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Development of effective vaccines for infectious diseases has been one of the most successful global health interventions in history. Though, while ideal subunit vaccines strongly rely on antigen and adjuvant(s) selection, the mode and time scale of exposure to the immune system has often been overlooked. Unfortunately, poor control over the delivery of many adjuvants, which play a key role in enhancing the quality and potency of immune responses, can limit their efficacy and cause off-target toxicities. There is a critical need for improved adjuvant delivery technologies to enhance their efficacy and boost vaccine performance. Nanoparticles have been shown to be ideal carriers for improving antigen delivery due to their shape and size, which mimic viral structures but have been generally less explored for adjuvant delivery. Here, we describe the design of self-assembled poly(ethylene glycol)-b-poly(lactic acid) nanoparticles decorated with CpG, a potent TLR9 agonist, to increase adjuvanticity in COVID-19 vaccines. By controlling the surface density of CpG, we show that intermediate valency is a key factor for TLR9 activation of immune cells. When delivered with the SARS-CoV-2 spike protein, CpG nanoparticle (CpG-NP) adjuvant greatly improves the magnitude and duration of antibody responses when compared to soluble CpG, and results in overall greater breadth of immunity against variants of concern. Moreover, encapsulation of CpG-NP into injectable polymeric-nanoparticle (PNP) hydrogels enhances the spatiotemporal control over codelivery of CpG-NP adjuvant and spike protein antigen such that a single immunization of hydrogel-based vaccines generates humoral responses comparable to those of a typical prime-boost regimen of soluble vaccines. These delivery technologies can potentially reduce the costs and burden of clinical vaccination, both of which are key elements in fighting a pandemic.

Designing yield stress fluids to exhibit desired functional properties is an integral challenge in many applications such as 3D printing, drilling, food formulation, fiber spinning, adhesives, and injectable biomaterials. Extensibility in particular has been found to be a highly beneficial characteristic for materials in these applications; however, few highly extensible, high water content materials have been reported to date. Herein we engineer a class of high water content nanocomposite hydrogel materials leveraging multivalent, noncovalent, polymer–nanoparticle (PNP) interactions between modified cellulose polymers and biodegradable nanoparticles. We show that modulation of the chemical composition of the PNP hydrogels controls the dynamic cross-linking interactions within the polymer network and directly impacts yielding and viscoelastic responses. These materials can be engineered to stretch up to 2000% strain and occupy an unprecedented property regime for extensible yield stress fluids. Moreover, a dimensional analysis of the relationships between extensibility and the relaxation and recovery time scales of these nanocomposite hydrogels uncovers generalizable design criteria that will be critical for future development of extensible materials.

Directing biological functions is at the heart of next-generation biomedical initiatives in tissue and immuno-engineering. However, the ambitious goal of engineering complex biological networks requires the ability to precisely perturb specific signaling pathways at distinct times and places. Using lipid nanotechnology and the principles of supramolecular self-assembly, we developed an injectable liposomal nanocomposite hydrogel platform to precisely control the release of multiple protein drugs. By integrating modular lipid nanotechnology into a hydrogel, we introduced multiple mechanisms of release based on liposome surface chemistry. To validate the utility of this system for multi-protein delivery, we demonstrated synchronized, sustained, and localized release of immunoglobulin G (IgG) antibody and interleukin-12 (IL-12) cytokine in vivo, despite the significant size differences between these two proteins. Overall, liposomal hydrogels are a highly modular platform technology with the ability to mediate orthogonal modes of protein release and the potential to precisely coordinate biological cues both in vitroand in vivo.

Polymer–nanoparticle hydrogels are a unique class of self‐assembled, shear‐thinning, yield‐stress fluids that have demonstrated potential utility in many impactful applications. Here, we present a thorough analysis of the gelation and yielding behavior of these materials with respect to the polymer and nanoparticle component stoichiometry. Through comprehensive rheological and diffusion studies, we reveal insights into the structural dynamics of the polymer nanoparticle network that identify that stoichiometry plays a key role in gelation and yielding, ultimately enabling the development of hydrogel formulations with unique shear‐thinning and yield‐stress behaviors. Access to these materials opens new doors for interesting applications in a variety of fields including tissue engineering, drug delivery, and controlled solution viscosity.

Derivatives of polycyclic aromatic hydrocarbons (PAHs) are widely used in optoelectronic materials. However, the poor solubility of unfunctionalized PAHs represents a challenge for the continued application of these compounds in emerging technologies. For organic compounds bearing one or more functional groups capable of engaging in directional hydrogen or halogen-bonding interactions, the crystal engineering toolkit currently offers many routes for optimizing the solid-state properties of these compounds. Such efforts typically lead to the discovery of periodic crystal forms that display strong adhesive intermolecular forces between the molecular fragments. By contrast, the crystal engineering of organic eutectic composites is relatively unexplored and poorly understood. Here, we report the mechanosynthesis and experimental characterization of the properties of three eutectic composites of pyrene (PYR) and anthracene (ANTH) that were discovered using the coformer bisphenol A (BPA) or phenothiazine (PTZ). The resulting eutectic composites (PYR-BPA, PYR-PTZ, and ANTH-PTZ) display significant melting point depressions ranging from 19 to 51 °C relative to the melting point of the PAH. The equilibrium solubilities of the composite materials were also observed to be 2–5 times greater than that of the PAH. The crystal engineering of eutectic solid forms is currently hampered by the lack of reliable empirical or theoretical tools for predicting their formation. A weighted Monte Carlo simulation was used to estimate the mixing energies and binding modes of a limited set of molecular pairs, leading to temperature-dependent interaction parameters that show promise in the selection of coformers with a high likelihood of forming eutectic composites. Complementary dispersion-corrected density functional theory (DFT-D) calculations on a set of PYRand ANTHcomposite models reveal that organic eutectic composites are not driven to form on the basis of favorable thermodynamics as evidenced by an average interaction energy of 2.60 kJ mol–1across the series. Synthon incompatibility and molecular shape mismatch appear to be important factors to consider in targeting eutectic solid forms. This work paves the way for the systematic crystal engineering of organic eutectic solid forms with tunable physicochemical properties using a synergistic computational modeling and mechanosynthesis approach.

Vaccines aim to elicit a robust, yet targeted, immune response. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system’s natural response to extended pathogen exposure during infection by designing an easily administered slow-delivery vaccine platform. We utilized an injectable and self-healing polymer–nanoparticle (PNP) hydrogel platform to prolong the codelivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique delivery characteristics, whereby physicochemically distinct compounds (such as antigen and adjuvant) could be codelivered over the course of weeks. When administered in mice, hydrogel-based sustained vaccine exposure enhanced the magnitude, duration, and quality of the humoral immune response compared to standard PBS bolus administration of the same model vaccine. We report that the creation of a local inflammatory niche within the hydrogel, coupled with sustained exposure of vaccine cargo, enhanced the magnitude and duration of germinal center responses in the lymph nodes. This strengthened germinal center response promoted greater antibody affinity maturation, resulting in a more than 1000-fold increase in antigen-specific antibody affinity in comparison to bolus immunization. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of subunit vaccines.

PurposeThe purpose of this study was to determine the attendance and success rates for seniors in voice therapy, identify any contributing patient-related factors, and compare results to existing findings for younger patients.MethodThis retrospective study included information from the voice records of 50 seniors seen by the same speech-language pathologist in a private practice. Analysis of attendance and outcome data divided participants into 6 groups. Outcomes for Groups 1–3 (64% of patients) were considered successful (positive voice change), while outcomes for Groups 4–6 (36% of patients) were considered unsuccessful. These data were compared to similar data collected for younger adults in a previous study.ResultsThe attendance and success rates for seniors in this study were higher than those previously reported for younger patients. Further consideration of patient factors revealed that reports of increased stress, Reflux Symptom Index scores > 13, and higher Voice Handicap Index functional subscale scores were significant in distinguishing between patients in the successful and unsuccessful treatment outcome groups.ConclusionsThe relatively high attendance and success rates among this sample of seniors suggest the desire to achieve voice improvement does not diminish with age, and chances for success in voice therapy among nonfrail seniors may be greater than for younger patients.

The number of biomedical applications of hydrogels is increasing rapidly on account of their unique physical, structural, and mechanical properties. The utility of hydrogels as drug delivery systems or tissue engineering scaffolds critically depends on the control of diffusion of solutes through the hydrogel matrix. Predicting or even modeling this diffusion is challenging due to the complex structure of hydrogels. Currently, the diffusivity of solutes in hydrogels is typically modeled by one of three main theories proceeding from distinct diffusion mechanisms: (i) hydrodynamic, (ii) free volume, and (iii) obstruction theory. Yet, a comprehensive predictive model is lacking. Thus, time and capital-intensive trial-and-error procedures are used to test the viability of hydrogel applications. In this work, we have developed a model for the diffusivity of solutes in hydrogels combining the three main theoretical frameworks, which we call the multiscale diffusion model (MSDM). We verified the MSDM by analyzing the diffusivity of dextran of different sizes in a series of poly(ethylene glycol) (PEG) hydrogels with distinct mesh sizes. We measured the subnanoscopic free volume by positron annihilation lifetime spectroscopy (PALS) to characterize the physical hierarchy of these materials. In addition, we performed a meta-analysis of literature data from previous studies on the diffusion of solutes in hydrogels. The model presented outperforms traditional models in predicting solute diffusivity in hydrogels and provides a practical approach to predicting the transport properties of solutes such as drugs through hydrogels used in many biomedical applications.

Background: Alzheimer’s Disease (AD) is the most common type of dementia characterized by amyloid plaques containing Amyloid Beta (Aβ) peptides and neurofibrillary tangles containing tau protein. In addition to neuronal loss, Cerebral Amyloid Angiopathy (CAA) commonly occurs in AD. CAA is characterized by Aβ deposition in brain microvessels. Recent studies have suggested that exosomes (cell-derived vesicles containing a diverse cargo) may be involved in the pathogenesis of AD. Objective: Isolate and characterize brain-derived exosomes from a transgenic mouse model of AD that presents CAA. Methods: Exosomes were isolated from serum obtained from 13-month-old wild type and AD transgenic female mice using an exosome precipitation solution. Characterization of exosomal proteins was performed by western blots and dot blots. Results: Serum exosomes were increased in transgenic mice compared to wild types as determined by increased levels of the exosome markers flotillin and alix. High levels of neuronal markers were found in exosomes, without any difference any between the 2 groups. Markers for endothelial-derived exosomes were decreased in the transgenic model, while astrocytic-derived exosomes were increased. Exosome characterization showed increased levels of oligomeric Aβ and oligomeric and monomeric forms tau on the transgenic animals. Levels of amyloid precursor protein were also increased. In addition, pathological and phosphorylated forms of tau were detected, but no difference was observed between the groups. Conclusion: These data suggest that monomeric and oligomeric forms of Aβ and tau are secreted into serum via brain exosomes, most likely derived from astrocytes in the transgenic mouse model of AD with CAA. Studies on the implication of this event in the propagation of AD are underway.

Fully-cycled depolymerization and repolymerization of a low ceiling temperature polymer, cyclic poly(phthalaldehyde) (cPPA), yielding high performance structural polymer is demonstrated. The facile conditions for cPPA depolymerization circumvent the extreme conditions required to break down and recycle traditional thermoplastics and thermosets. cPPA depolymerizes in as little as 14 min at 120 °C, with concurrent evaporation and quantitative recovery of the monomer. Polymerization of the recovered monomer produces cPPA with molecular and mechanical properties identical to the original material. Depolymerization of cPPA is also demonstrated in the presence of various carbon fiber reinforcements. Continuous carbon fibers retain 100% of their moduli and tensile strength through multiple generations of recycling, while fully recycled cPPA/carbon nanofiber composites exhibit mechanical properties equivalent to the original composite and show no degradation with cycling.

Parkinson’s disease (PD) is a multisystem disorder, and besides the classical motor symptoms it is now known that patients also suffer from a variety of non-motor symptoms that adversely affect quality of life (QOL). Since data on Hispanic populations on this issue are scarce, our aim was to study the association of non-motor symptoms and QOL in patients with PD. This study is a cross-sectional observational study involving patients with PD using the following instruments: Quality of Life Questionnaire (PDQ-8), Unified Parkinson’s Disease Rating Scale part III (UPDRS part III), and Non-Motor Symptom Scale (NMSS). We included 52 patients, with a median age of 64 years. Sleep/fatigue and mood/cognitive domains were the most common non-motor symptoms. Only sleep/fatigue, mood/cognition and gastrointestinal domains were associated with worse PDQ-8 scores. After adjusting for confounding variables, NMSS scores were significantly associated with a high PDQ-8 score. Higher NMSS scores were associated with and predicted higher PDQ-8 scores. The focus of management in PD should shift to a comprehensive strategy that incorporates care of non-motor symptoms and improves QOL.

Ed: For the complete article, visit circuitsassembly.com/cms/content/view/5291. We selected two handheld and three desktop XRF spectrometers because of their main specifications, performance and cost. They are Vendor 1-D, Vendor 2-D, [...]

Materials capable of rapidly modifying their physical properties in response to stimuli are desirable for on-demand deployment and adaptive engineering structures. Frontal polymerization is a self-propagating reaction that can quickly transform liquid reactants into solid products. In this contribution, we demonstrate that frontal polymerization enables facile, rapid stiffening of a vascular network embedded in a flexible matrix. Systematic variation of the vascular architecture shows that polymerization fronts in a polydimethylsiloxane (PDMS) matrix are self-propagating in channels as small as 838 μm and even when curves, branch points and converging geometries are present. After polymerization the composite structure was dramatically stiffened (up to 18 times the original Young’s modulus) based on tensile testing results. This work demonstrates the use of frontal polymerization as an efficient methodology for transforming flexible materials into functional supports or surfaces through endoskeletal stiffening.

Methamphetamine (Meth) is a highly addictive drug of abuse which alters the dopaminergic system and damages the blood-brain barrier (BBB), structure that protects the brain tissue from the circulating substances in the blood, keeping a low permeability through the presence of tight junctions (TJs) between endothelial cells. Meth increases BBB permeability by decreasing the TJs proteins claudin-5 and occludin and by decreasing the viability of endothelial cells. Individuals abused of Meth have increased blood concentrations of prolactin (PRL); hormone related with milk production, but able to increase the expression of TJs proteins and to decrease permeability on the mammary epithelium and brain endothelial cells. However, the effects of PRL on the permeability of the BBB in the presence of Meth have not been studied. Here, we report Meth-induced apoptosis and decreased cellular proliferation as well as the trans-endothelial electrical resistance (TEER), related to a decrease of claudin-5 and occludin in primary cultured bovine brain microvessel endothelial cells. The expression of the PRL receptor was not altered. Administration of PRL prevented a decrease in cellular proliferation, an increase in apoptosis and restored the TEER and TJs proteins to basal levels. This protection was absent at high Meth concentrations. These data suggest that PRL protects brain endothelial cells against the Meth-induced toxicity. Further investigation is required to study the mechanisms involved and to confirm these effects in vivo.

The blood-brain barrier (BBB) consists in part of a highly specialized set of cells which separates the brain from the vascular system. The BBB controls the entry and exit of substances from the brain tissue through tight junctions (TJs) between endothelial cells. It is known that the hormone prolactin (PRL) is able to regulate endothelial-dependent processes, like the balance between proliferation and apoptosis and the mammary epithelial permeability. However, the effects of PRL and the role it plays in the BBB permeability are still not well understood. A primary culture of bovine brain microvessel endothelial cells was used as in vitro model of BBB. Cells were treated with PRL (0.1, 1, 10 and 100 nM) for 24 hours. PRL significantly increased cellular proliferation at 10 and 100 nM, but did not modify basal apoptosis. These effects were dependent on the production of the mitogenic factor nitric oxide (NO). PRL significantly decreased the permeability and promoted an increase in trans-endothelial electrical resistance in a NO-independent way. PRL also increased the expression of the TJs proteins claudin-5 and occludin. The short form of the PRL receptor was detected in these cells but its expression was not modified by PRL. Together, these results suggest that PRL has the ability to increase cellular proliferation associated with a decrease on BBB permeability by increasing the expression of TJs proteins.

This study aimed to evaluate the effects of betacarotene (BC) supplementation on ovulation rate (OR) and luteinizing hormone (LH) secretion in adult goats during the breeding season. Additionally, total ovarian activity (TOA) comprising the total number of ultrasonographically detectable antral follicles (AF) and corpora lutea (OR) was also assessed. In early October, adult goats [n=22, 3.5 years of age, 7/8 Sannen-Alpine; 26°N, 103°W at 1117m.a.s.l.] were randomly assigned to: (i) BC group (BCG), orally supplemented with 50mg of BC/goat/day [n=10; live weight (LW)=45.9±2.0kg, body condition score (BCS; range: 0-emaciated to 5-obese)=3.0±0.1], and (ii) control group (CONT) [n=12; LW=46.2±2.0kg, BCS=3.0±0.1]. All animals received a basal diet of alfalfa hay, corn silage and corn grain, with free access to water and mineral salts. The whole experimental period spanned 34 days before and 17 days after ovulation. On day 23 of the experiment, estrus was synchronized with progestin-releasing intravaginal sponges; 36h prior to estrus, an intensive blood sampling (every 15min for 6h) was performed to determine mean LH concentrations, pulsatility (LH-PULSE) and area under the curve (LH-AUC) for serial LH concentrations. Afterwards, by the end of the luteal phase (i.e., 17 days after the onset of estrus), an ultrasonographic scanning was performed to evaluate OR and TOA [AF+OR]. The average LW and BCS did not differ (p>0.05) during the experimental period. BC-supplemented goats showed an increase in OR (3.4±0.2 versus 2.8±0.2; p<0.05) and exhibited lower (p<0.05) serum LH concentrations, LH-AUC and LH-PULSE compared to CONT. A positive correlation was recorded between OR and LW (r2=0.42, p<0.05) and BCS (r2=0.47, p<0.05). In addition, AF (5.0±0.6 versus 3.4±0.6) and TOA (8.4±0.6 versus 6.2±0.6) were greater (p<0.05) in the BC-supplemented group than CONT. Supplementation with BC enhanced ovarian follicular development and ovulation rate in adult female goats under decreased photoperiods through LHRH-independant pathways or direct effects of BC on ovarian function.

Water hydration is ubiquitous to biological molecules and surfaces at the nanoscale and critical to the mediation of all biological processes. Still, the wetting of biological surfaces, such as proteins and DNA, is not completely understood due to a lack of methods with sufficient resolution and/or sensitivity under bioactive conditions or moisturized environments. Moreover, a fundamental understanding of hydrophobic nonspecific interactions is still emerging. Here, we describe the mechanisms leading to height formation in ambient atomic force microscopy AFM and use them to show how the apparent height of DNA molecules is affected by their local hydrophilicity/hydrophobicity relative to the supporting surface. In the case of mica, a common substrate for imaging DNA, water films with heights of up to 2 nm form on its surface in ambient conditions. These films might partially cover dsDNA molecules and lead to apparent molecular height loss. Nevertheless, such decrease in molecular height is not solely affected by substrate and surface hydration but by limitations in AFM height measurements of nanoscale structures and the chemistry of the surface, the tip, and the molecule. Our study on apparent height measurements is consistent with partial hydration of the molecule relative to the supporting surface. Our approach to nanoscale water affinity mapping could impact the study of biological processes where the role of water films and fluidity is relevant such as protein folding and protein–DNA interactions.

ABSTRACTClostridium difficileis the leading cause of nosocomial antibiotic-associated diarrhea, and recent outbreaks of strains with increased virulence underscore the importance of identifying novel approaches to treat and prevent relapse of Clostridium difficile-associated diarrhea (CDAD). CDAD pathology is induced by two exotoxins, toxin A and toxin B, which have been shown to be cytotoxic and, in the case of toxin A, enterotoxic. In this report we describe fully human monoclonal antibodies (HuMAbs) that neutralize these toxins and prevent disease in hamsters. Transgenic mice carrying human immunoglobulin genes were used to isolate HuMAbs that neutralize the cytotoxic effects of either toxin A or toxin B in cell-based in vitro neutralization assays. Three anti-toxin A HuMAbs (3H2, CDA1, and 1B11) could all inhibit the enterotoxicity of toxin A in mouse intestinal loops and the in vivo toxicity in a systemic mouse model. Four anti-toxin B HuMAbs (MDX-1388, 103-174, 1G10, and 2A11) could neutralize cytotoxicity in vitro, although systemic toxicity in the mouse could not be neutralized. Anti-toxin A HuMAb CDA1 and anti-toxin B HuMAb MDX-1388 were tested in the well-established hamster model of C. difficiledisease. CDA1 alone resulted in a statistically significant reduction of mortality in hamsters; however, the combination treatment offered enhanced protection. Compared to controls, combination therapy reduced mortality from 100% to 45% (P< 0.0001) in the primary disease hamster model and from 78% to 32% (P< 0.0001) in the less stringent relapse model.

ABSTRACTSince 1989, we have been involved in the development of a vaccine against Haemophilus influenzaetype b. The new vaccine is based on the conjugation of synthetic oligosaccharides to tetanus toxoid. Our main goals have been (i) to verify the feasibility of using the synthetic antigen and (ii) to search for new production alternatives for this important infant vaccine. Overall, eight trials have already been conducted with adults, children (4 to 5 years old), and infants. We have described herein the details from the first two phase I clinical trials conducted with human adult volunteers under double blind, randomized conditions. The participants each received a single intramuscular injection to evaluate safety and initial immunogenicity. We have found an excellent safety profile and an antibody response similar to the one observed for the control vaccine.

The development of de novo autoimmune hepatitis as a long-term complication after liver transplantation has been recently reported. The authors describe five liver allograft recipients who developed chronic hepatitis associated with autoimmune features.

To ensure adequate safety and product quality levels in the operation of a batch alkyd polymer reactor, its concentration of acid groups, molecular weight, and viscosity must be monitored. However, in an industrial setting these variables can be measured in discrete time form and with a significant delay. In this work is presented a nonlinear estimator that, built from an uncertain kinetics-viscosity model and driven by the discrete-delayed measurements of viscosity, provides robustly convergent estimates of the variables of interest. The estimator has a robust convergence criterion, a simple construction-tuning procedure, and its functioning is shown with experimental data.

ABSTRACTIn infection with Schistosoma mansoni, hepatic granuloma formation is mediated by CD4+T helper (Th) cells sensitized to schistosomal egg antigens. There is considerable variation among infected individuals with respect to both severity of disease and the T-cell response to egg antigens. In the BL/6 mouse, the egg granulomas are relatively small and the relevant sensitizing egg antigens are largely unknown. We investigated the CD4+Th cell response of infected BL/6 mice to egg antigens fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and found a prominent lymphoproliferative response to be directed against a 62-kDa component. With the aid of a specific T-cell hybridoma, 4E6, the 62-kDa antigen was isolated; following partial digestion with endoproteinase Glu-C, an internal amino acid sequence was found to be identical with one present in the enzyme phosphoenolpyruvate carboxykinase (PEPCK) of the organisms Caenorhabditis elegansand Treponema pallidumand to differ by one residue from PEPCK of various other species. In CD4+Th cells from 7.5- 8.5-week-infected BL/6 mice, the purified 62-kDa molecule elicited a potent proliferative response which, based on cytokine analysis, was of a mixed Th-1 and Th-2 type. Our results reveal a novel egg antigen of particular prominence in the BL/6 mouse and suggest that the immune response in schistosomiasis is a product of sensitization to egg antigens that may vary considerably in immunogenicity from strain to strain.

Topical glaucoma therapies may induce adverse systemic side effects. This study was designed to determine the potential for drug-induced cardiovascular side effects of various glaucoma therapies applied topically to the eye. Data from three short-term double-blind studies in a total of 19 normal healthy adult volunteers were used to discriminate potential cardiovascular side effects. Baseline pulse rates and blood pressures were measured before and after exercise. Subsequent measurements were made 3 hr after topical ocular treatment with two drops of each glaucoma medication. Each individual was used to test each glaucoma therapy after washout of a 1 week period between treatments. The therapies included an alpha agonist (ALO 2145), three beta-blockers (betaxolol, bunolol, and timolol), and a placebo. No drug related pre- and post-exercise mean arterial pressure changes were observed. However, the two nonselective beta-blockers, timolol (0.5%) and bunolol (1%), consistently decreased the resting and/or exercise pulse rate, while the beta-1 selective blocker, betaxolol, did not. ALO 2145, the alpha agonist, did not alter the pulse rate or mean arterial pressure. Thus, some glaucoma therapies have the potential to reduce the heart rate especially under stress situations.

Six ophthalmic beta-blockers-betaxolol, timolol, levobunolol, pindolol, befunolol, and metipranolol-and placebo eyedrops were tested in six normal volunteers for their effect on exercise heart rate, blood pressure, and electrocardiogram tracings. None of the solutions affected blood pressure or electrocardiogram results. Betaxolol and placebo did not affect heart rate. However, all the other agents significantly (p < 0.05) suppressed the heart's ability to respond to exercise.These same formulations were tested by spirometry in six asdimatic patients. Betaxolol and placebo had no effect on forced expiratory volume at 1 sec (FEV,), whereas all the other agents significantly (p < 0.05) depressed vital lung function.

The development of computed tomography and functional endoscopic sinus surgery has improved diagnosis and management of sinusitis. It has also renewed interest in the developmental anatomy of the paranasal sinuses. There are significant differences between adult and pediatric sinus anatomy, and to safely perform functional endoscopic sinus surgery in children, the surgeon must be aware of these differences. To define the developmental anatomy of the paranasal sinuses, we analyzed 145 computed tomograms from patients under 18 years of age. The study emphasized landmarks at the level of the maxillary sinus ostium. In addition, distances and angles from the nasal spine to various points in the sinuses were determined. The structures were identified and traced on a digitizing tablet. Means and standard deviations were calculated for each measure as a function of age. This study can aid a better understanding of sinus development in children and provide guidance to the endoscopic sinus surgeon.

Hernandez, H. J., Edson, C. M., Harn, D. A., Ianelli, C. J., and Stadecker, M. J. 1998.Schistosoma mansoni: Genetic restriction and cytokine profile of the CD4+ T helper cell response to dominant epitope peptide of major egg antigen Sm-p40.Experimental Parasitology90, 122–130. Granuloma formation in schistosomiasis is mediated by MHC class II-restricted CD4 + T helper lymphocytes sensitized to egg antigens. We previously reported that C3H mice, which develop large granulomas, display strong CD4 + T helper cell responses to the major egg antigen Sm-p40. Moreover, all members of a panel of egg antigen-specific T cell hybridomas responded to the Sm-p40 antigen. Given the significance of the Sm-p40 molecule in the C3H T cell repertoire against schistosomal egg antigens, the current work was undertaken to map its immunogenic epitopes, using a library of 15 synthetic overlapping 30-mer peptides. The dominant epitope recognized by polyclonal CD4 + Th cells was located in peptide 10 (amino acids 229–258); subdominant epitopes were detected in peptides 8 (amino acids 179–208) and 12 (amino acids 279–308). The anti-Sm-p40 T cell hybridomas variously responded to any one of the same three stimulatory peptides. Furthermore, studies with various mouse strains demonstrated that a strong anti-Sm-p40 response was restricted by H-2k. Interestingly, the cells responding to peptide 10 and to the Sm-p40 antigen only secreted IL-2 and IFN-γ, but not IL-4 and IL-10, indicating that they are entirely of the Th-1-type, a subset with demonstrated capacity to mediate egg granuloma formation. The identification of dominant epitopes within key egg antigens offers opportunities for desensitization of the CD4 + Th cells that mediate pathology in schistosomia sis.

ObjectiveTo determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19.DesignLiving systematic review and network meta-analysis.Data sourcesWorld Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021.Study selectionRandomised trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.MethodsRandom effects bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach.ResultsThe first iteration of this living network meta-analysis includes nine randomised trials—six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain.ConclusionsHydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection.Systematic review registrationThis review was not registered. The protocol established a priori is included as a supplement.Readers’ noteThis article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

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ObjectiveTo compare the effects of treatments for coronavirus disease 2019 (covid-19).DesignLiving systematic review and network meta-analysis.Data sourcesUS Centers for Disease Control and Prevention COVID-19 Research Articles Downloadable Database, which includes 25 electronic databases and six additional Chinese databases to 20 July 2020.Study selectionRandomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.MethodsAfter duplicate data abstraction, a bayesian random effects network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance.Results23 randomised controlled trials were included in the analysis performed on 26 June 2020. The certainty of the evidence for most comparisons was very low because of risk of bias (lack of blinding) and serious imprecision. Glucocorticoids were the only intervention with evidence for a reduction in death compared with standard care (risk difference 37 fewer per 1000 patients, 95% credible interval 63 fewer to 11 fewer, moderate certainty) and mechanical ventilation (31 fewer per 1000 patients, 47 fewer to 9 fewer, moderate certainty). These estimates are based on direct evidence; network estimates for glucocorticoids compared with standard care were less precise because of network heterogeneity. Three drugs might reduce symptom duration compared with standard care: hydroxychloroquine (mean difference −4.5 days, low certainty), remdesivir (−2.6 days, moderate certainty), and lopinavir-ritonavir (−1.2 days, low certainty). Hydroxychloroquine might increase the risk of adverse events compared with the other interventions, and remdesivir probably does not substantially increase the risk of adverse effects leading to drug discontinuation. No other interventions included enough patients to meaningfully interpret adverse effects leading to drug discontinuation.ConclusionGlucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care. The effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.Systematic review registrationThis review was not registered. The protocol is included as a supplement.Readers’ noteThis article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

ObjectiveTo develop an instrument to evaluate the credibility of anchor based minimal important differences (MIDs) for outcome measures reported by patients, and to assess the reliability of the instrument.DesignInstrument development and reliability study.Data sourcesInitial criteria were developed for evaluating the credibility of anchor based MIDs based on a literature review (Medline, Embase, CINAHL, and PsycInfo databases) and the experience of the authors in the methodology for estimation of MIDs. Iterative discussions by the team and pilot testing with experts and potential users facilitated the development of the final instrument.ParticipantsWith the newly developed instrument, pairs of masters, doctoral, or postdoctoral students with a background in health research methodology independently evaluated the credibility of a sample of MID estimates.Main outcome measuresCore credibility criteria applicable to all anchor types, additional criteria for transition rating anchors, and inter-rater reliability coefficients were determined.ResultsThe credibility instrument has five core criteria: the anchor is rated by the patient; the anchor is interpretable and relevant to the patient; the MID estimate is precise; the correlation between the anchor and the outcome measure reported by the patient is satisfactory; and the authors select a threshold on the anchor that reflects a small but important difference. The additional criteria for transition rating anchors are: the time elapsed between baseline and follow-up measurement for estimation of the MID is optimal; and the correlations of the transition rating with the baseline, follow-up, and change score in the patient reported outcome measures are satisfactory. Inter-rater reliability coefficients (ĸ) for the core criteria and for one item from the additional criteria ranged from 0.70 to 0.94. Reporting issues prevented the evaluation of the reliability of the three other additional criteria for the transition rating anchors.ConclusionsResearchers, clinicians, and healthcare policy decision makers can consider using this instrument to evaluate the design, conduct, and analysis of studies estimating anchor based minimal important differences.

The combination of osteomyelitis, Salmonella infection, and sickle-cell anemia was found in three patients aged 33, 8, and 19 years. The infecting organism was identified as Sal. typhi, Sal. st. paul, and Sal. typhimurium, respectively, in the three cases. One patient had been treated with penicillin for two years without success. It is important both to identify the organism and to recognize the nature of the anemia in cases of this sort, for open suppurating lesions that discharge Salmonella are dangerous to attendants and antibiotics are of no avail unless they are adapted to the causative organism.

The study of the Aloe-Vera employed as the protection of the stainless steel 316 using different electrochemical techniques like linear polarization resistance, electrochemical impedance spectroscopy and polarization curves. The Aloe-Vera shows that the optimal concentration (100 ppm) is considered the ideal to decrease the corrosion process, getting a 90% of inhibitor efficiency. Finally, the Aloe-Vera can be considered as mixed type inhibitor under these experimental conditions.

The response of Scott Parker to several letters to the editor including one about the C5 Z06 brake caliper, one about the Tsm with iron heads mile-per-hour record holder and one about the safety of a 427 kit or a 408 stoker.

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