Numerical assessments of geometry, proximity and multi-electrode effects on electroporation in mitochondria and the endoplasmic reticulum to nanosecond electric pulses.

Most simulations of electric field driven bioeffects have considered spherical cellular geometries or probed symmetrical structures for simplicity. This work assesses cellular transmembrane potential build-up and electroporation in a Jurkat cell that includes the endoplasmic reticulum (ER) and mitochondria, both of which have complex shapes, in response to external nanosecond electric pulses. The simulations are based on a time-domain nodal analysis that incorporates membrane poration utilizing the Smoluchowski model with angular-dependent changes in membrane conductivity. Consistent with prior experimental reports, the simulations show that the ER requires the largest electric field for electroporation, while the inner mitochondrial membrane (IMM) is the easiest membrane to porate. Our results suggest that the experimentally observed increase in intracellular calcium could be due to a calcium induced calcium release (CICR) process that is initiated by outer cell membrane breakdown. Repeated pulsing and/or using multiple electrodes are shown to create a stronger poration. The role of mutual coupling, screening, and proximity effects in bringing about electric field modifications is also probed. Finally, while including greater geometric details might refine predictions, the qualitative trends are expected to remain.

Maps of Membrane Pore Dynamics From Picosecond to Millisecond Pulse Durations.

Electroporation occurs when cells are exposed to an electric pulse of sufficient intensity E0 and pulse duration τ. Many studies have attempted to develop universal scaling laws to predict membrane pore dynamics for pulsed electric fields (PEFs) of different durations; however, the differences in pore dynamics across these parameters makes this difficult both experimentally and numerically. This study uses the asymptotic Smoluchowski equation (ASME) to quantify the number of pores, average pore radius, and fractional pore area (FPA) during exposure to PEFs with durations from hundreds of picoseconds to a millisecond. We highlight pulse parameter regimes that favor increases in pore radius and number and show that the FPA is dominated by the number of pores formed on the cell membrane. Furthermore, the number of pores and the FPA depend almost entirely on E0 for τ exceeding the charging time of the cell and both E0 and τ for τ shorter than the charging time. Finally, the maps of pore number, average radius, and FPA demonstrate that a universal scaling law for pore dynamics across a wide range of pulse durations does not exist, although certain scaling behaviors may be valuable over narrow regimes. Practically, these maps provide a guideline for selecting PEF parameters to achieve desired membrane permeabilization.

Simple model to incorporate statistical noise based on a modified hodgkin-huxley approach for external electrical field driven neural responses.

Noise activity is known to affect neural networks, enhance the system response to weak external signals, and lead to stochastic resonance phenomenon that can effectively amplify signals in nonlinear systems. In most treatments, channel noise has been modeled based on multi-state Markov descriptions or the use stochastic differential equation models. Here we probe a computationally simple approach based on a minor modification of the traditional Hodgkin-Huxley approach to embed noise in neural response. Results obtained from numerous simulations with different excitation frequencies and noise amplitudes for the action potential firing show very good agreement with output obtained from well-established models. Furthermore, results from the Mann-Whitney U Test reveal a statistically insignificant difference. The distribution of the time interval between successive potential spikes obtained from this simple approach compared very well with the results of complicated Fox and Lu type methods at much reduced computational cost. This present method could also possibly be applied to the analysis of spatial variations and/or differences in characteristics of random incident electromagnetic signals.

Immunomodulation of streptozotocin induced Type 1 diabetes mellitus in mouse model by Macrophage migration inhibitory factor-2 (MIF-2) homologue of human lymphatic filarial parasite, Wuchereria bancrofti.

Helminth parasites modulate the host immune system to ensure a long-lasting asymptomatic form of infection generally, mediated by the secretion of immunomodulatory molecules and one such molecule is a homologue of human host cytokine, Macrophage migratory Inhibitory Factor (hMIF). In this study, we sought to understand the role of homologue of hMIF from the lymphatic filarial parasite, Wuchereria bancrofti (Wba-MIF2), in the immunomodulation of the Streptozotocin (STZ)-induced Type1 Diabetes Mellitus (T1DM) animal model. Full-length recombinant Wba-MIF2 was expressed and found to have both oxidoreductase and tautomerase activities. Wba-MIF2 recombinant protein was treated to STZ induced T1DM animals, and after 5 weeks pro-inflammatory (IL-1, IL-2, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4, IL-10) cytokines and gene expressions were determined in sera samples and spleen respectively. Pro-inflammatory and anti-inflammatory cytokine levels were significantly (p<0.05) up-regulated and down-regulated respectively, in the STZ-T1DM animals, as compared to treated groups. Histopathology showed macrophage infiltration and greater damage of islets of beta cells in the pancreatic tissue of STZ-T1DM animals, than Wba-MIF2 treated STZ-T1DM animals. The present study clearly showed the potential of Wba-MIF2 as an immunomodulatory molecule, which could modulate the host immune system in the STZ-T1DM mice model from a pro-inflammatory to anti-inflammatory milieu.

The impact of healthy pregnancy on features of heart rate variability and pulse wave morphology derived from wrist-worn photoplethysmography.

Due to the association between dysfunctional maternal autonomic regulation and pregnancy complications, tracking non-invasive features of autonomic regulation derived from wrist-worn photoplethysmography (PPG) measurements may allow for the early detection of deteriorations in maternal health. However, even though a plethora of these features-specifically, features describing heart rate variability (HRV) and the morphology of the PPG waveform (morphological features)-exist in the literature, it is unclear which of these may be valuable for tracking maternal health. As an initial step towards clarity, we compute comprehensive sets of HRV and morphological features from nighttime PPG measurements. From these, using logistic regression and stepwise forward feature elimination, we identify the features that best differentiate healthy pregnant women from non-pregnant women, since these likely capture physiological adaptations necessary for sustaining healthy pregnancy. Overall, morphological features were more valuable for discriminating between pregnant and non-pregnant women than HRV features (area under the receiver operating characteristics curve of 0.825 and 0.74, respectively), with the systolic pulse wave deterioration being the most valuable single feature, followed by mean heart rate (HR). Additionally, we stratified the analysis by sleep stages and found that using features calculated only from periods of deep sleep enhanced the differences between the two groups. In conclusion, we postulate that in addition to HRV features, morphological features may also be useful in tracking maternal health and suggest specific features to be included in future research concerning maternal health.

Establishing proof of concept for utility of Trueprep®-extracted DNA in line-probe assay testing.

BACKGROUND AND OBJECTIVES: With an increased demand for rapid, diagnostic tools for TB and drug resistance detection, Truenat® MTB-RIF assay has proven to be a rapid point of care molecular test. The present study aimed to establish a proof of concept of using Trueprep-extracted DNA for line-probe assay (LPA) testing.METHODS: A total of 150 sputum samples (MTB-positive at Truenat sites) were divided into two aliquots. One aliquot was used for DNA extraction using the Trueprep device and MTB testing. The second aliquot of the sample was subjected to GenoLyse® DNA extraction. DNA from both the Trueprep and GenoLyse methods was subjected to first-line (FL) and second-line (SL) LPA testing.RESULTS: Of 139 Trueprep-extracted DNA, respectively 135 (97%) and 105 (75%) had interpretable results by FL and SL-LPA testing. Of 128 GenoLyse-extracted DNA, all 128 (100%) had interpretable FL-LPA results and 114 (89%) had interpretable SL-LPA results.CONCLUSION: The results obtained in this study indicate that Trueprep-extracted DNA can be used in obtaining valid LPA results. However, the study needs to be conducted on a larger sample size before our recommendations can be used for policy-making decisions.

Selective Electroporation of Tumor Cells Under AC Radiofrequency Stimulation - A Numerical Study.

Self-consistent evaluations of membrane electroporation along with local heating in single spherical cells arising from external AC radiofrequency electrical stimulation have been carried out. The present numerical study seeks to determine whether healthy and malignant cells exhibit separate electroporative responses with regards to operating frequency. It is shown that cells of Burkitt's lymphoma would respond to frequencies >4.5 MHz, while normal B-cells would have negligible porative effects in that higher frequency range. Similarly, a frequency separation between the response of healthy T-cells and malignant species is predicted with a threshold of about 4 MHz for cancer cells. The present simulation technique is general and so would be able to ascertain the beneficial frequency range for different cell types. The demonstration of higher frequencies to induce poration in malignant cells, while having minimal affecting healthy ones, suggests the possibility of selective electrical targeting for tumor treatments and protocols. It also opens the doorway for tabulating selectivity enhancement regimes as a guide for parameter selection towards more effective treatments while minimizing deleterious effects on healthy cells and tissues.

Importance of surface morphology on secondary electron emission: a case study of Cu covered with carbon, carbon pairs, or graphitic-like layers.

Understanding the relationship between surface adsorbates and secondary electronic emission is critical for a variety of technologies, since the secondary electrons can have deleterious effects on the operation of devices. The mitigation of such phenomena is desirable. Here, using the collective efforts of first-principles, molecular dynamics, and Monte Carlo simulations, we studied the effects of a variety of carbon adsorbates on the secondary electron emission of Cu (110). It was demonstrated that the adsorption of atomic C and C[Formula: see text] pair layers can both reduce and increase the number of secondary electrons depending on the adsorbate coverage. It was shown that under electron irradiation, the C-Cu bonds can be dissociated and reformed into C[Formula: see text] pairs and graphitic-like layers, in agreement with experimental observation. It was verified that the lowest secondary electron emission was due to the formation of the graphitic-like layer. To understand the physical reason for changes in number of secondary electrons for different systems from an electronic structure perspective, two-dimensional potential energy surfaces and charge density contour plots were calculated and analyzed. It was shown that the changes are strongly influenced by the Cu surface morphology and depends highly on the nature of the interactions between the surface Cu and C atoms.

On the distinct differences in autonomic regulation between pregnant and non-pregnant women - a heart rate variability analysis.

Objective. Appropriate adaptation of the maternal autonomic nervous system to progressing gestation is essential to a healthy pregnancy. This is partly evidenced by the association between pregnancy complications and autonomic dysfunction. Therefore, assessing maternal heart rate variability (HRV)-a proxy measure for autonomic activity-may offer insights into maternal health, potentially enabling the early detection of complications. However, identifying abnormal maternal HRV requires a thorough understanding of normal maternal HRV. While HRV in women of childbearing age has been extensively investigated, less is known concerning HRV during pregnancy. Subsequently, we investigate the differences in HRV between healthy pregnant women and their non-pregnant counterparts.Approach. We use a comprehensive suite of HRV features (assessing sympathetic and parasympathetic activity, heart rate (HR) complexity, HR fragmentation, and autonomic responsiveness) to quantify HRV in large groups of healthy pregnant (n= 258) and non-pregnant women (n= 252). We compare the statistical significance and effect size of the potential differences between the groups.Main results. We find significantly increased sympathetic and decreased parasympathetic activity during healthy pregnancy, along with significantly attenuated autonomic responsiveness, which we hypothesize serves as a protective mechanism against sympathetic overactivity. HRV differences between these groups typically had a large effect size (Cohen'sd> 0.8), with the largest effect accompanying the significantly reduced HR complexity and altered sympathovagal balance observed in pregnancy (Cohen'sd> 1.2).Significance. Healthy pregnant women are autonomically distinct from their non-pregnant counterparts. Subsequently, assumptions based on HRV research in non-pregnant women cannot be readily translated to pregnant women.

Vaccination saves lives: a real-time study of patients with chronic diseases and severe COVID-19 infection.

OBJECTIVES: This study aims to describe the demographic and clinical profile and ascertain the determinants of outcome among hospitalized coronavirus disease 2019 (COVID-19) adult patients enrolled in the National Clinical Registry for COVID-19 (NCRC). METHODS: NCRC is an on-going data collection platform operational in 42 hospitals across India. Data of hospitalized COVID-19 patients enrolled in NCRC between 1st September 2020 to 26th October 2021 were examined. RESULTS: Analysis of 29 509 hospitalized, adult COVID-19 patients [mean (SD) age: 51.1 (16.2) year; male: 18 752 (63.6%)] showed that 15 678 (53.1%) had at least one comorbidity. Among 25 715 (87.1%) symptomatic patients, fever was the commonest symptom (72.3%) followed by shortness of breath (48.9%) and dry cough (45.5%). In-hospital mortality was 14.5% (n = 3957). Adjusted odds of dying were significantly higher in age group ≥60 years, males, with diabetes, chronic kidney diseases, chronic liver disease, malignancy and tuberculosis, presenting with dyspnoea and neurological symptoms. WHO ordinal scale 4 or above at admission carried the highest odds of dying [5.6 (95% CI: 4.6-7.0)]. Patients receiving one [OR: 0.5 (95% CI: 0.4-0.7)] or two doses of anti-SARS CoV-2 vaccine [OR: 0.4 (95% CI: 0.3-0.7)] were protected from in-hospital mortality. CONCLUSIONS: WHO ordinal scale at admission is the most important independent predictor for in-hospital death in COVID-19 patients. Anti-SARS-CoV2 vaccination provides significant protection against mortality.

Comparative Analyses of Clinical, Laboratory, and Radiological Findings between COVID-19 Deceased and Recovered Patients.

Background Understanding the coronavirus disease 2019 (COVID-19)-specific indices has become important with increasing cases of COVID-related in-hospital mortality. Objective This case-control study compared clinical, laboratory, and radiological findings between deceased and recovered COVID-19 patients and identified the significant biomarkers associated with deceased patients. Method An analysis of clinical, laboratory, and radiological findings of COVID-19 patients admitted to the COVID-dedicated wards of Nepal Armed Police Force Hospital between March and December 2021 was performed using SPSS version 17.0, with statistical significance considered at p < 0.05. Result A total of 187 COVID-19 patients, comprising deceased [n=95, median (interquartile range, IQR) age: 66 (53-76) years, male: 61 (64.2%) (p=0.024)] and recovered [n=92, median (IQR) age: 51 (38-61) years, male: 44 (47.8%)], were included in the study. Compared to recovered COVID-19 patients, deceased patients had increased median respiratory (20 versus 29.5 breaths/minute) and pulse (83 vs. 86 beats/minute) rates; multiple co-morbidities (≥ 2) (11.9% vs. 32.6%) (p < 0.001); significantly (p < 0.05) lowered alkaline phosphatase (ALP), total protein (TP), albumin, lymphocytes, monocytes, eosinophil, hemoglobin and significantly (p < 0.05) elevated glucose, lactate dehydrogenase (LDH), alanine transaminase (ALT), aspartate aminotransferase (AST), leucocytes, neutrophils, D-dimer and C-reactive protein (CRP); and chest abnormalities including bilateral (p < 0.001), peripheral (p < 0.001) interstitial (p < 0.001) and ground glass opacity (GGO) (p=0.002). Conclusion Elderly, male sex, increased respiratory and pulse rate, presence of multiple comorbidities, lowered levels of ALP, TP, albumin, lymphocytes, monocytes, eosinophils, hemoglobin, elevated levels of glucose, LDH, ALT, AST, leucocytes, neutrophils, D-dimer, CRP, and chest X-rays showing bilateral, peripheral interstitial and GGO abnormalities were the significant indices associated with deceased COVID-19 patients.

Assessment of prescribing pattern of drugs and completeness of prescriptions as per the World Health Organization prescribing indicators in various Indian tertiary care centers: A multicentric study by Rational Use of Medicines Centers-Indian Council of Medical Research network under National Virtual Centre Clinical Pharmacology activity.

OBJECTIVE: The rational use of medicines as per the World Health Organization (WHO) should be practiced globally. However, data regarding the completeness of the prescriptions and their rational use is lacking from developing countries like India. Thus, the aim of this study was to assess the prescribing patterns of drugs and completeness of prescriptions as per WHO core drug use and complementary indicators to provide real-life examples for the Indian Council of Medical Research (ICMR) online prescribing skill course for medical graduates. METHODS: Prescriptions of the patients, fulfilling inclusion criteria, attending Outpatient Departments of various specialties of tertiary care hospitals, were collected by thirteen ICMR Rational use of medicines centers located in tertiary care hospitals, throughout India. Prescriptions were evaluated for rational use of medicines according to the WHO guidelines and for appropriateness as per standard treatment guidelines using a common protocol approved by local Ethics committees. RESULTS: Among 4838 prescriptions, an average of about three drugs (3.34) was prescribed to the patients per prescription. Polypharmacy was noted in 83.05% of prescriptions. Generic drugs were prescribed in 47.58% of the prescriptions. Further, antimicrobials were prescribed in 17.63% of the prescriptions and only 4.98% of prescriptions were with injectables. During the prescription evaluation, 38.65% of the prescriptions were incomplete due to multiple omissions such as dose, duration, and formulation. CONCLUSION: Most of the parameters in the present study were out of the range of WHO-recommended prescribing indicators. Therefore, effective intervention program, like training, for the promotion of rational drug use practice was recommended to improve the prescribing pattern of drugs and the quality of prescriptions all over the country.

Characterizing the effect of demographics, cardiorespiratory factors, and inter-subject variation on maternal heart rate variability in pregnancy with statistical modeling: a retrospective observational analysis.

Pregnancy complications are associated with insufficient adaptation of the maternal autonomic nervous system to the physiological demands of pregnancy. Consequently, assessing maternal heart rate variability (mHRV)-which reflects autonomic regulation-is a promising tool for detecting early deterioration in maternal health. However, before mHRV can be used to screen for complications, an understanding of the factors influencing mHRV during healthy pregnancy is needed. In this retrospective observational study, we develop regression models to unravel the effects of maternal demographics (age, body mass index (BMI), gestational age (GA), and parity), cardiorespiratory factors (heart rate and breathing rate), and inter-subject variation on mHRV. We develop these models using two datasets which are comprised of, respectively, single measurements in 290 healthy pregnant women and repeated measurements (median = 8) in 29 women with healthy pregnancies. Our most consequential finding is that between one-third and two-thirds of the variation in mHRV can be attributed to inter-subject variability. Additionally, median heart rate dominantly affects mHRV (p < 0.001), while BMI and parity have no effect. Moreover, we found that median breathing rate, age, and GA all impact mHRV (p < 0.05). These results suggest that personalized, long-term monitoring would be necessary for using mHRV for obstetric screening.

Surface waves and crustal structure on Mars.

We detected surface waves from two meteorite impacts on Mars. By measuring group velocity dispersion along the impact-lander path, we obtained a direct constraint on crustal structure away from the InSight lander. The crust north of the equatorial dichotomy had a shear wave velocity of approximately 3.2 kilometers per second in the 5- to 30-kilometer depth range, with little depth variation. This implies a higher crustal density than inferred beneath the lander, suggesting either compositional differences or reduced porosity in the volcanic areas traversed by the surface waves. The lower velocities and the crustal layering observed beneath the landing site down to a 10-kilometer depth are not a global feature. Structural variations revealed by surface waves hold implications for models of the formation and thickness of the martian crust.

Maternal autonomic responsiveness is attenuated in healthy pregnancy: a phase rectified signal averaging analysis.

Autonomic regulation is essential in enabling a healthy pregnancy. In fact, several pregnancy complications are associated with autonomic dysfunction. Better understanding of the maternal autonomic state during healthy pregnancy may aid in the early detection of such complications. One aspect of autonomic regulation is autonomic responsiveness, which can by assessed by phase rectified signal averaging (PRSA). While other areas of research have found blunted physiological responses in pregnancy, this paper presents the first investigation of maternal autonomic responsiveness as assessed by PRSA. We find significantly reduced rates of responses, as well as an attenuated capacity for heart rate acceleration when comparing pregnant women to non-pregnant controls. We hypothesize that this attenuated autonomic control may serve to protect the mother against her imbalanced autonomic state, as increased sympathetic and decreased parasympathetic modulation accompany healthy pregnancies. Clinical Relevance- Maternal autonomic responsiveness is attenuated in pregnancy in comparison to non-pregnant women. Understanding maternal autonomic state not only improves our knowledge of gestational physiology but also forms the basis for the early detection of pregnancy complications associated with maternal autonomic dysfunction.

Carbon-oxygen surface formation enhances secondary electron yield in Cu, Ag and Au.

First-principles calculations coupled with Monte Carlo simulations are used to probe the role of a surface CO monolayer formation on secondary electron emission (SEE) from Cu, Ag, and Au (110) materials. It is shown that formation of such a layer increases the secondary electron emission in all systems. Analysis of calculated total density of states (TDOS) in Cu, Ag, and Au, and partial density of states (PDOS) of C and O confirm the formation of a covalent type bonding between C and O atoms. It is shown that such a bond modifies the TDOS and extended it to lower energies, which is then responsible for an increase in the probability density of secondary electron generation. Furthermore, a reduction in inelastic mean free path is predicted for all systems. Our predicted results for the secondary electron yield (SEY) compare very favorably with experimental data in all three materials, and exhibit increases in SEY. This is seen to occur despite increases in the work function for Cu, Ag, and Au. The present analysis can be extended to other absorbates and gas atoms at the surface, and such analyses will be present elsewhere.

A systematic review on SARS-CoV-2 remission: an emerging challenge for its management, treatment, immunization strategies, and post-treatment guidelines.

The COVID-19 disease caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) has posed as a major health concern for people all across the globe. Along with the increasing confirmed patients being readmitted with complaints for fever, cough, cold, the effective monitoring of 'relapse' of the SARS-CoV-2 virus in the previously discharged patients have become the next area of focus. However, availability of limited data on reactivation of SARS-CoV-2 makes the disease prognosis as well as the effective control of re-infection an immense challenge. Prompted by these challenges, we assessed the possibility of re-infection in discharged patients and the risk of the transmission, proficiency of RT-PCR results and approximate period required for the quarantine, and the real challenges for the development of vaccine. In the present review, the published literature on all the possible cases of re-infection from February to July were reported, thereby selected 142 studies from a hub of overall 669 studies after full text screening. The incomplete virus clearance, poor sensitivity of the present diagnostic testing, emergence of mutant strains, insufficient mucus collection from the throat swab etc., are some of the possible causes of re-infection. The new protocols for management of COVID-19 discharged patients should be revised in the guidelines.

Using Spelling Error Analyses to Examine Individual Differences in German Students From Diverse Linguistic Backgrounds: A Latent Class Approach.

The current study examined German spelling errors among students with German as their first language (L1) and those with German as their second language (L2) in Grades 3-4 (elementary school students; n = 127) and Grades 5-7 (secondary school students; n = 379). Five hundred and six students participated in the study. We performed two separate latent class analyses on elementary and secondary school students. Results indicate that elementary school students can be categorized as good (Class 1), consonant error dominant (Class 2), or poor (Class 3) spellers. However, secondary students can be categorized as addition and sequence error dominant (Class 1), substitution and omission error dominant (Class 2), or poor (Class 3) spellers. The three-step multinomial logistic regression analyses suggested that decoding was associated with the highest chances of being poor spellers in both elementary and secondary schools. Speaking German as L1 or L2 was a significant predictor of heterogeneities in secondary, but not elementary, school students. Polish L1 secondary students had the highest possibility of being poor spellers. The results suggest heterogeneities of student profiles. In addition, special attention should be given to secondary school students with the Polish L1 background in their spelling struggles associated with German orthography.

International Perspectives on Spelling and Writing in Different Orthographies: Introduction to the Special Series.

This article serves as an introduction to the special issue on spelling and writing in different orthographies. Most studies and theoretical models of writing are based on the English language, and it is generally assumed that what is true for English is also true for other languages. Further, there are more studies on reading compared to studies of writing and spelling. Considering that 80% of the world's population speaks a language other than English, we need more studies on writing and spelling in languages other than English. With this intention, we are presenting 6 papers on writing and spelling in different languages of different orthographic depth, from highly transparent orthographies like Spanish and Italian to highly opaque orthography like Cantonese.