Geographical variation in case fatality rate and doubling time during the COVID-19 pandemic.

Case fatality rate (CFR) and doubling time are important characteristics of any epidemic. For coronavirus disease 2019 (COVID-19), wide variations in the CFR and doubling time have been noted among various countries. Early in the epidemic, CFR calculations involving all patients as denominator do not account for the hospitalised patients who are ill and will die in the future. Hence, we calculated cumulative CFR (cCFR) using only patients whose final clinical outcomes were known at a certain time point. We also estimated the daily average doubling time. Calculating CFR using this method leads to temporal stability in the fatality rates, the cCFR stabilises at different values for different countries. The possible reasons for this are an improved outcome rate by the end of the epidemic and a wider testing strategy. The United States, France, Turkey and China had high cCFR at the start due to low outcome rate. By 22 April, Germany, China and South Korea had a low cCFR. China and South Korea controlled the epidemic and achieved high doubling times. The doubling time in Russia did not cross 10 days during the study period.

Task experience influences coordinative structures and performance variables in learning a slalom ski-simulator task.

The experiment investigated the progressions of the qualitative and quantitative changes in the movement dynamics of learning the ski-simulator as a function of prior-related task experience. The focus was the differential timescales of change in the candidate collective variable, neuromuscular synergies, joint motions, and task outcome as a function of learning over 7 days of practice. Half of the novice participants revealed in day 1 a transition of in-phase to anti-phase coupling of center of mass (CoM)-platform motion whereas the remaining novices and experienced group all produced on the first trial an anti-phase CoM-platform coupling. The experienced group also had initially greater amplitude and velocity of platform motion-a performance advantage over the novice group that was reduced but not eliminated with 7 days of practice. The novice participants who had an in-phase CoM-platform coupling on the initial trials of day 1 also showed the most restricted platform motion in those trials. Prior-related practice experience differentially influenced the learning of the task as evidenced by both the qualitative organization and the quantitative motion properties of the individual degrees of freedom (dof) to meet the task demands. The findings provide further evidence to the proposition that CoM-platform coupling is a candidate collective variable in the ski-simulator task that provides organization and boundary conditions to the motions of the individual joint dof and their couplings.

In-situ electrochemical Fe(VI) for removal of microcystin-LR from drinking water: comparing dosing of the ferrate ion by electrochemical and chemical means.

Harmful algal blooms (HAB) release microtoxins that contaminate drinking water supplies and risk the health of millions annually. Crystalline ferrate(VI) is a powerful oxidant capable of removing algal microtoxins. We investigate in-situ electrochemically produced ferrate from common carbon steel as an on-demand alternative to crystalline ferrate for the removal of microcystin-LR (MC-LR) and compare the removal efficacy for both electrochemical (EC) and chemical dosing methodologies. We report that a very low dose of EC-ferrate in deionized water (0.5 mg FeO42- L-1) oxidizes MC-LR (MC-LR0 = 10 µg L-1) to below the guideline limit (1.0 µg L-1) within 10 minutes' contact time. With bicarbonate or natural organic matter (NOM), doses of 2.0-5.0 mg FeO42- L-1 are required, with lower efficacy of EC-ferrate than crystalline ferrate due to loss of EC-ferrate by water oxidation. To evaluate the EC-ferrate process to concurrently oxidize micropollutants, coagulate NOM, and disinfect drinking water, we spiked NOM-containing real water with MC-LR and Escherichia coli, finding that EC-ferrate is effective at 10.0 mg FeO42- L-1 under normal operation or 2.0 mg FeO42- L-1 if the test water has initial pH optimized. We suggest in-situ EC-ferrate may be appropriate for sporadic HAB events in small water systems as a primary or back-up technology.

Second primary malignancies in multiple myeloma: an overview and IMWG consensus.

Background: Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians. Design: A Panel of International Myeloma Working Group members reviewed the most relevant data published in the literature as full papers, or presented at meetings of the American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, or International Myeloma Workshops, up to June 2016. Here, we present the recommendations of the Panel, based on this literature review. Results: Overall, the risk of SPMs in MM is low, multifactorial, and partially related to the length of patients' survival and MM intrinsic susceptibility. Studies suggest a significantly increased incidence of SPMs when lenalidomide is administered either following, or concurrently with, oral melphalan. Increased SPM incidence has also been reported with lenalidomide maintenance following high-dose melphalan, albeit to a lesser degree. In both cases, the risk of death from MM was significantly higher than the risk of death from SPMs, with lenalidomide possibly providing a survival benefit. No increase in SPM incidence was reported with lenalidomide plus dexamethasone (without melphalan), or with bortezomib plus oral melphalan, dexamethasone, or thalidomide. Conclusion: In general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options.

Investigation on the temporal variation and source tracking of faecal bacteria in a forest dominated watershed (Comox Lake), British Columbia, Canada.

AIMS: The aims of this study were to investigate the temporal variation in Escherichia coli density and its sources at the drinking water intake of Comox Lake for a period of 3 years (2011-2013). METHODS AND RESULTS: Density of E. coli was assessed by standard membrane filtration method. Source tracking of E. coli were done by using BOX-A1R-based rep-PCR DNA fingerprinting method. Over the years, the mean E. coli density ranged from nondetectable to 9·8 CFU 100 ml(-1) . The density of E. coli in each of the years did not show any significant difference (P > 0·05); however, a comparatively higher density was observed during the fall. Wildlife was (64·28%, 153/238) identified as the major contributing source of E. coli, followed by human (18·06%, 43/238) and unknown sources (17·64%, 42/238). Although the sources were varied by year and season, over all, the predominant contributing sources were black bear, human, unknown, elk, horse and gull. CONCLUSIONS: The findings of this investigation identified the multiple animal sources contributing faecal bacteria into the drinking water intake of Comox Lake and their varying temporal occurrence. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study can reliably inform the authorities about the most vulnerable period (season) of faecal bacterial loading and their potential sources in the lake for improving risk assessment and pollution mitigation.

Towards next generation digital twin in robotics: Trends, scopes, challenges, and future.

With the advent of Industry 4.0, several cutting-edge technologies such as cyber-physical systems, digital twins, IoT, robots, big data, cloud computation have emerged. However, how these technologies are interconnected or fused for collaborative and increased functionality is what elevates 4.0 to a grand scale. Among these fusions, the digital twin (DT) in robotics is relatively new but has unrivaled possibilities. In order to move forward with DT-integrated robotics research, a complete evaluation of the literature and the creation of a framework are now required. Given the importance of this research, the paper seeks to explore the trends of DT incorporated robotics in both high and low research saturated robotic domains in order to discover the gap, rising and dying trends, potential scopes, challenges, and viable solutions. Finally, considering the findings, the study proposes a framework based on a hypothesis for the future paradigm of DT incorporated robotics.

Multivariate, longitudinal analysis of the impact of changes in office work environments on surface electromyography measures.

PURPOSE: To detect impacts of changes in work environment and worker-equipment interface variables upon surface electromyography (EMG) measures using multivariate, longitudinal analysis. METHODS: For 33 office workers, yearly measurements (1999-2001) were taken during normal work. Independent variables were related to work environment (expert-observed equipment dimensions, work organization on questionnaire) and interface (expert-observed postures, self-reported workstation-equipment relative fit i.e. inside or outside guidelines-informed location, and 30 min video-based task analysis). Internal mechanical exposure (EMG) was recorded bilaterally from extensor carpi radialis brevis (ECRB) and upper trapezius sites, each side, also for 30 min. Dependent variables were amplitude probability distribution functions (APDF 50 and 90%) and gaptime for entire record EMG (over all tasks) and task-specific EMG (for four separate tasks). Multivariate mixed models used independent variables to predict EMG measures (4 muscle sites × (1 entire record + 4 task specific) = 20 models total). RESULTS: Among EMG measures, 9/16 means and 2/16 variances were significantly different across years (p < 0.1). Environment and interface variables explained part of the variation in EMG measures in 13/20 models. The most consistent predictors included: (1) increased monitor distance predicted reduced APDFs and increased gaptimes; (2) wrist extension <20° predicted decreases in left ECRB APDFs; (3) keyboard location within guidelines predicted improvements in all right ECRB EMG measures during keyboarding; and (4) longer task duration predicted higher APDFs and lower gaptimes. CONCLUSION: Longitudinal analysis with multivariate models can detect the impacts of changes in environment and interface exposures on EMG measures among office workers.

Potential public health significance of faecal contamination and multidrug-resistant Escherichia coli and Salmonella serotypes in a lake in India.

OBJECTIVE: To assess the prevalence of faecal coliform bacteria and multiple drug resistance among Escherichia coli and Salmonella serotypes from Vembanadu Lake. STUDY DESIGN: Systematic microbiological testing. METHODS: Monthly collection of water samples were made from ten stations on the southern and northern parts of a salt water regulator constructed in Vembanadu Lake in order to prevent incursion of seawater during certain periods of the year. Density of faecal colifrom bacteria was estimated. E. coli and Salmonella were isolated and their different serotypes were identified. Antibiotic resistance analysis of E. coli and Salmonella serotypes was done and the MAR index of individual isolates was calculated. RESULTS: Density of faecal coliform bacteria ranged from mean MPN value 2900 -7100/100ml. Results showed multiple drug resistance pattern among the bacterial isolates. E. coli showed more than 50% resistance to amickacin, oxytetracycline, streptomycin, tetracycline and kanamycin while Salmonella showed high resistance to oxytetracycline, streptomycin, tetracycline and ampicillin. The MAR indexing of the isolates showed that they have originated from high risk source such as humans, poultry and dairy cows. CONCLUSIONS: The high density of faecal coliform bacteria and prevalence of multi drug resistant E. coli and Salmonella serotypes in the lake may pose severe public health risk through related water borne and food borne outbreaks.

Successful immunotherapy of natural killer-resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin 2.

In previous in vitro studies, we have shown that murine splenocytes or cancer patient lymphocytes incubated in IL-2 become lytic for fresh syngeneic or autologous tumors. We have now performed the adoptive transfer of such lymphokine-activated killer (LAK) cells in a murine B16 metastasis model to test their in vivo efficacy. 1 X 10(8) LAK cells, infused intravenously into C57BL/6 mice with established B16 pulmonary metastases, led to a marked decreased in the number of lung nodules and improved survival. LAK cells administered 3 d after amputation of a tumor-bearing limb also decreased the incidence of spontaneous pulmonary metastases. LAK cells generated from tumor-bearer splenocytes had effects equivalent to those from normal animals, and this antimetastatic effect of the LAK cells did not require the prior administration of cyclophosphamide or other immunosuppressants. Fresh or unstimulated splenocytes had no effect. The antitumor effectors and precursors in vivo and in vitro were Thy-1+. The lymphokine required for the activation appeared to be interleukin 2 (IL-2), since incubation in partially purified supernatants from PMA pulsed EL-4 or Con A-pulsed splenocytes or purified Jurkat IL-2 led to the generation of LAK cells equally active in vivo. The use of IL-2-activated cells may provide a valuable method for the adoptive therapy of human neoplasms as well.

Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes.

Activation in lectin-free interleukin 2 (IL-2) containing supernatants of peripheral blood mononuclear leukocytes (PBL) from cancer patients or normal individuals resulted in expression of cytotoxicity toward 20 of 21 natural killer (NK)-resistant fresh solid tumor cells tested. Fresh solid tumor cells were resistant to NK-mediated lysis in 10 autologous patients' PBL-tumor interactions, and from 17 normal individuals tested against 13 allogeneic fresh tumors. Culture of PBL in IL-2 for 2-3 d was required for the lymphokine activated killers (LAK) to be expressed, and lytic activity toward a variety of NK-resistant fresh and cultured tumor targets developed in parallel. Autologous IL-2 was functional in LAK activation, as well as interferon-depleted IL-2 preparations. Irradiation of responder PBL before culture in IL-2 prevented LAK development. Precursors of LAK were present in PBL depleted of adherent cells and in NK-void thoracic duct lymphocytes, suggesting that the precursor is neither a monocyte nor an NK cell. LAK effectors expressed the serologically defined T cell markers of OKT.3, Leu-1, and 4F2, but did not express the monocyte/NK marker OKM-1. Lysis of autologous fresh solid tumors by LAK from cancer patients' PBL was demonstrated in 85% of the patient-fresh tumor combinations. Our data present evidence that the LAK system is a phenomenon distinct from either NK or CTL systems that probably accounts for a large number of reported nonclassical cytotoxicities. The biological role of LAK cells is not yet known, although it is suggested that these cells may be functional in immune surveillance against human solid tumors.

Lymphokine-activated killer cell phenomenon. II. Precursor phenotype is serologically distinct from peripheral T lymphocytes, memory cytotoxic thymus-derived lymphocytes, and natural killer cells.

Culture of human peripheral blood lymphocytes (PBL) in partially purified and lectin-free interleukin 2 results in the generation of cytotoxic effector cells which have the unique property of lysing natural killer (NK)-resistant fresh human tumor cells. We have termed these effector cells "lymphokine- activated killer" cells (LAK). LAK are generated from both normal and cancer patients' PBL and are able to lyse both autologous and allogeneic tumor cells from all histologic tumor types tested. Our previous studies suggested that the LAK phenomenon was distinct from either the cytotoxic thymus-derived lymphocyte (CTL) or NK systems based on a variety of criteria. This study reports that the cell type involved is also distinct, as determined by phenotypic characteristics. The LAK effector cell phenotype was analyzed in parallel with alloimmune CTL, and LAK were found to be similarly susceptible to the monoclonal anti-T cell antibodies OKT-3 or OKT-8 plus complement. In contrast the LAK precursor was not susceptible to the OKT-3 or Leu-1 antibodies plus complement, while the ability to generate alloimmune CTL was totally obliterated when tested using the same PBL responder population; in fact, generation of LAK was found to be augmented five- to sixfold, clearly suggesting that LAK precursor cells are not T lymphocytes as defined by these antibodies. LAK precursors were found to be abundant in NK cell-enriched Percoll gradient fractions, which had been depleted of the 29 degrees C E- rosetting "high affinity" T cells. However, LAK precursors were found to be distinct from the majority of NK cells since lysis of fresh PBL with the monoclonal antibodies OKM-1, Leu-7, or OKT-11 significantly depleted or totally eliminated NK activity, while subsequent activation of the remaining cells generated high levels of LAK and in some cases augmented levels of LAK. LAK precursors were found to be distributed in the thymus, bone marrow, spleen, lymph node, and thoracic duct in addition to the PBL. Therefore, while the cell(s) responsible for activation and expression of LAK activity have some common features with the classic T cell-mediated CTL and NK cell systems, the LAK precursor cells are clearly distinct as determined by phenotype analysis using monoclonal antibodies and complement, and at present must be classified as a "null" cell.

Effects of fish and plankton and lake temperature and mixing depth.

A comparative study of small temperate lakes (<20 square kilometers) indicates that the mixing depth or epilimnion is directly related to light penetration measured as Secchi depth. Clearer lakes have deeper mixing depths. This relation is the result of greater penetration of incident solar radiation in lakes and enclosures with high water clarity. Data show that light penetration is largely a function of size distribution and biomass of algae as indicated by a relation between the index of plankton size distribution (slope) and Secchi depth. Larger or steeper slopes (indicative of communities dominated by small plankton) are associated with shallower Secchi depth. In lakes with high abundances of planktivorous fish, water clarity or light penetration is reduced because large zooplankton, which feed on small algae, are reduced by fish predation. The net effect is a shallower mixing depth, lower metalimnetic temperature and lower heat content in the water column. Consequently, the biomass and size distribution of plankton can change the thermal structure and heat content of small lakes by modifying light penetration.

Comparative efficacy of five different rep-PCR methods to discriminate Escherichia coli populations in aquatic environments.

Development of efficient techniques to discriminate the sources of E. coli in aquatic environments is essential to improve the surveillance of fecal pollution indicators, to develop strategies to identify the sources of fecal contamination, and to implement appropriate management practices to minimize gastrointestinal disease transmission. In this study the robustness of five different rep-PCR methods, such as REP-PCR, ERIC-PCR, ERIC2-PCR, BOX-PCR and (GTG)(5)-PCR were evaluated to discriminate 271 E. coli strains isolated from two watersheds (Lakelse Lake and Okanagan Lake) located in British Columbia, Canada. Cluster analysis of (GTG)(5)-PCR, BOX-PCR, REP-PCR, ERIC-PCR and ERIC2-PCR profiles of 271 E. coli revealed 43 clusters, 35 clusters, 28 clusters, 23 clusters and 14 clusters, respectively. The discriminant analysis of rep-PCR genomic fingerprints of 271 E. coli isolates yielded an average rate of correct classification (watershed-specific) of 86.8%, 82.3%, 78.4%, 72.6% and 55.8% for (GTG)(5)-PCR, BOX-PCR, REP-PCR, ERIC-PCR and ERIC2-PCR, respectively. Based on the results of cluster analysis and discriminant function analysis, (GTG)(5)-PCR was found to be the most robust molecular tool for differentiation of E. coli populations in aquatic environments.

Modeling of trihalomethane (THM) formation via chlorination of the water from Dongjiang River (source water for Hong Kong's drinking water).

The Dongjiang River is the major source of drinking water supply for Hong Kong. The deterioration of the water quality of the Dongjiang River and excessive trihalomethanes (THMs) in the tap water of some districts in Hong Kong have become causes for public concern. The main objective of the present study is to investigate and model THM formation due to the chlorination of the Dongjiang River water under different chlorination conditions. The results showed that the total THM formation ranged between 11.7 and 91.8 mg L(-1) and that control of the levels was primarily due to the reaction time and the Br(-) level in the water. Bromide concentration was a key factor in determining bromine-containing THM formation and consequently the speciation of THMs. Higher concentrations of bromide shifted THM species to more-bromine-containing ones, while the kinetics reflected the competing halogenation reactions. As the two mixed-halogen THMs had high cancer potency, the cancer risk of total THMs appeared to reach a peak at a bromide concentration ranging between 218 and 262 mg L(-1) (with a bromide to dissolved organic carbon molar ratio (Br(-)/DOC) ranging between 15 and 18 mM/mM).

Purification and characterization of a novel caffeine oxidase from Alcaligenes species.

Alcaligenes species CF8 isolated from surface water of a lake produced a novel serine type metallo-caffeine oxidase. The optimal medium for caffeine oxidase production by this strain was (w/v) NaNO(3), 0.4%; KH(2)PO(4), 0.15%; Na(2)HPO(4), 0.05%; FeCl(3).6H(2)O, 0.0005%; CaCl(2).2H(2)O, 0.001%; MgSO(4).7H(2)O, 0.02%; glucose, 0.2%; caffeine, 0.05%, pH 7.5. The enzyme was purified to 63-fold by using ammonium sulfate precipitation, dialysis, ion exchange (diethylaminoethyl-cellulose) and gel filtration (Sephadex G-100) chromatographic techniques. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the purified caffeine oxidase was monomeric with a molecular mass of 65 kDa. The purified caffeine oxidase with a half-life of 20 min at 50 degrees C had maximal activity at pH 7.5 and 35 degrees C. The purified caffeine oxidase had strict substrate specificity towards caffeine (K(m) 8.94 microM and V(max) 47.62 U mg protein(-1)) and was not able to oxidize xanthine and hypoxanthine. The enzyme activity was not inhibited by para-chloromercuribenzoic acid, iodoacetamide, n-methylmaleimide, salicylic acid and sodium arsenite indicating the enzyme did not belong to xanthine oxidase family. The enzyme was not affected by Ca(+2), Mg(+2) and Na(+), but was completely inhibited by Co(+2), Cu(+2) and Mn(+2) at 1mM level. The novel caffeine oxidase isolated here from Alcaligenes species CF8 may be useful in biotechnological processes including waste treatment and biosensor development.

DNA synthesis and thymidine kinase activity of rat colon epithelial cells fractionated by discontinuous Ficoll gradient.

Epithelial cells from colons of adult Sprague-Dawley rats were fractionated on a discontinuous Ficoll gradient at low centrifugal forces (170 x g) for approximately 60 minutes. Epithelial cells were separated into three distinct zones, whereas cell debris, yeast, and bacteria remained at the top of the gradient. The percentage of cells in each zone was inversely related to the density of the gradient. More than 95% of the cells were morphologically intact and viable (excluded trypan blue). Cells sedimenting at higher densities of Ficoll exhibited higher thymidine kinase activity and DNA synthesis, suggestive of active cell division. The cells sedimenting at lower densities of Ficoll showed the least thymidine kinase activity and DNA synthesis, properties that are compatible with those of mature absorptive cells. Tall columnar cells with vesicular nuclei were predominant in the fraction sedimenting at the lowest density (top fraction). At higher densities (middle and lower fractions), most of the cells were short and columnar with basally located condensed dark-staining nuclei.

Successful therapy of natural killer-resistant pulmonary metastases by the synergism of gamma-interferon with tumor necrosis factor and interleukin-2 in mice.

The problem associated with lymphokine (gamma-interferon, interleukin-2, and tumor necrosis factor) therapy in cancer is that high toxic doses of these lymphokines must be administered for any significant antitumor results. Therefore this study was undertaken to investigate the antitumor efficacy of these lymphokines in a disseminated pulmonary metastasis when used in combination with each other at dosages well below the toxic level. The role of the immune system of the host, sequencing of lymphokines, and histopathological aspects of lymphokine therapy were also investigated.

Synergistic antitumor effects of interleukin 2 and the monoclonal Lym-1 against human Burkitt lymphoma cells in vitro and in vivo.

Interleukin 2 (IL-2) regulates immune responses by inducing proliferation and differentiation of T-cells into cytotoxic cells, inducing lymphokine activated killer activity and enhancing antibody dependent cellular cytotoxicity (ADCC). Lym-1, a monoclonal antibody, recognizes a membrane antigen present on the surface of B-lymphoma cells and can be used for ADCC. We therefore used Raji (human Burkitt lymphoma) cells to study the efficacy of combination therapy with IL-2, lymphokine activated killer activity, and Lym-1. In vitro ADCC assays using Lym-1 showed that preincubation of peripheral blood lymphocytes with IL-2 had a synergistic antitumor effect. The maximum synergism was achieved when peripheral blood lymphocytes were incubated with IL-2 for 3 days as compared to 1 or 2 days, with the optimal concentration of IL-2 being 1000 units/ml. This effect was specific for Lym-1 as demonstrated by experiments using an irrelevant (antimelanoma) monoclonal antibody or an irrelevant target cell (A375). The ADCC was blocked by an anti-Fe receptor antibody (3G8). In vivo experiments performed by growing Raji tumors in nude mice also demonstrated the increase in ADCC and the synergism between IL-2 and Lym-1 in terms of decreased tumor size and growth. The mechanism of this synergy is probably from activation of cells mediating ADCC. This raises the possibility that treatment of patients with low doses of IL-2 in combination with Lym-1 may enhance immune responses and thereby antitumor activity.