When stratified by sex or age, higher levels of cumulative PA were associated with increased LADi in males and in participants <65 years only. Indexed LV mass (LVMi) increased significantly more in Moderate than in Low PA (+3.9 g/m2.7, 95% CI 0.23–7.57, p = 0.037). When stratified by sex or age, these changes in LVMi and indexed LV diameter (LVDi) were only significant in females. No significant associations were observed between cumulative PA and change in relative wall thickness, E/e' ratio, e' velocity, LV ejection fraction, and LADi/LVDi ratio.ConclusionHigher levels of cumulative PA were associated with increased LADi in males and participants <65 years, and with increased LVMi and LVDi in females. Despite cardiac chamber enlargement, the pump function of the heart did not change with higher levels of PA, and the atrioventricular ratio was unchanged. Our results indicate that cardiac chamber enlargement is a physiological response to PA.

Differentiating Online Posting Behaviors of Violent and Nonviolent Right-Wing Extremists

There is an ongoing need for researchers, practitioners, and policymakers to detect and assess online posting behaviors of violent extremists prior to their engagement in violence offline, but little is empirically known about their online behaviors generally or the differences in their behaviors compared with nonviolent extremists who share similar ideological beliefs particularly. In this study, we drew from a unique sample of violent and nonviolent right-wing extremists to compare their posting behaviors in the largest White supremacy web-forum. We used logistic regression and sensitivity analysis to explore how users’ time of entry into the lifespan of an extremist sub-forum and their cumulative posting activity predicted their violence status. We found a number of significant differences in the posting behaviors of violent and nonviolent extremists which may inform future risk factor frameworks used by law enforcement and intelligence agencies to identify credible threats online.

Antimicrobial activity of serum of cystic fibrosis patients before and after lung transplantation

Cystic fibrosis (CF) is a systemic congenital disease characterized by chronic bronchopulmonary infection of bacterial and fungal origins. Numerous antimicrobial peptides (AMP) play a special role in humoral immunity in CF patients. Each AMP was characterized in detail earlier. A new method has been developed recently in the Russian Federation for estimation of the cumulative antimicrobial activity of all AMPs in different bioliquids.The aim of the study was the application of this method for the estimation of antimicrobial activity of whole sera and the AMP-containing low molecular serum fractions in patients with CF before and after lung transplantation.Methods. Sera from 11 CF patients of 24 – 33 years old obtained before and after lung transplantation were used in the study. Antimicrobial activities of the whole serum and its fractions with the molecular mass under 100 kDa were estimated by the effect of the specimens on Candida albicans test culture cells and by spectrophotometric assay of dye, which was internalized by the killed cells, as compared to the control untreated cells.Results. The total serum activity and AMP fractions activity in patients with CF were lower than in the healthy volunteers (medians): 82.3% vs 87.8 % (p ≤ 0.01) and 17.2% vs 41.9% (p ≤ 0.01). After the lung transplantation, both activities increased to 84.5% vs 33.3%, respectively. The improvement of AMP fractions activity was observed during 12 months after the transplantation. Serum albumin levels were lower in CF patients as compared to the reference values but normalized after lung transplantation.Conclusion. Obviously, the activity of the serum components of humoral immunity, which are responsible for direct antimicrobial defense, is decreased in CF patients compared to the reference values. The lung transplantation increased their activity considerably.

Threshold limit values of the antiviral drug interferon inducer amixin in the air of the working area and in the atmospheric air of urban and rural settlements

Introduction. Amiksin (tiloron) is a low molecular weight inducer of interferon, antiviral and immunomodulatory agent, used for the treatment and prevention of viral diseases, shown the effectiveness of including amixin in the complex therapy of SARS-CoV-2 infection (COVID-19) mild and moderate severity. Materials and methods. Experimental studies to determine the parameters of amixin toxicometry were carried out using mice, rats, rabbits and guinea pigs. The substance was administered into the stomach, intraperitoneally, into the conjunctival sac of the eye, on the skin, intradermal and inhalation. Results. It is shown that amixin belongs to the 3rd hazard class (moderately hazardous substances) when injected into the stomach according to GOST 12.1.007-76: DL50 for male mice - 500 mg/kg, for female mice - 760 mg/kg; low toxicity when injected into the abdominal cavity, DL50 for male mice - 150 mg/kg. Amiksin has a weak irritant effect on the mucous membranes of the eyes, does not irritate the skin, has a skin-resorptive effect and functional cumulative activity. The threshold for acute inhalation exposure to amixin is set at 16,2 mg/m3 according to the effect on the functional state of the liver and kidneys. Limitations. When developing and substantiating the hygienic standards for amixin in the air, various ways of the substance entering the body of several animal species in representative groups were studied. Conclusion. For amixin aerosol, hygienic standards have been approved - 0,4 mg/m3 in the air of the working area and 0,01 mg/m3 in the atmospheric air.

Capital Market Reaction to The Tax Amnesty Policy (Study on Banking Sector Share in Indonesia)

An event or a policy taken by the government can be one of the considerations for investors in making investment decisions in a country. The existence of these events certainly contains information that can be interpreted to carry out transactions in the capital market. The tax amnesty policy is assumed to contain information that is able to respond to capital market players. The reaction of capital market participants can be measured by abnormal returns and trading volume activity. Therefore, it is necessary to conduct research on the reaction of the capital market to the tax amnesty policy in Indonesia on shares in the banking sector because banks are the gateway for the entry of tax amnesty funds. There are 14 bank shares included in the study that fall into the criteria of government perception banks and have IPOs. This study uses the event study analysis method with an observation period of 11 days, namely t-5 to t+5 and t0 as event dates in all tax amnesty policy periods, period I (1 July 2016), period II (1 October 2016), period III (1 January 2017). The research analysis technique used a paired sample t test. The results of the study indicate that there is a reaction in banking stocks to the tax amnesty policy which can be seen from the significant positive difference between the cumulative average abnormal return before and after the tax amnesty policy period I and II, as well as the difference in cumulative average trading volume activity between before and after the tax amnesty policy period I, II, and III. The results of the study conclude that the tax amnesty policy has succeeded in increasing trading activities and providing abnormal returns to investors for two periods on banking stocks so that this issue provides meaningful information and is good news for investors.

Exercise And The Development Of Transthyretin Amyloid Cardiomyopathy - Is There An Association?

Introduction Cardiac amyloidosis is an infiltrative heart disease that is associated with multi-organ dysfunction as a result of systemic misfolded protein deposition. Transthyretin (ATTR) amyloidosis is a type of amyloidosis that is increasingly being recognized as a cause of heart failure. Novel pharmacologic treatments for ATTR amyloid cardiomyopathy (ATTR-CM) have recently become available sparking a renewed interest in the pathophysiology of this disease. Other than certain genetic mutations, risk factors for the development of ATTR-CM are largely unknown. In the experience of our heart failure clinic, we have empirically observed that ATTR-CM patients frequently have a substantial history of vigorous athletic activity. We sought to identify a novel association between exercise and ATTR-CM. Hypothesis Cumulative lifetime strenuous physical activity is a novel risk factor for the development of ATTR-CM. Methods In this single-center observational study, we recruited adults diagnosed with ATTR-CM and control subjects diagnosed with heart failure from non-amyloid cause. 50 ATTR-CM subjects and 22 controls were administered an in-depth lifetime physical activity survey. The survey identified type and quantity of physical activity from age 20 years until present day. Cumulative lifetime strenuous physical activity was quantified in metabolic equivalents of task (MET-minutes) of strenuous physical activity per active decade. Clinical and biochemical data were obtained retrospectively from the time of initial heart failure diagnosis. Results Wild-type ATTR amyloidosis was present in 82% (N=41) of ATTR-CM subjects, and 18% (N=9) of ATTR-CM subjects had genotype-confirmed hereditary ATTR amyloidosis. Both the ATTR-CM group and control group were male predominant (94% [N=47] vs 90.9% [N=20], p=0.63). ATTR-CM subjects were older at the time of diagnosis than controls (75.7 ±8.8 years vs. 63.6 ±9.4 years, p<0.0001). Left ventricular ejection fraction at the time of diagnosis was higher in ATTR-CM subjects than controls (49 ±14% vs. 32 ±15%, p<0.0001). Cumulative lifetime strenuous physical activity was higher in the ATTR-CM subjects than controls (1.44 × 106 MET-minutes per active decade vs. 0.751 × 106 MET-minutes per active decade, p=0.04). Conclusions Findings from this study suggest that increased cumulative lifetime strenuous physical activity per active decade is associated with ATTR-CM compared to other types of CM. Though larger prospective studies are needed to confirm this association, identifying strenuous exercise as a novel risk factor for ATTR-CM may offer new insight into the pathophysiology of this disease. Cardiac amyloidosis is an infiltrative heart disease that is associated with multi-organ dysfunction as a result of systemic misfolded protein deposition. Transthyretin (ATTR) amyloidosis is a type of amyloidosis that is increasingly being recognized as a cause of heart failure. Novel pharmacologic treatments for ATTR amyloid cardiomyopathy (ATTR-CM) have recently become available sparking a renewed interest in the pathophysiology of this disease. Other than certain genetic mutations, risk factors for the development of ATTR-CM are largely unknown. In the experience of our heart failure clinic, we have empirically observed that ATTR-CM patients frequently have a substantial history of vigorous athletic activity. We sought to identify a novel association between exercise and ATTR-CM. Cumulative lifetime strenuous physical activity is a novel risk factor for the development of ATTR-CM. In this single-center observational study, we recruited adults diagnosed with ATTR-CM and control subjects diagnosed with heart failure from non-amyloid cause. 50 ATTR-CM subjects and 22 controls were administered an in-depth lifetime physical activity survey. The survey identified type and quantity of physical activity from age 20 years until present day. Cumulative lifetime strenuous physical activity was quantified in metabolic equivalents of task (MET-minutes) of strenuous physical activity per active decade. Clinical and biochemical data were obtained retrospectively from the time of initial heart failure diagnosis. Wild-type ATTR amyloidosis was present in 82% (N=41) of ATTR-CM subjects, and 18% (N=9) of ATTR-CM subjects had genotype-confirmed hereditary ATTR amyloidosis. Both the ATTR-CM group and control group were male predominant (94% [N=47] vs 90.9% [N=20], p=0.63). ATTR-CM subjects were older at the time of diagnosis than controls (75.7 ±8.8 years vs. 63.6 ±9.4 years, p<0.0001). Left ventricular ejection fraction at the time of diagnosis was higher in ATTR-CM subjects than controls (49 ±14% vs. 32 ±15%, p<0.0001). Cumulative lifetime strenuous physical activity was higher in the ATTR-CM subjects than controls (1.44 × 106 MET-minutes per active decade vs. 0.751 × 106 MET-minutes per active decade, p=0.04). Findings from this study suggest that increased cumulative lifetime strenuous physical activity per active decade is associated with ATTR-CM compared to other types of CM. Though larger prospective studies are needed to confirm this association, identifying strenuous exercise as a novel risk factor for ATTR-CM may offer new insight into the pathophysiology of this disease.

Precision dosimetry in yttrium-90 radioembolization through CT imaging of radiopaque microspheres in a rabbit liver model

PurposeTo perform precision dosimetry in yttrium-90 radioembolization through CT imaging of radiopaque microspheres in a rabbit liver model and to compare extracted dose metrics to those produced from conventional PET-based dosimetry.Materials and methodsA CT calibration phantom was designed containing posts with nominal microsphere concentrations of 0.5 mg/mL, 5.0 mg/mL, and 25.0 mg/mL. The mean Hounsfield unit was extracted from the post volumes to generate a calibration curve to relate Hounsfield units to microsphere concentration. A nominal bolus of 40 mg of microspheres was administered to the livers of eight rabbits, followed by PET/CT imaging. A CT-based activity distribution was calculated through the application of the calibration curve to the CT liver volume. Post-treatment dosimetry was performed through the convolution of yttrium-90 dose-voxel kernels and the PET- and CT-based cumulated activity distributions. The mean dose to the liver in PET- and CT-based dose distributions was compared through linear regression, ANOVA, and Bland–Altman analysis.ResultsA linear least-squares fit to the average Hounsfield unit and microsphere concentration data from the calibration phantom confirmed a strong correlation (r2 > 0.999) with a slope of 14.13 HU/mg/mL. A poor correlation was found between the mean dose derived from CT and PET (r2 = 0.374), while the ANOVA analysis revealed statistically significant differences (p < 10−12) between the MIRD-derived mean dose and the PET- and CT-derived mean dose. Bland–Altman analysis predicted an offset of 15.0 Gy between the mean dose in CT and PET. The dose within the liver was shown to be more heterogeneous in CT than in PET with an average coefficient of variation equal to 1.99 and 1.02, respectively.ConclusionThe benefits of a CT-based approach to post-treatment dosimetry in yttrium-90 radioembolization include improved visualization of the dose distribution, reduced partial volume effects, a better representation of dose heterogeneity, and the mitigation of respiratory motion effects. Post-treatment CT imaging of radiopaque microspheres in yttrium-90 radioembolization provides the means to perform precision dosimetry and extract accurate dose metrics used to refine the understanding of the dose–response relationship, which could ultimately improve future patient outcomes.