Decline Phase Research Articles

Observed Power and Frequency Variations of Solar Rossby Waves with Solar Cycles

Several recent studies utilizing different helioseismic methods have confirmed the presence of large-scale vorticity waves known as solar Rossby waves within the Sun. Rossby waves are distinct from acoustic waves, typically with longer periods and lifetimes, and their general properties, even if only measured at the surface, may be used to infer properties of the deeper convection zone, such as the turbulent viscosity and entropy gradients that are otherwise difficult to observe. In this study, we utilize 12 yr of inverted subsurface velocity fields derived from the Solar Dynamics Observatory/Helioseismic and Magnetic Imager’s time–distance and ring-diagram pipelines to investigate the properties of the solar equatorial Rossby waves. By covering the maximum and the decline phases of Solar Cycle 24, these data sets enable a systematic analysis of any potential cycle dependence of these waves. Our analysis provides evidence of a correlation between the average power of equatorial Rossby waves and the solar cycle, with stronger Rossby waves during the solar maximum and weaker waves during the minimum. Our result also shows that the frequency of the Rossby waves is lower during the magnetic active years, implying a larger retrograde drift relative to the solar rotation. Although the underlying mechanism that enhances the Rossby wave power and lowers its frequency during the cycle maximum is not immediately known, this observation has the potential to provide new insights into the interaction of large-scale flows with the solar cycle.

Corporate governance quality, corporate life cycle and investor confidence in commercial banks: Evidence from Nigeria

A dominant strand of literature advances a positive association between corporate governance quality and investor confidence. However, the corporate life cycle may influence the relationship. Therefore, this study investigated the moderating role of the corporate life cycle in the association between corporate governance quality and investor confidence in the Nigerian banking industry. Corporate governance quality was proxied using a composite measure of board characteristics comprising board size, board meeting, independence, and board gender diversity, while investor confidence was proxied using the price-earnings ratio. Secondary data were obtained from the audited annual financial statements of 12 banks from 2006 to 2021. The study adopted a pooled regression model based on the results of Hausman, and the Breusch and Pagan Lagrangian multiplier test. The results showed that corporate governance quality positively and significantly impacted investor confidence at the introduction (coef = .318, p = 0.017) and decline (coef = 383, p = 0.011) phases of the life cycle. Banks at the introduction and decline phases of the life cycle were characterized by a narrow resource base, low profitability, and higher risky investments sufficient to attract investor confidence. The study concludes that corporate governance quality enhanced investor confidence at the introduction and decline phases of the banks’ life cycle.

Firm life cycle and cost of debt

Theory provides several channels linking the corporate life cycle and lending risks. Using a sample of 20,307 firm-loan observations spanning 5,076 publicly traded U.S. firms, we find an economically significant relationship between firm life cycle stage and lending spreads. Based on the Owen and Yawson (2010) life cycle stage classification, young firms are expected to pay at least 15 bps more than mature firms, whereas mature firms pay at least 11 bps more than old firms. According to the Dickinson (2011) cash flow classification, firms in the introduction and decline phases pay lending spreads that are 6 and 12 percent greater than firms in the mature phase. We explore omitted variables bias and instrumental variable estimation in robustness testing to alleviate endogeneity concerns. A mechanism analysis shows that credit risk, systematic risk, and idiosyncratic risk follow the corporate life pattern in accordance with loan spreads, suggesting that banks charge a premium to compensate for risk. Our results support the theoretical prediction that structural changes occur as firms evolve across the corporate life cycle.

Randomness accelerates the dynamic clearing process of the COVID-19 outbreaks in China

During the implementation of strong non-pharmaceutical interventions (NPIs), more than one hundred COVID-19 outbreaks induced by different strains in China were dynamically cleared in about 40 days, which presented the characteristics of small scale clustered outbreaks with low peak levels. To address how did randomness affect the dynamic clearing process, we derived an iterative stochastic difference equation for the number of newly reported cases based on the classical stochastic SIR model and calculate the stochastic control reproduction number (SCRN). Further, by employing the Bayesian technique, the change points of SCRNs have been estimated, which is an important prerequisite for determining the lengths of the exponential growth and decline phases. To reveal the influence of randomness on the dynamic zeroing process, we calculated the explicit expression of the mean first passage time (MFPT) during the decreasing phase using the relevant theory of first passage time (FPT), and the main results indicate that random noise can accelerate the dynamic zeroing process. This demonstrates that powerful NPI measures can rapidly reduce the number of infected people during the exponential decline phase, and enhanced randomness is conducive to dynamic zeroing, i.e. the greater the random noise, the shorter the average clearing time is. To confirm this, we chose 26 COVID-19 outbreaks in various provinces in China and fitted the data by estimating the parameters and change points. We then calculated the MFPTs, which were consistent with the actual duration of dynamic zeroing interventions.

Isolation, in vitro expansion and characterization of ovine fetal adnexa-derived mesenchymal stem cells reveals a source dependent trilineage differentiation and growth kinetics

This study was designed to isolate, cultivate, characterize and evaluate the growth kinetics of mesenchymal stem cells (MSCs) derived from fetal adnexa of sheep. The gravid uteri of ewes were collected from a local abattoir. The MSCs isolated from different fetal regions (Wharton’s Jelly [oWJ], cord blood [oCB], amniotic fluid [oAF] and amniotic Sac [oAS]) were expanded in vitro and characterized for surface and pluripotency markers. The growth kinetics of MSCs was compared at 3rd and 5th passages. Similarly, the colony-forming efficiency (CFE) assay was performed at 3rd passage. The fetal adnexa-derived ovine MSCs showed the expression of CD73, CD90 and CD105. Similarly, the MSCs also expressed pluripotency markers, OCT4 and SOX2. Besides, cells also differentiated into osteogenic, chondrogenic and adipogenic lineages. The MSCs in culture showed a typical growth curve with initial lag phase, an exponential phase, a plateau phase and a decline phase. The growth rate was highest in oAF-MSCs at P5. The population doubling time (PDT) was highest in oAS-MSCs (87.28 ± 3.24 h), whereas the colony number was highest in oAF-MSCs (53.67 ± 4.06). The study reveals that oAF-MSCs were superior which outperformed other MSCs indicating that oAF-derived MSCs could be utilized for regenerative medicine.

Longitudinal estimated glomerular filtration rate (eGFR) modeling in long-term renal function to inform clinical trial design in kidney transplantation.

Kidney transplantation is the preferred treatment for individuals with end-stage kidney disease. From a modeling perspective, our understanding of kidney function trajectories after transplantation remains limited. Current modeling of kidney function post-transplantation is focused on linear slopes or percent decline and often excludes the highly variable early timepoints post-transplantation, where kidney function recovers and then stabilizes. Using estimated glomerular filtration rate (eGFR), a well-known biomarker of kidney function, from an aggregated dataset of 4904 kidney transplant patients including both observational studies and clinical trials, we developed a longitudinal model of kidney function trajectories from time of transplant to 6 years post-transplant. Our model is a nonlinear, mixed-effects model built in NONMEM that captured both the recovery phase after kidney transplantation, where the graft recovers function, and the long-term phase of stabilization and slow decline. Model fit was assessed using diagnostic plots and individual fits. Model performance, assessed via visual predictive checks, suggests accurate model predictions of eGFR at the median and lower 95% quantiles of eGFR, ranges which are of critical clinical importance for assessing loss of kidney function. Various clinically relevant covariates were also explored and found to improve the model. For example, transplant recipients of deceased donors recover function more slowly after transplantation and calcineurin inhibitor use promotes faster long-term decay. Our work provides a generalizable, nonlinear model of kidney allograft function that will be useful for estimating eGFR up to 6 years post-transplant in various clinically relevant populations.

Spatiotemporal Patterns of the Omicron Wave of COVID-19 in the United States.

COVID-19 has undergone multiple mutations, with the Omicron variant proving to be highly contagious and rapidly spreading across many countries. The United States was severely hit by the Omicron variant. However, it was still unclear how Omicron transferred across the United States. Here, we collected daily COVID-19 cases and deaths in each county from 1 December 2021 to 28 February 2022 as the Omicron wave. We adopted space-time scan statistics, the Hoover index, and trajectories of the epicenter to quantify spatiotemporal patterns of the Omicron wave of COVID-19. The results showed that the highest and earliest cluster was located in the Northeast. The Hoover index for both cases and deaths exhibited phases of rapid decline, slow decline, and relative stability, indicating a rapid spread of the Omicron wave across the country. The Hoover index for deaths was consistently higher than that for cases. The epicenter of cases and deaths shifted from the west to the east, then southwest. Nevertheless, cases were more widespread than deaths, with a lag in mortality data. This study uncovers the spatiotemporal patterns of Omicron transmission in the United States, and its underlying mechanisms deserve further exploration.

MECHANISMS OF COMMERCIAL BANK FINANCIAL MANAGEMENT

Abstract. The article examines the main financial management mechanisms of a commercial bank, as well as the prospect of creating a modern financial mechanism. The article analyzes the approach to the definition of the term "finances" and the focus of management on the placement of financial resources to obtain income. Emphasis is placed on the importance of productive financial relations between the bank and clients through financial management. The role of elements of planning, operational management and controlling in the creation of modern financial management methods is also considered. The stability of the banking sector largely determines the stability of the economy in general and its successful development. Therefore, the primary task of state bodies at the macro level and the management of credit organizations at the micro level should be to ensure such stability through the implementation of a rational monetary policy; assessment and monitoring of the state of the real and financial sectors of the economy; the fall of all types of risks and the acquisition of income, which multiplied aggregate costs. All this will contribute to the modernization and improvement of the quality of banking services provided to individuals and legal entities. An unreasonable and hasty policy in the field of banking business will not only lead to a decline in the financial stability of credit organizations, but will affect the economy as a whole. The article analyzes the financial management of foreign banking organizations, as a result of which the author came to the conclusion that the most important indicators in the development of a bank's financial strategy are the value of a financial organization, the level of bank capital, a certain number of active innovative projects, an increase in the range of products and services provided by banks, an increase management of external and internal risks, as well as development of an effective investment policy. As a result of the study, the relationship between effective financial management and a high level of liquidity management of the bank and the adequacy of its capital was revealed. The theoretical recommendations made by the author can be used by bank managers during the development of tactical measures aimed at increasing the financial stability of the credit organization, as well as during the clarification of the bank's development strategy in the phases of economic growth and decline in the interests of owners and other economic entities that enter into financial relations with banks.

Turning the Spotlight to Cholinergic Pharmacotherapy of the Human Language System.

Even though language is essential in human communication, research on pharmacological therapies for language deficits in highly prevalent neurodegenerative and vascular brain diseases has received little attention. Emerging scientific evidence suggests that disruption of the cholinergic system may play an essential role in language deficits associated with Alzheimer's disease and vascular cognitive impairment, including post-stroke aphasia. Therefore, current models of cognitive processing are beginning to appraise the implications of the brain modulator acetylcholine in human language functions. Future work should be directed further to analyze the interplay between the cholinergic system and language, focusing on identifying brain regions receiving cholinergic innervation susceptible to modulation with pharmacotherapy to improve affected language domains. The evaluation of language deficits in pharmacological cholinergic trials for Alzheimer's disease and vascular cognitive impairment has thus far been limited to coarse-grained methods. More precise, fine-grained language testing is needed to refine patient selection for pharmacotherapy to detect subtle deficits in the initial phases of cognitive decline. Additionally, noninvasive biomarkers can help identify cholinergic depletion. However, despite the investigation of cholinergic treatment for language deficits in Alzheimer's disease and vascular cognitive impairment, data on its effectiveness are insufficient and controversial. In the case of post-stroke aphasia, cholinergic agents are showing promise, particularly when combined with speech-language therapy to promote trained-dependent neural plasticity. Future research should explore the potential benefits of cholinergic pharmacotherapy in language deficits and investigate optimal strategies for combining these agents with other therapeutic approaches.

China’s CO2 Emissions: A Thorough Analysis of Spatiotemporal Characteristics and Sustainable Policy from the Agricultural Land-Use Perspective during 1995–2020

Agricultural land use is an important source of CO2 emissions. Therefore, taking the CO2 emissions of China’s agricultural land use during 1995–2020 as a case, we firstly calculated its composition and analyzed the spatiotemporal evolution characteristics. Then, the Tapio decoupling model and logarithmic mean Divisia index (LMDI) were, respectively, used to identify the decoupling relationship between the CO2 emission change and economic growth, and analyze the driving factors for CO2 emissions. (1) The CO2 emissions of China’s agricultural land use were composed of two main phases (fluctuating growth phase (1995–2015) and rapid decline phase (2016–2020)). The total CO2 emissions exhibited a non-equilibrium spatial distribution. The inter-provincial CO2 emissions differences first expanded and then shrank, but the inter-provincial differences of CO2 emissions intensity continuously decreased. (2) The total CO2 emissions of China’s agricultural land use increased from 50.443 Mt in 1995 to 79.187 Mt in 2020, with an average annual growth rate of 1.82%. Fertilizer, agricultural diesel and agricultural (plastic) film were the main sources of anthropogenic agricultural-land-use CO2 emissions. Controlling the use of fertilizer and agricultural diesel and improving the utilization efficiency of agricultural (plastic) film could be an effective way to reduce CO2 emissions. (3) The Tapio decoupling relationship between the CO2 emission change and economic growth was a weak decoupling state during 1995–2015 and a strong decoupling state during 2016–2020. This result indicates that China’s agricultural land use can be effectively controlled. (4) The agricultural economic level is the decisive factor in promoting CO2 emissions increase, and its cumulative contribution was 476.09%. Inversely, the CO2 emission intensity, agricultural structure and agricultural labor force were three key factors, with cumulative contributions of −189.51%, −16.86% and −169.72%, respectively. Collectively, based on the findings obtained from the present research, we have proposed some suggestions to promote the sustainable use of agriculture lands in China.

Influence of Horizontal Loading in Changing the Ultimate Uplift Bearing Capacity of Monopile Foundation of Offshore Wind Turbine

Throughout their lifespan, monopile foundations supporting offshore wind turbines inevitably experience horizontal loads from waves, winds, and currents, resulting in cumulative deformation. It has been believed that deformation caused by horizontal loading weakens the interaction between the pile and the soil, leading to a reduction in the ultimate uplift bearing capacity of the pile foundation. However, there is a scarcity of literature investigating this issue, particularly regarding monopiles used in offshore wind turbine installations. Therefore, this study aims to explore the impact of horizontal cyclic loads on the ultimate uplift bearing capacity of monopile, focusing on the pile–soil interaction. To achieve this, a series of 1 g model tests were conducted on a rigid model pile embedded in silt with varying relative compaction. The test results indicate that the ultimate uplift bearing capacity of the pile is significantly diminished after experiencing horizontal cyclic loading, and the extent of reduction is closely linked to the amplitude of the horizontal deformation. A semi-empirical model is developed to predict the ultimate uplift bearing capacity of the pile foundation following horizontal cyclic loading. The key findings of this study are as follows: (1) The earth pressure in the active zone gradually decreases with an increasing number of cycles, while the earth pressure in the passive zone experiences a slight increase under horizontal cyclic loading. (2) The position of the pile rotation center under horizontal cyclic loading is approximately 0.84 times the depth at which the pile is buried, and this relationship appears to be independent of soil density and cyclic load ratio. (3) The variation of earth pressure corresponding to the horizontal deformation of the pile in the active zone can be divided into three phases: a rapid decline phase, a slow decline phase, and a stable phase. (4) The reduction in the ultimate uplift capacity is influenced by the cyclic ratio and number of cycles but does not appear to have a significant relationship with soil density.

Algal organic matter impact on 2-methylisopropanol and geosmin adsorption by activated carbon: Variation with algae growth and decay, prediction by fluorescence surrogates

Algae-producing odorants have negative effects on the aesthetic quality of drinking water, and activated carbon adsorption is commonly used to abate the odorants. However, in eutrophic waters, algal organic matter (AOM) produced by the dominant cyanobacteria (e.g., Microcystis aeruginosa) strongly interferes with the activated carbon adsorption of trace odorants from source waters. In this study, the applicability of using spectrometric surrogates to evaluate the effect of AOM from Microcystis aeruginosa on odorant adsorption by activated carbon was investigated. During the stationary phase, the DOC concentration of extracellular organic matter (EOM) increased due to algal metabolism (from 3.52 mg/L to 7.81 mg/L) and further accumulated (to 12.40 mg/L) during the decline phase due to the release of intracellular organic matter (IOM), resulting in increased competition against odorants. The adsorption of chromogenic organics in AOM was first evaluated to screen possible spectrometric surrogates for predicting odorant adsorption. The fluorescence component (Ex: 260 nm/Em: 400–460 nm) was the best candidate for predicting odorant adsorption in both AOM solutions and reservoir water. In contrast, poor performance was found for the commonly used UV absorbance at 254 nm and protein-like fluorescence components, due to the weak adsorbability of corresponding chromogenic materials. Our results indicate that fluorescence spectroscopy is promising in predicting odorant adsorption with AOM interference in source waters.

Modeling repair demand in existence of a nonstationary installed base

Life cycles of products consist of 3 phases, namely growth, maturity, and decline phases. Modeling repair demand is particularly difficult in the growth and decline stages due to nonstationarity. In this study, we suggest respective stochastic models that capture the dynamics of repair demand in these two phases. We apply our theory to two different operations management problems. First, using the moments of spare parts demand, we suggest an algorithm that selects a parametric distribution from the hypergeometric family (Ord, 1967) for each period in time. We utilize the algorithm in a single echelon inventory control problem. Second, we focus on investment decisions of Original Equipment Manufacturers (OEMs) to extend economic lifetimes of products with technology upgrades. Our results indicate that the second moment is sufficient for growing customer bases, whereas using the third moment doubles the approximation quality of theoretical distributions for a declining customer base. From a cost minimization perspective, using higher moments of demand leads to savings up to 13.6% compared to the single-moment approach. Also, we characterize the optimal investment policy for lifetime extension decisions from risk-neutral and risk-averse perspectives. We find that there exists a critical level of investment cost and installed base size for profitability of lifetime extension for OEMs. From a managerial point of view, we find that a risk-neutral decision maker finds the lifetime extension problem profitable. In contrast, even a slight risk aversion can make the lifetime extension decision economically undesirable.

Variable Levels of Oxytocin During Sepsis: The Role of Oxytocin in Sepsis Pathophysiology.

Although the role of oxytocin in the pathophysiology of sepsis is still unknown, rising preclinical evidence suggests that oxytocin is possibly involved. However, no direct clinical studies have measured the levels of oxytocin during sepsis. In this preliminary study, the serum oxytocin levels were evaluated throughout the duration of sepsis. Twenty-two male patients over 18 years of age with a SOFA score of 2 points or more who were admitted to the ICU were included. Patients with a history of neuroendocrine, psychiatric, and neurologic disorders, cancer, an infection caused by COVID-19, shock due to reasons other than sepsis, a history of psychiatric or neurologic medication use, and those who died during the study were excluded. The main endpoint included the measurement of serum oxytocin levels using radioimmunoassay at 6, 24, and 48 h of the ICU admission. Mean serum oxytocin level was higher at 6 h of ICU admission (41.27 ± 13.14 ng/L) than after 24 and 48 h of ICU admission (22.63 ± 5.75 and 20.97 ± 7.61 ng/L respectively) (P-value < .001). Our study, while reporting increased serum oxytocin levels in the initial phase of sepsis and decline afterward, supports the possible contribution of oxytocin in the pathophysiology of sepsis. Given that oxytocin seems to modulate the innate immune system, future investigations are necessary to assess the potential role of oxytocin in the pathophysiology of sepsis.

Polymorphism, gigantism, and cannibalism, one stylonychid ciliate (Ciliophora, Hypotricha) to rule them all.

The morphology, ontogenesis, and molecular phylogeny of the polymorphic and cannibalistic giant forming Tetmemena polymorpha n. sp., found in a brackish water sample in South Korea, were investigated. The present species has long been misidentified as "Oxytricha bifaria." The new investigation shows that the species produces three morphologically different morphs. The small morph is bacterivorous and characterized by its small body size and slim body and it is found only in the stationary and decline phases of the culture. The large morph has a wide body, larger oral apparatus, and feeds on small eukaryotes such as yeast cells and small ciliates. It divides very quickly and produces the other two morphs and found in the exponential phase of the cultures. The giant morph is characterized by its huge body and oral apparatus. It feeds on the small morph cells of the same species and other ciliates, and occurs together with the small morph. Phylogenetic analyses based on the 18S rRNA gene sequences show that the new species is placed in a sister subclade to that containing other Tetmemena sequences. Moreover, Tetmemena indica Bharti et al., 2019 nov. stat. is raised to species level based on the differences in the cyst morphology and the dorsal ciliature to the authoritative Tetmemena pustulata population.

1 H NMR-based process understanding and biochemical marker identification methodology for monitoring CHO cell culture process during commercial-scale manufacturing.

Controlling the process of CHO cell fed-batch culture is critical for biologics quality control. However, the biological complexity of cells has hampered the reliable process understanding for industrial manufacturing. In this study, a workflow was developed for the consistency monitoring and biochemical marker identification of the commercial-scale CHO cell culture process through 1 H NMR assisted with multivariate data analysis (MVDA). Firstly, a total of 63 metabolites were identified in this study object in 1 H NMR spectra of the CHO cell-free supernatants. Secondly, multivariate statistical process control (MSPC) charts were used to evaluate process consistency. According to MSPC charts, the batch-to-batch quality consistency was high, indicating the CHO cell culture process at the commercial scale was well-controlled and stable. Then, the biochemical marker identification was provided through orthogonal partial least square discriminant analysis (OPLS-DA) based S-line plots during the cell logarithmic expansion, stable growth, and decline phases. Identified biochemical markers of the three cell growth phases were as follows: L-glutamine, pyroglutamic acid, 4-hydroxyproline, choline, glucose, lactate, alanine, and proline were of the logarithmic growth phase; isoleucine, leucine, valine, acetate, and alanine were of the stable growth phase; acetate, glycine, glycerin, and gluconic acid were of the cell decline phase. Additional potential metabolic pathways that might influence the cell culture phase transitions were demonstrated. The workflow proposed in this study demonstrates that the combination of MVDA tools and 1 H NMR technology is highly appealing to the research of the biomanufacturing process, and applies well to provide guidance in future work on consistency evaluation and biochemical marker monitoring of the production of other biologics.

Terminal Decline in Physical Function in Older Adults.

It is currently unclear whether (and when) physical function exhibits a terminal decline phase, that is, a substantial acceleration of decline in the very last years before death. 702 deceased adults aged 70 years and older from the Yale PEP Study provided 4 133 measurements of physical function (Short Physical Performance Battery, SPPB) up to 20 years before death. In addition, continuous gait and chair rise subtest scores (in seconds) were assessed. Generalized mixed regression models with random change points were used to estimate the onset and the steepness of terminal decline in physical function. Decline accelerated in the last years of life in all 3 measures of physical function. The onset of terminal decline occurred 1 year before death for the SPPB, and at 2.5 and 2.6 years before death for chair rise and gait speed test scores, respectively. Terminal declines in physical function were 6-8 times steeper than pre-terminal declines. Relative to those whose condition leading to death was frailty, participants who died from dementia and cancer had an up to 6 months earlier and 3 months later onset of terminal decline in SPPB, respectively. Terminal decline in physical function among older adults is comparable to the more established terminal decline phenomenon in cognition. Our results provide additional evidence of late-life rapid decline in physical function due to impending death.

Untargeted metabolomic analysis reveals the mechanism of Enterococcus faecium agent induced CaCO3 scale inhibition.

In this study, a lactic acid bacterium, Enterococcus faecium, was found to prevent CaCO3 precipitation through its metabolism. On analysis of all stages of E. faecium growth, static jar tests demonstrated that stationary phase E. faecium broth possessed the highest inhibition efficiency of 97.3% at a 0.4% inoculation dosage, followed by the decline and log phases with efficiencies of 90.03% and 76.07%, respectively. Biomineralization experiments indicated that E. faecium fermented the substrate to produce organic acid, which resulted in modulation of the pH and alkalinity of the environment and thus inhibited CaCO3 precipitation. Surface characterization techniques indicated that the CaCO3 crystals precipitated by the E. faecium broth tended to be significantly distorted and formed other organogenic calcite crystals. The scale inhibition mechanisms were revealed by untargeted metabolomic analysis on log and stationary phase E. faecium broth. In total, 264 metabolites were detected, 28 of which were differential metabolites (VIP ≥ 1 and p < 0.05). Of these, 15 metabolites were upregulated in stationary phase broth, and 13 metabolites were downregulated in log phase broth. Metabolic pathway analysis suggested that improved glycolysis and the TCA cycle were the main reasons for enhancement of the antiscaling performance of E. faecium broth. These findings have significant implications for microbial metabolism-induced CaCO3 scale inhibition.

High rifampicin peak plasma concentrations accelerate the slow phase of bacterial decline in tuberculosis patients: Evidence for heteroresistance.

Antibiotic treatments are often associated with a late slowdown in bacterial killing. This separates the killing of bacteria into at least two distinct phases: a quick phase followed by a slower phase, the latter of which is linked to treatment success. Current mechanistic explanations for the in vitro slowdown are either antibiotic persistence or heteroresistance. Persistence is defined as the switching back and forth between susceptible and non-susceptible states, while heteroresistance is defined as the coexistence of bacteria with heterogeneous susceptibilities. Both are also thought to cause a slowdown in the decline of bacterial populations in patients and therefore complicate and prolong antibiotic treatments. Reduced bacterial death rates over time are also observed within tuberculosis patients, yet the mechanistic reasons for this are unknown and therefore the strategies to mitigate them are also unknown. We analyse a dose ranging trial for rifampicin in tuberculosis patients and show that there is a slowdown in the decline of bacteria. We show that the late phase of bacterial killing depends more on the peak drug concentrations than the total drug exposure. We compare these to pharmacokinetic-pharmacodynamic models of rifampicin heteroresistance and persistence. We find that the observation on the slow phase's dependence on pharmacokinetic measures, specifically peak concentrations are only compatible with models of heteroresistance and incompatible with models of persistence. The quantitative agreement between heteroresistance models and observations is very good ([Formula: see text]). To corroborate the importance of the slowdown, we validate our results by estimating the time to sputum culture conversion and compare the results to a different dose ranging trial. Our findings indicate that higher doses, specifically higher peak concentrations may be used to optimize rifampicin treatments by accelerating bacterial killing in the slow phase. It adds to the growing body of literature supporting higher rifampicin doses for shortening tuberculosis treatments.

Solar cycle 25 amplitude prediction based on sunspot number increase rate

We propose a prediction of the amplitude of the 25th cycle of solar activity based on the analysis of data on 24 previous solar cycles, which relate to the statistical relationship between the rate of increase in the number of sunspots in the phase of the growth curve and the amplitude of the cycle. It turned out that the forecasting result depends on several initial assumptions, in particular, which section of the growth curve is taken into account for forecasting, as well as whether all 24 cycles are considered, or only the odd ones. The assumption of a monotonic or non-monotonic growth curve also plays an important role. Regarding the latter, the cluster analysis showed that until the 35th month of the cycle, there are no visible signs of non-monotonicity of the growth curve, similar to the one that was in the 24th cycle. We conclude that the maximum smoothed number of sunspots in the 25th cycle Wmax (25), most likely, should be equal to 185 ± 18 units in the new system, which corresponds to the average power of the solar cycle, with the implementation of the Hnievyshev-Ohl rule. With such parameters of this cycle, there are no signs of approaching the deep minimum of the age cycle in the middle 21st century. This does not exclude the fact that this deep age minimum can occur suddenly and sharply immediately after the 25th cycle, as was the case, for example, in the Dalton minimum. A possible sign of the upcoming age cycle may be the abnormally long decline phase of the current 25th cycle, about 10 years, as it was in the 4th cycle.