Impact of waning immunity against SARS-CoV-2 severity exacerbated by vaccine hesitancy.

The SARS-CoV-2 pandemic has generated a considerable number of infections and associated morbidity and mortality across the world. Recovery from these infections, combined with the onset of large-scale vaccination, have led to rapidly-changing population-level immunological landscapes. In turn, these complexities have highlighted a number of important unknowns related to the breadth and strength of immunity following recovery or vaccination. Using simple mathematical models, we investigate the medium-term impacts of waning immunity against severe disease on immuno-epidemiological dynamics. We find that uncertainties in the duration of severity-blocking immunity (imparted by either infection or vaccination) can lead to a large range of medium-term population-level outcomes (i.e. infection characteristics and immune landscapes). Furthermore, we show that epidemiological dynamics are sensitive to the strength and duration of underlying host immune responses; this implies that determining infection levels from hospitalizations requires accurate estimates of these immune parameters. More durable vaccines both reduce these uncertainties and alleviate the burden of SARS-CoV-2 in pessimistic outcomes. However, heterogeneity in vaccine uptake drastically changes immune landscapes toward larger fractions of individuals with waned severity-blocking immunity. In particular, if hesitancy is substantial, more robust vaccines have almost no effects on population-level immuno-epidemiology, even if vaccination rates are compensatorily high among vaccine-adopters. This pessimistic scenario for vaccination heterogeneity arises because those few individuals that are vaccine-adopters are so readily re-vaccinated that the duration of vaccinal immunity has no appreciable consequences on their immune status. Furthermore, we find that this effect is heightened if vaccine-hesitants have increased transmissibility (e.g. due to riskier behavior). Overall, our results illustrate the necessity to characterize both transmission-blocking and severity-blocking immune time scales. Our findings also underline the importance of developing robust next-generation vaccines with equitable mass vaccine deployment.

Comparison of Physicochemical Properties of Native Mucus and Reconstituted Mucin Gels.

Simulating native mucus with model systems such as gels made from reconstituted mucin or commercially available polymers presents experimental advantages including greater sample availability and reduced inter- and intradonor heterogeneity. Understanding whether these gels reproduce the complex physical and biochemical properties of native mucus at multiple length scales is critical to building relevant experimental models, but few systematic comparisons have been reported. Here, we compared bulk mechanical properties, microstructure, and biochemical responses of mucus from different niches, reconstituted mucin gels (with similar pH and polymer concentrations as native tissues), and commonly used commercially available polymers. To evaluate gel properties across these length scales, we used small-amplitude oscillatory shear, single-particle tracking, and microaffinity chromatography with small analytes. With the exception of human saliva, the mechanical response of mucin gels was qualitatively similar to that of native mucus. The transport behavior of charged peptides through native mucus gels was qualitatively reproduced in gels composed of corresponding isolated mucins. Compared to native mucus, we observed substantial differences in the physicochemical properties of gels reconstituted from commercially available mucins and the substitute carboxymethylcellulose, which is currently used in artificial tear and saliva treatments. Our study highlights the importance of selecting a mucus model system guided by the length scale relevant to the scientific investigation or disease application.

Distributed medium viscosity yields quasi-exponential step-size probability distributions in heterogeneous media.

The analysis of the statistics of random walks undertaken by passive particles in complex media has important implications in a number of areas including pathogen transport and drug delivery. In several systems in which heterogeneity is important, the distribution of particle step-sizes has been found to be exponential in nature, as opposed to the Gaussian distribution associated with Brownian motion. Here, we first develop a theoretical framework to study a simplified version of this problem: the motion of passive tracers in a range of sub-environments with different viscosity. We show that in the limit of a large number of equi-distributed sub-environments spanning a broad viscosity range, an exact analytical expression for the underlying particle step-size distribution can be derived, which approaches an exponential distribution when step sizes are small. We then validate this using a simple experimental system of glycerol-water mixtures, in which the volume fraction of glycerol is systematically varied. Overall, the assumption of exponentially distributed step sizes may substantially over-estimate the incidence of large steps in heterogeneous systems, with important implications in the analysis of various biophysical processes.

"If Their Face Starts Turning Purple, You Are Probably Doing Something Wrong": Young Men's Experiences with Choking During Sex.

Choking/strangulation during sex has become prevalent in the United States. Yet, no qualitative research has addressed men's choking experiences. Through interviews with 21 young adult men, we examined the language men use to refer to choking, how they first learned about it, their experiences with choking, and consent and safety practices. Men learned about choking during adolescence from pornography, partners, friends, and mainstream media. They engaged in choking to be kinky, adventurous, and to please partners. While many enjoyed or felt neutral about choking, others were reluctant to choke or be choked. Safety and verbal/non-verbal consent practices varied widely.

"It Was Scary, But Then It Was Kind of Exciting": Young Women's Experiences with Choking During Sex.

Choking/strangulation during sex is prevalent among young adults, with one study finding that 58% of women college students had ever been choked during sex. However, no qualitative study has examined women's experiences with choking/strangulation during sex outside of intimate partner violence. The purpose of our qualitative interview study was to investigate women's experiences with choking and/or being choked during partnered sex. Through in-depth interviews with 24 undergraduate and graduate women students ages 18 to 33, we sought to understand how women communicate about choking, their learning about and initiation into choking, their feelings about being choked and choking others, as well as consent and safety practices used in relation to choking. We found that women had first learned about choking through diverse sources including pornography, erotic stories, magazines, social media, friends, and partners. While all 24 women had been choked during sex, only 13 of 24 had ever choked a partner. They described having engaged in choking with men as well as women and with committed as well as more casual partner types. Participants described consensual and non-consensual choking experiences. While many women enjoyed choking, others did it largely to please their sexual partner. Women described different methods and intensities of having been choked. Although very few had ever sought out information on safety practices or risk reduction, and only some had established safe words or safe gestures with partners, participants consistently expressed a belief that the ways in which they and their partner(s) engaged in choking were safe.

Non-Gaussian, non-ergodic, and non-Fickian diffusion of tracers in mucin hydrogels.

Native mucus is polymer-based soft-matter material of paramount biological importance. How non-Gaussian and non-ergodic is the diffusive spreading of pathogens in mucus? We study the passive, thermally driven motion of micron-sized tracers in hydrogels of mucins, the main polymeric component of mucus. We report the results of the Bayesian analysis for ranking several diffusion models for a set of tracer trajectories [C. E. Wagner et al., Biomacromolecules, 2017, 18, 3654]. The models with "diffusing diffusivity", fractional and standard Brownian motion are used. The likelihood functions and evidences of each model are computed, ranking the significance of each model for individual traces. We find that viscoelastic anomalous diffusion is often most probable, followed by Brownian motion, while the model with a diffusing diffusion coefficient is only realised rarely. Our analysis also clarifies the distribution of time-averaged displacements, correlations of scaling exponents and diffusion coefficients, and the degree of non-Gaussianity of displacements at varying pH levels. Weak ergodicity breaking is also quantified. We conclude that-consistent with the original study-diffusion of tracers in the mucin gels is most non-Gaussian and non-ergodic at low pH that corresponds to the most heterogeneous networks. Using the Bayesian approach with the nested-sampling algorithm, together with the quantitative analysis of multiple statistical measures, we report new insights into possible physical mechanisms of diffusion in mucin gels.

Diselenoamino acid derivatives as GPx mimics and as substrates of TrxR: in vitro and in silico studies.

Excessive production of reactive species in living cells usually has pathological effects. Consequently, the synthesis of compounds which can mimic the activity of antioxidant enzymes has inspired great interest. In this study, a variety of diselenoamino acid derivatives from phenylalanine and valine were tested to determine whether they could be functional mimics of glutathione peroxidase (GPx) and substrates for liver thioredoxin reductase (TrxR). Diselenides C and D showed the best GPx mimicking properties when compared with A and B. We suppose that the catalytic activity of diselenide GPx mimics depends on the steric effects, which can be influenced by the number of carbon atoms between the selenium atom and the amino acid residue and/or by the amino acid lateral residue. Compounds C and D stimulated NADPH oxidation in the presence of partially purified hepatic mammalian TrxR, indicating that they are substrates for TrxR. Our study indicates a possible dissociation between the two pathways for peroxide degradation (i.e., via a substrate for TrxR or via mimicry of GPx) for compounds tested in this study, except for PhSeSePh, and the antioxidant activity of diselenoamino acids can also be attributed to their capacity to mimic GPx and to be a substrate for mammalian TrxR.

Protective effect of (-)-α-bisabolol on rotenone-induced toxicity in Drosophila melanogaster.

(-)-α-Bisabolol (BISA) is a sesquiterpene alcohol, which has several recognized biological activities, including anti-inflammatory, anti-irritant, and antibacterial properties. In the present study, we investigated the influence of BISA (5, 25, and 250 µmol/L) on rotenone (500 µmol/L)-induced toxicity in Drosophila melanogaster for 7 days. BISA supplementation significantly decreased rotenone-induced mortality and locomotor deficits. The loss of motor function induced by rotenone correlated with a significant change in stress response factors; it decreased thiol levels, inhibited mitochondria complex I, and increased the mRNA expression of antioxidant marker proteins such as superoxide dismutase (SOD), catalase (CAT), and the keap1 gene product. Taken together, our findings indicate that the toxicity of rotenone is likely due to the direct inhibition of complex I activity, resulting in a high level of oxidative stress. Dietary supplementation with BISA affected the expression of SOD mRNA only at a concentration of 250 µmol/L, and did not affect any other parameter measured. Our results showed a protective effect of BISA on rotenone-induced mortality and locomotor deficits in Drosophila; this effect did not correlate with mitochondrial complex I activity, but may be related to the antioxidant protection afforded by eliminating superoxide generated as a result of rotenone-induced mitochondrial dysfunction.

A Rheological Study of the Association and Dynamics of MUC5AC Gels.

The details of how a mucus hydrogel forms from its primary structural component, mucin polymers, remain incompletely resolved. To explore this, we use a combination of macrorheology and single-particle tracking to investigate the bulk and microscopic mechanical properties of reconstituted MUC5AC mucin gels. We find that analyses of thermal fluctuations on the length scale of the micrometer-sized particles are not predictive of the linear viscoelastic response of the mucin gels, and that taken together, the results from both techniques help to provide complementary insight into the structure of the network. In particular, we show that macroscopic stiffening of MUC5AC gels can be brought about in different ways by targeting specific associations within the network using environmental triggers such as modifications to the pH, surfactant, and salt concentration. Our work may be important for understanding how environmental factors, including pathogens and therapeutic agents, alter the mechanical properties of fully constituted mucus.

Harpagophytum Procumbens Ethyl Acetate Fraction Reduces Fluphenazine-Induced Vacuous Chewing Movements and Oxidative Stress in Rat Brain.

Long-term treatment with fluphenazine is associated with manifestation of extrapyramidal side effects, such as tardive dyskinesia. The molecular mechanisms related to the pathophysiology of TD remain unclear, and several hypotheses, including a role for oxidative stress, have been proposed. Harpagophytum procumbens is an herbal medicine used mainly due to anti-inflammatory effects, but it also exhibits antioxidant effects. We investigated the effect of ethyl acetate fraction of H. procumbens (EAF HP) in fluphenazine-induced orofacial dyskinesia by evaluating behavioral parameters at different times (vacuous chewing movements (VCM's) and locomotor and exploratory activity), biochemical serological analyses, and biochemical markers of oxidative stress of the liver, kidney, cortex, and striatum. Chronic administration of fluphenazine (25 mg/kg, intramuscular (i.m) significantly increased the VCMs at all analyzed times (2, 7, 14, and 21 days), and this was inhibited by EAF HP (especially at a dose of 30 mg/kg). Fluphenazine decreased locomotion and exploratory activity, and EAF HP did not improve this decrease. Fluphenazine induced oxidative damage, as identified by changes in catalase activity and ROS levels in the cortex and striatum, which was reduced by EAF HP, especially in the striatum. In the cortex, EAF HP was protective against fluphenazine-induced changes in catalase activity but not against the increase in ROS level. Furthermore, EAF HP was shown to be safe, since affected serum biochemical parameters or parameters of oxidative stress in the liver and kidney. These findings suggest that the H. procumbens is a promising therapeutic agent for the treatment of involuntary oral movements.

Effects of diphenyl diselenide on behavioral and biochemical changes induced by amphetamine in mice.

Diphenyl diselenide (PhSe)2, an organoselenium compound, has been studied as a potential pharmacological agent in different in vitro and in vivo models, mainly due to its antioxidant properties. However, there are few studies concerning the effects of (PhSe)2 on dopaminergic system. Thus, the purpose of the present study was to evaluate the effects of acute and sub-chronic treatment of (PhSe)2 on amphetamine-induced behavioral and biochemical parameters. In acute protocol, mice were pre-treated with 5 or 10 mg/kg of (PhSe)2 and 30 min after, amphetamine was administered. In sub-chronic protocol, mice were pre-treated with 5 or 10 mg/kg of (PhSe)2 during 7 days and 24 h after, amphetamine was administered. Twenty-five minutes after amphetamine administration, behavioral (crossing, rearing, time of stereotypy and immobility) and biochemical (MAO activity, DCFH-DA oxidation, protein and non-protein thiol groups) parameters were analyzed. Amphetamine increased the number of crossing and rearing and (PhSe)2 prevented only the increase in the number of crossings when acutely administered to mice. Furthermore, amphetamine increased stereotypy and time of immobility in mice. (PhSe)2, at 10 mg/kg, increased per se the stereotypy and time of immobility when sub-chronically administered. (PhSe)2, at 10 mg/kg, potentiated the stereotypy caused by amphetamine in both protocols. Sub-chronic treatment with (PhSe)2 either alone (5 and 10 mg/kg) or in combination (10 mg/kg) with amphetamine decreased brain MAO-B activity. Oxidative stress parameters were not modified by (PhSe)2 and/or amphetamine treatments. In conclusion, sub-chronic administration of (PhSe)2 can promote a behavioral sensitization that seems to be, at least in part, dependent of MAO-B inhibition.

Continuity of care in the cross-border context: insights from a survey of German patients treated abroad.

BACKGROUND: Continuity of care is important for outcomes and patient satisfaction and includes additional considerations in the context of cross-border health care. Although this has been discussed in research and was picked up in the recently transposed Directive on patients' rights (2011/24/EU), there is limited evidence about related issues actually encountered by patients crossing borders. METHODS: An anonymous postal survey was carried out by the Techniker Krankenkasse, one of the largest sickness funds in Germany. The questionnaire was sent to 45 189 individuals who had received treatment in EU/EEA countries and included items on relational, management and informational continuity. RESULTS: The survey had a response rate of 41% (n = 17 543). Of those respondents who had travelled for care (n = 3307), ∼19% (n = 570) did so due to a relationship of trust with a given provider. Only 8% of all respondents required emergency follow-up services due to complications, the majority of which was obtained back in Germany. Twelve percentage of those who were prescribed medication abroad (n = 4208) reported problems, spanning unknown products, dispensation and reimbursement. Information exchange between providers across borders was rare and largely carried out by the patients themselves. CONCLUSIONS: Although relational continuity may be important to specific groups of patients travelling for care, it is primarily informational continuity and its interrelation with management continuity that need to be addressed in the cross-border context. Information exchange should be endorsed at European level. Additional focus is required on informing patients about documentation rights and requirements and providing health records that are comprehensive and comprehensible.

Copper and selenium: auxiliary measure to control infection by Haemonchus contortus in lambs.

The aim of this study was to evaluate the effects of selenium and copper on oxidative stress and its performance in lambs experimentally infected with Haemonchus contortus. Twenty-eight five-months old lambs were experimentally infected by the oral route with 5000 third-stage infective larvae and allocated into four groups, i.e., untreated animals, animals treated intramuscularly with sodium selenite (0.2 mg kg(-1)), animals treated subcutaneously with copper (3.5 mg kg(-1)), and animals treated with sodium selenite (IM; 0.2 mg kg(-1)) and copper (SC; 3.5 mg kg(-1)). These animals received oat hay (Avena sativa) and commercial concentrate, totaling 15% of crude protein, 30% being derived from oat hay and 70% of the concentrate. Lipid peroxidation, antioxidant enzymes, eggs per gram of feces (EPG) and body weight were assessed on the day of infection and after 20, 40, 60 and 80 days post-infection. The number of H. contortus adults was assessed at the end of the experiment. The selenium associated or not with copper reduced the effects of oxidative stress caused by infection. The groups supplemented with copper had increased body weight, and the combination of these two minerals reduced the EPG and number of H. contortus adults in lambs. The use of selenium associated with copper may help the control of infection by H. contortus.

Implications of the EU patients' rights directive in cross-border healthcare on the German sickness fund system.

We examine the implications of the EU directive on the application of patients' rights in cross-border healthcare on the German sickness fund system. Since Germany implemented most requirements of the directive already in 2004, we first review Germany's experience with EU cross-border healthcare. We then focus on the possible effects of increased EU cross-border healthcare. While this gives patients more choice, the German sickness fund system faces a number of challenges. EU cross-border care may undermine efforts to keep healthcare expenditure under control. Cross-border care can also increase inequality of access. Furthermore, promoting cross-border care can be a means for sickness funds to attract good risks. We discuss these challenges and point out possible policy responses.

Thiazide-Induced Hyponatremia Presenting as a Fall in an Older Adult.

Background: Regardless of age, first-line therapy for uncomplicated hypertension includes thiazide diuretics, long-acting calcium channel blockers, and renin-angiotensin system inhibitors. Even though older adults are often at increased risk of adverse drug events, specific guidelines for choosing between different classes of antihypertensives are lacking. Given the prevalence of hypertension in older adults, clinicians should be aware of the increased risk of electrolyte disorders after the initiation of thiazide diuretics in this population. Case Presentation: A patient aged > 90 years fell getting out of his bed 2 weeks following initiation of hydrochlorothiazide 25 mg daily medication therapy. Laboratory tests revealed a urine sodium of 35 mmol/L most consistent with hypovolemic hypoosmotic hyponatremia secondary to thiazide initiation. Hydrochlorothiazide was discontinued and sodium gradually normalized over the next 2 weeks without any other intervention. Conclusions: Despite being recommended as first-line therapy for uncomplicated hypertension, thiazide diuretics may cause more harm than good in older adults with risk factors for thiazide-induced hyponatremia, which should be considered before initiation.

Harpagophytum procumbens prevents oxidative stress and loss of cell viability in vitro.

Harpagophytum procumbens, popularly known as devil's claw, is a plant commonly used in the treatment of diseases of inflammatory origin. The anti-inflammatory effects of H. procumbens have been studied; however, the mechanism of action is not elucidated. It is known that excess of reactive oxygen and nitrogen species may contribute to increasing tissue damage due to inflammation. In the present study, we examined the effects of H. procumbens infusion, crude extract and fractions on lipid peroxidation (brain homogenates) induced by different pro-oxidants (Fe(2+) or sodium nitroprusside) and the effects of ethyl acetate fraction (rich in phenolic compounds) on antioxidant defenses (catalase activity and thiol levels) and cell damage (brain cortical slices) induced by different pro-oxidants. All tested extracts of H. procumbens inhibited lipid peroxidation in a concentration-dependent manner. Furthermore, the ethyl acetate fraction had the highest antioxidant effects either by decreasing lipid peroxidation and cellular damage or restoring thiols levels and catalase activity. Taken together, our results showed that H. procumbens acts either by preventing oxidative stress or loss of cell viability. Thus, the previously reported anti-inflammatory effect of H. procumbens could also be attributed to its antioxidant activity.

Effect of Hypericum perforatum on different models of movement disorders in rats.

The effects of Hypericum perforatum, a plant with antidepressant action, were evaluated in models of abnormal movements in rats, brought about by administration of fluphenazine or reserpine. The number of vacuous chewing movements (VCMs) and locomotor activity (the number of crossings and rears in the open field test) were measured. In experiment 1, rats received a single administration of fluphenazine enanthate (25 mg/kg, intramuscular) and/or daily treatment with H. perforatum (300 mg/kg, in place of drinking water) for 7 days. Fluphenazine increased VCMs and decreased locomotor activity. H. perforatum had no effect on either the number of VCMs or the locomotor activity. In experiment 2, rats received reserpine every 2 days for 6 days (0.5 mg/kg, subcutaneous) and/or H. perforatum (300 mg/kg, in place of drinking water) daily for 16 days beginning 10 days before the first administration of reserpine. Reserpine treatment increased VCMs and decreased locomotor activity. H. perforatum had no effect on either the number of VCMs or the number of rears but did prevent the effect of reserpine on the number of crossings. In conclusion, H. perforatum failed to protect against orofacial movements induced by fluphenazine or reserpine in rats.