Tri-layered elastomeric scaffolds for engineering heart valve leaflets

Tissue engineered heart valves (TEHVs) that can grow and remodel have the potential to serve as permanent replacements of the current non-viable prosthetic valves particularly for pediatric patients. A major challenge in designing functional TEHVs is to mimic both structural and anisotropic mechanical characteristics of the native valve leaflets. To establish a more biomimetic model of TEHV, we fabricated tri-layered scaffolds by combining electrospinning and microfabrication techniques. These constructs were fabricated by assembling microfabricated poly(glycerol sebacate) (PGS) and fibrous PGS/poly(caprolactone) (PCL) electrospun sheets to develop elastic scaffolds with tunable anisotropic mechanical properties similar to the mechanical characteristics of the native heart valves. The engineered scaffolds supported the growth of valvular interstitial cells (VICs) and mesenchymal stem cells (MSCs) within the 3D structure and promoted the deposition of heart valve extracellular matrix (ECM). MSCs were also organized and aligned along the anisotropic axes of the engineered tri-layered scaffolds. In addition, the fabricated constructs opened and closed properly in an ex vivo model of porcine heart valve leaflet tissue replacement. The engineered tri-layered scaffolds have the potential for successful translation towards TEHV replacements.     

Controlled cyclic stretch bioreactor for tissue-engineered heart valves

A tissue-engineered heart valve (TEHV) represents the ultimate valve replacement, especially for juvenile patients given its growth potential. To date, most TEHV bioreactors have been developed based on pulsed flow of culture medium through the valve lumen to induce strain in the leaflets. Using a strategy for controlled cyclic stretching of tubular constructs reported previously, we developed a controlled cyclic stretch bioreactor for TEHVs that leads to improved tensile and compositional properties. The TEHV is mounted inside a latex tube, which is then cyclically pressurized with culture medium. The root and leaflets stretch commensurately with the latex, the stretching being dictated by the stiffer latex and thus controllable. Medium is also perfused through the lumen at a slow rate in a flow loop to provide nutrient delivery. Fibrin-based TEHVs prepared with human dermal fibroblasts were subjected to three weeks of cyclic stretching with incrementally increasing strain amplitude. The TEHV possessed the tensile stiffness and stiffness anisotropy of leaflets from sheep pulmonary valves and could withstand cyclic pulmonary pressures with similar distension as for a sheep pulmonary artery.     

A Novel Flex-Stretch-Flow Bioreactor for the Study of Engineered Heart Valve Tissue Mechanobiology

Tissue engineered heart valves (TEHV) have been observed to respond to mechanical conditioning in vitro by expression of activated myofibroblast phenotypes followed by improvements in tissue maturation. In separate studies, cyclic flexure, stretch, and flow (FSF) have been demonstrated to exhibit both independent and coupled stimulatory effects. Synthesis of these observations into a rational framework for TEHV mechanical conditioning has been limited, however, due to the functional complexity of tri-leaflet valves and the inherent differences of separate bioreactor systems. Toward quantifying the effects of individual mechanical stimuli similar to those that occur during normal valve function, a novel bioreactor was developed in which FSF mechanical stimuli can be applied to engineered heart valve tissues independently or in combination. The FSF bioreactor consists of two identically equipped chambers, each having the capacity to hold up to 12 rectangular tissue specimens (25 × 7.5 × 1 mm) via a novel “spiral-bound” technique. Specimens can be subjected to changes-in-curvature up to 50 mm⁻¹ and uniaxial tensile strains up to 75%. Steady laminar flow can be applied by a magnetically coupled paddlewheel system. Computational fluid dynamic (CFD) simulations were conducted and experimentally validated by particle image velocimetry (PIV). Tissue specimen wall shear stress profiles were predicted as a function of paddlewheel speed, culture medium viscosity, and the quasi-static state of specimen deformation (i.e., either undeformed or completely flexed). Velocity profiles predicted by 2D CFD simulations of the paddlewheel mechanism compared well with PIV measurements, and were used to determine boundary conditions in localized 3D simulations. For undeformed specimens, predicted inter-specimen variations in wall shear stress were on average ±7%, with an average wall shear stress of 1.145 dyne/cm² predicted at a paddlewheel speed of 2000 rpm and standard culture conditions. In contrast, while the average wall shear stress predicted for specimens in the quasi-static flexed state was ∼59% higher (1.821 dyne/cm²), flexed specimens exhibited a broad intra-specimen wall shear stress distribution between the convex and concave sides that correlated with specimen curvature, with peak wall shear stresses of ∼10 dyne/cm². This result suggests that by utilizing simple flexed geometric configurations, the present system can also be used to study the effects of spatially varying shear stresses. We conclude that the present design provides a robust tool for the study of mechanical stimuli on in vitro engineered heart valve tissue formation. George C. Engelmayr, Jr. and Lorenzo Soletti are contributed equally.     

Lateral diffusion of manganese in the rat brain determined by T<Subscript>1</Subscript> relaxation time measured by <Superscript>1</Superscript>H MRI

In order to optimize manganese ion-enhanced MRI in thalamic and hypothalamic nuclei, we analyzed the diffusion of manganese in the brain followed by the intra-cerebroventricular application of manganese-bicine (Mn-bicine). T₁-weighted MRI intensities, with 9-pixel ROIs in the hypothalamus perpendicular to the third ventricle, were measured during continuous infusion of Mn-bicine solution in the lateral cerebroventricle. Using a relationship between the image intensity of T₁-weighted MRI and T₁ relaxation time, the image intensity was converted into the concentration of manganese. Assuming a simple diffusion process, the apparent diffusion coefficient (D _ap) of manganese (4.2 × 10⁻⁵ mm² s⁻¹) is much lower than that of water (6 × 10⁻⁴ mm² s⁻¹), and the D _ap tended to decrease when the distance from the third ventricle increased. These results suggest (1) the Mn²⁺ ion is trapped by neural cells during diffusion and (2) the manganese efflux is discharged from the brain via veins.     

The natural history of fibrodysplasia ossificans progressiva: A prospective,global 36-month study

PurposeWe report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues.MethodsIndividuals aged ≤65 years with classical FOP (ACVR1^R206H variant) were assessed at baseline and over 36 months.ResultsIn total, 114 individuals participated; 33 completed the study (mean follow up: 26.8 months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%). After 84 days, 14 of 52 (26.9%) imaged flare-ups had new HO at the flare-up site (mean new HO volume: 28.8 × 10³ mm³). Mean baseline low-dose whole-body computed tomography (excluding head) HO volume was 314.4 × 10³ mm³; lowest at 2 to <8 years (68.8 × 10³ mm³) and increasing by age (25-65 years: 575.2 × 10³ mm³). The mean annualized volume of new HO was 23.6 × 10³ mm³/year; highest at 8 to <15 and 15 to <25 years (21.9 × 10³ and 41.5 × 10³ mm³/year, respectively) and lowest at 25 to 65 years (4.6 × 10³ mm³/year).ConclusionResults from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.     

Measurement and modeling of diffusion time dependence of apparent diffusion coefficient and fractional anisotropy in prostate tissue ex vivo

The purpose of this study was to measure and model the diffusion time dependence of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) derived from conventional prostate diffusion‐weighted imaging methods as used in recommended multiparametric MRI protocols. Diffusion tensor imaging (DTI) was performed at 9.4 T with three radical prostatectomy specimens, with diffusion times in the range 10–120 ms and b‐values 0–3000 s/mm². ADC and FA were calculated from DTI measurements at b‐values of 800 and 1600 s/mm². Independently, a two‐component model (restricted isotropic plus Gaussian anisotropic) was used to synthesize DTI data, from which ADC and FA were predicted and compared with the measured values. Measured ADC and FA exhibited a diffusion time dependence, which was closely predicted by the two‐component model. ADC decreased by about 0.10–0.15 μm²/ms as diffusion time increased from 10 to 120 ms. FA increased with diffusion time at b‐values of 800 and 1600 s/mm² but was predicted to be independent of diffusion time at b = 3000 s/mm². Both ADC and FA exhibited diffusion time dependence that could be modeled as two unmixed water pools — one having isotropic restricted dynamics, and the other unrestricted anisotropic dynamics. These results highlight the importance of considering and reporting diffusion times in conventional ADC and FA calculations and protocol recommendations, and inform the development of improved diffusion methods for prostate cancer imaging.     

Influence of fat–water separation and spatial resolution on automated volumetric MRI measurements of fibroglandular breast tissue

The aim of this study was to investigate the influence of fat–water separation and spatial resolution in MRI on the results of automated quantitative measurements of fibroglandular breast tissue (FGT). Ten healthy volunteers (age range, 28–71 years; mean, 39.9 years) were included in this Institutional Review Board‐approved prospective study. All measurements were performed on a 1.5‐T scanner (Siemens, AvantoFit) using an 18‐channel breast coil. The protocols included isotropic (Di) [TR/TE₁/TE₂ = 6.00 ms/2.45 ms/2.67 ms; flip angle, 6.0°; 256 slices; matrix, 360 × 360; 1 mm isotropic; field of view, 360°; acquisition time (TA) = 3 min 38 s] and anisotropic (Da) (TR/TE₁/TE₂ = 10.00 ms/2.39 ms/4.77 ms; flip angle, 24.9°; 80 slices; matrix 360 × 360; voxel size, 0.7 × 0.7 × 2.0 mm³; field of view, 360°; TA = 1 min 25 s) T₁ three‐dimensional (3D) fast low‐angle shot (FLASH) Dixon sequences, and a T₁ 3D FLASH sequence with the same resolution (T₁) without (TR/TE = 11.00 ms/4.76 ms; flip angle, 25.0°; 80 slices; matrix, 360 × 360; voxel size, 0.7 × 0.7 × 2.0 mm³; field of view, 360°; TA = 50 s) and with (TR/TE = 29.00 ms/4.76 ms; flip angle, 25.0°; 80 slices; matrix, 360 × 360; voxel size, 0.7 × 0.7 × 2.0 mm³; field of view, 360°; TA = 2 min 35 s) fat saturation. Repeating volunteer measurements after 20 min and repositioning were used to assess reproducibility. An automated and quantitative volumetric breast density measurement system was used for FGT calculation. FGT with Di, Da and T₁ measured 4.6–63.0% (mean, 30.6%), 3.2–65.3% (mean, 32.5%) and 1.7–66.5% (mean, 33.7%), respectively. The highest correlation between different MRI sequences was found with the Di and Da sequences (R² = 0.976). Coefficients of variation (CVs) for FGT calculation were higher in T₁ (CV = 21.5%) compared with Dixon (Di, CV = 5.1%; Da, CV = 4.2%) sequences. Dixon‐type sequences worked well for FGT measurements, even at lower resolution, whereas the conventional T₁‐weighted sequence was more sensitive to decreasing resolution. The Dixon fat–water separation technique showed superior repeatability of FGT measurements compared with conventional sequences. A standard dynamic protocol using Dixon fat–water separation is best suited for combined diagnostic purposes and prognostic measurements of FGT. Copyright © 2016 John Wiley & Sons, Ltd.     

Valvular interstitial cell seeded poly(glycerol sebacate) scaffolds: Toward a biomimetic in vitro model for heart valve tissue engineering

Tissue engineered replacement heart valves may be capable of overcoming the lack of growth potential intrinsic to current non-viable prosthetics, and thus could potentially serve as permanent replacements in the surgical repair of pediatric valvular lesions. However, the evaluation of candidate combinations of cells and scaffolds lacks a biomimetic in vitro model with broadly tunable, anisotropic and elastomeric structural–mechanical properties. Toward establishing such an in vitro model, in the current study, porcine aortic and pulmonary valvular interstitial cells (i.e. biomimetic cells) were cultivated on anisotropic, micromolded poly(glycerol sebacate) scaffolds (i.e. biomimetic scaffolds). Following 14 and 28 days of static culture, cell-seeded scaffolds and unseeded controls were assessed for their mechanical properties, and cell-seeded scaffolds were further characterized by confocal fluorescence and scanning electron microscopy, and by collagen and DNA assays. Poly(glycerol sebacate) micromolding yielded scaffolds with anisotropic stiffnesses resembling those of native valvular tissues in the low stress–strain ranges characteristic of physiologic valvular function. Scaffold anisotropy was largely retained upon cultivation with valvular interstitial cells; while the mechanical properties of unseeded scaffolds progressively diminished, cell-seeded scaffolds either retained or exceeded initial mechanical properties. Retention of mechanical properties in cell-seeded scaffolds paralleled the accretion of collagen, which increased significantly from 14 to 28 days. This study demonstrates that valvular interstitial cells can be cultivated on anisotropic poly(glycerol sebacate) scaffolds to yield biomimetic in vitro models with which clinically relevant cells and future scaffold designs can be evaluated.     

A novel bioreactor for the dynamic flexural stimulation of tissue engineered heart valve biomaterials

Dynamic flexure is a major mode of deformation in the native heart valve cusp, and may effect the mechanical and biological development of tissue engineered heart valves (TEHV). To explore this hypothesis, a novel bioreactor was developed to study the effect of dynamic flexural stimulation on TEHV biomaterials. It was implemented in a study to compare the effect of uni-directional cyclic flexure on the effective stiffness of two candidate TEHV scaffolds: a non-woven mesh of polyglycolic acid (PGA) fibers, and a non-woven mesh of PGA and poly L-lactic acid (PLLA) fibers, both coated with poly 4-hydroxybutyrate (P4HB). The bioreactor has the capacity to dynamically flex 12 rectangular samples (25 x 7.5 x 2mm) under sterile conditions in a cell culture incubator. Sterility was maintained in the bioreactor for at least 5 weeks of incubation. Flexure tests to measure the effective stiffness in the "with-flexure" (WF) and opposing "against-flexure" (AF) directions indicated that dynamically flexed PGA/PLLA/P4HB scaffolds were approximately 72% (3 weeks) and 76% (5 weeks) less stiff than static controls (p<0.01), and that they developed directional anisotropy by 3 weeks of incubation (stiffer AF, p<0.01). In contrast, both dynamically flexed and static PGA/P4HB scaffolds exhibited a trend of decreased stiffness with incubation, with no development of directional anisotropy. Dynamically flexed PGA/P4HB scaffolds were significantly less stiff than static controls at 3 weeks (p<0.05). Scanning electron microscopy revealed signs of heterogeneous P4HB coating and fiber disruption, suggesting possible explanations for the observed mechanical properties. These results indicate that dynamic flexure can produce quantitative and qualitative changes in the mechanical properties of TEHV scaffolds, and suggest that these differences need to be accounted for when comparing the effects of mechanical stimulation on the development of cell-seeded TEHV constructs.     

Considerations for measuring the fractional anisotropy of metabolites with diffusion tensor spectroscopy

Diffusion tensor spectroscopy of metabolites in brain is challenging because of their lower diffusivity (i.e. less signal attenuation for a given b value) and much poorer signal‐to‐noise ratio relative to water. Although diffusion tensor acquisition protocols have been studied in detail for water, they have not been evaluated systematically for the measurement of the fractional anisotropy of metabolites such as N‐acetylaspartate, creatine and choline in the white and gray matter of human brain. Diffusion tensor spectroscopy was performed in vivo with variable maximal b values (1815 or 5018 s/mm²). Experiments were also performed on simulated spectra and isotropic alcohol phantoms of various diffusivities, ranging from approximately 0.54 × 10^?3 to 0.13 × 10^?3 mm²/s, to assess the sensitivity of diffusion tensor spectroscopic parameters to low diffusivity, noise and b value. The low maximum b value of 1815 s/mm² yielded elevated fractional anisotropy (0.53–0.60) of N‐acetylaspartate in cortical gray matter relative to the more isotropic value (0.25–0.30) obtained with a higher b value of 5018 s/mm²; in contrast, the fractional anisotropy of white matter was consistently anisotropic with the different maximal b values (i.e. 0.43–0.54 for b = 1815 s/mm² and 0.47–0.51 for b = 5018 s/mm²). Simulations, phantoms and in vivo data indicate that greater signal attenuation, to a degree, is desirable for the accurate quantification of diffusion‐weighted spectra for slowly diffusing metabolites. Copyright © 2010 John Wiley & Sons, Ltd.     

Carbohydrate intake reduces fat oxidation during exercise in obese boys

The recent surge in childhood obesity has renewed interest in studying exercise as a therapeutic means of metabolizing fat. However, carbohydrate (CHO) intake attenuates whole body fat oxidation during exercise in healthy children and may suppress fat metabolism in obese youth. To determine the impact of CHO intake on substrate utilization during submaximal exercise in obese boys, seven obese boys (mean age: 11.4 ± 1.0 year; % body fat: 35.8 ± 3.9%) performed 60 min of exercise at an intensity that approximated maximal fat oxidation. A CHO drink (CARB) or a placebo drink (CONT) was consumed in a double-blinded, counterbalanced manner. Rates of total fat, total CHO, and exogenous CHO (CHO_exo) oxidation were calculated for the last 20 min of exercise. During CONT, fat oxidation rate was 3.9 ± 2.4 mg × kg fat-free mass (FFM)⁻¹ × min⁻¹, representing 43.1 ± 22.9% of total energy expenditure (EE). During CARB, fat oxidation was lowered (p = 0.02) to 1.7 ± 0.6 mg × kg FFM⁻¹ × min⁻¹, contributing to 19.8 ± 4.9% EE. Total CHO oxidation rate was 17.2 ± 3.1 mg × kg FFM⁻¹ × min⁻¹ and 13.2 ± 6.1 mg × kg FFM⁻¹ × min⁻¹ during CARB and CONT, respectively (p = 0.06). In CARB, CHO_exo oxidation contributed to 23.3 ± 4.2% of total EE. CHO intake markedly suppresses fat oxidation during exercise in obese boys.     

Insight in Human Skin Microcirculation Using In Vivo Reflectance-Mode Confocal Laser Scanning Microscopy

Reflectance-mode confocal laser scanning microscopy allows in vivo imaging of the human skin. We hypothesized that this high-resolution technique enables observation of dynamic changes of the cutaneous microcirculation. Twenty-two volunteers were randomly divided in two groups. Group 1 was exposed to local heating and group 2 to local cold stress. Confocal microscopy was performed prior t ₀ (control), directly t ₁ and 5 min t ₂ after local temperature changes to evaluate quantitative blood cell flow, capillary loop diameter, and density of dermal capillaries. In group 1, blood flow increased at t ₁ (75.82 ± 2.86/min) and further at t ₂ (84.09 ± 3.39/min) compared to the control (61.09 ± 3.21/min). The control capillary size was 9.59 ± 0.25 μm, increased to 11.16 ± 0.21 μm (t ₁) and 11.57 ± 0.24 μm (t ₂). The dermal capillary density increased in t ₁ (7.26 ± 0.76/mm²) and t ₂ (8.16 ± 0.52/mm²), compared to the control (7.04 ± 0.62/mm²). In group 2, blood flow decreased at t ₁ (41.73 ± 2.61/min) and increased at t ₂ (83.27 ± 3.29/min) compared to the control (60.73 ± 2.90/min). The control capillary size was 9.55 ± 0.25 μm, decreased at t ₁ (7.78 ± 0.26 μm) and increased at t ₂ (11.38 ± 0.26 μm). Capillary density decreased at t ₁ (5.01 ± 0.49/mm²) and increased at t ₂ (7.28 ± 0.53/mm²) compared to the control (7.01 ± 0.52/mm²). Confocal microscopy is a sensitive and noninvasive imaging tool for characterizing and quantifying dynamic changes of cutaneous microcirculation on a histomorphological level.     

Effect of exercise on glutamine metabolism in macrophages of trained rats

This study investigated the effect of exercise on glutamine metabolism in macrophages of trained rats. Rats were divided into three groups: sedentary (SED); moderately trained (MOD) rats that were swim trained 1 h/day, 5 days/week for 6 weeks; and exhaustively trained (EXT) rats that were similarly trained as MOD for 5 weeks and, in the 6th week, trained in three 1-h sessions/day with 150 min of rest between sessions. The animals swam with a load equivalent to 5.5% of their body weight and were killed 1 h after the last exercise session. Cells were collected, and glutamine metabolism in macrophage and function were assayed. Exercise increased phagocytosis in MOD when compared to SED (34.48 ± 1.79 vs 15.21 ± 2.91%, P < 0.05); however, H₂O₂ production was higher in MOD (75.40 ± 3.48 nmol h × 10⁵ cell⁻¹) and EXT (79.20 ± 1.18 nmol h × 10⁵ cell⁻¹) in relation to SED (32.60 ± 2.51 nmol h × 10⁵ cell⁻¹, P < 0.05). Glutamine consumption increased in MOD and EXT (26.53 ± 3.62 and 19.82 ± 2.62 nmol h × 10⁵ cell⁻¹, respectively) relative to SED (6.72 ± 0.57 nmol h × 10⁵ cell⁻¹, P < 0.05). Aspartate increased in EXT (9.72 ± 1.14 nmol h × 10⁵ cell⁻¹) as compared to SED (1.10 ± 0.19 nmol h × 10⁵ cell⁻¹, P < 0.05). Glutamine decarboxylation was increased in MOD (12.10 ± 0.27 nmol h × 10⁵ cell⁻¹) and EXT (16.40 ± 2.17 nmol h × 10⁵ cell⁻¹) relative to SED (1.10 ± 0.06 nmol h × 10⁵ cell⁻¹, P < 0.05). This study suggests an increase in macrophage function post-exercise, which was supported by enhanced glutamine consumption and metabolism, and highlights the importance for glutamine after exercise.     

Validity of perceived skin wettedness mapping to evaluate heat strain

The purpose of this study was to investigate the validity of a newly developed method for quantifying perceived skin wettedness (W _p) as an index to evaluate heat strain. Eight male subjects underwent 12 experimental conditions: activities (rest and exercise) × clothing (Control, Tyvek and Vinyl condition) × air temperatures (25 and 32°C). To quantify the W _p, a full body map with 21 demarcated regions was presented to the subject. The results showed that (1) at rest in 25°C, W _p finally reached 4.4, 8.3 and 51.6% of the whole body surface area for Control, Tyvek, and Vinyl conditions, respectively, while W _p at rest in 32°C rose to 35.8, 61.4 and 89.8%; (2) W _p has a distinguishable power to detect the most wetted and the first wetted regions. The most wetted body regions were the upper back, followed by the chest, front neck, and forehead. The first perceived regions in the skin wetted map were the chest, forehead, and upper back; (3) W _p at rest showed a significant relationship with the calculated skin wettedness (w) (r = 0.645, p < 0.01) and (4) W _p had a significant relationship with core temperature, skin temperature, heart rate, total sweat rate, thermal comfort, and humidity sensation (p < 0.05), but these relationships were dependent on the level of activities and clothing insulation. W _p in hot environments was more valid as a heat strain index of workers wearing normal clothing in light works, rather than wearing impermeable protective clothing in strenuous works.     

Severe immunosuppression is related to poorer immunogenicity to SARS-CoV-2 vaccines among people living with HIV

ObjectivesThe aim of this study was to assess the immunogenicity of SARS-CoV-2 available vaccines among people living with HIV (PLWH) after a complete vaccination scheme, and determine predictors of seroconversion.MethodsThis multicentre prospective cohort study included 420 PLWH who had received a standard immunization, either with mRNA or adenoviral-vectored COVID-19 vaccines. Antibody response was evaluated within 1 to 2 months after the last dose of the vaccine with a quantitative determination of antitrimeric spike protein-specific IgG antibodies and IgG neutralizing antibodies.ResultsOverall, 384 of 420 PLWH (91%) showed antibody response to vaccination. Seroconversion was observed in 308 of 326 individuals with cluster of differentiation 4 (CD4) counts ≥350 cells/mm³ (95%), 55 of 61 PLWH with 200 to 349 cells/mm³ (90%), and 21 of 33 PLWH with CD4 counts <200 cells/mm³ (64%; p < 0.001). The median log₁₀ IgG neutralization levels were 2.4 IU/mL (Q1–Q3, 1.0–3.1) among PLWH with CD4 counts <200 cells/mm³, 3.1 IU/mL (Q1–Q3, 2.8–3.4) for the 200 to 349 cells/mm³ group, and 3.1 IU/mL (Q1–Q3, 2.7–3.4) for PLWH with CD4 counts ≥350 cells/mm³ (p = 0.016). In the multivariate analysis, CD4 counts ≥350 cells/mm³ (OR: 7.10; 95% CI, 1.91–26.46; p = 0.004) and receiving mRNA-vectored COVID-19 vaccines (OR: 8.19; 95% CI, 3.24–20.70; p ≤ 0.001) were independently associated with a higher probability of response to vaccination.DiscussionHIV-related immunosuppression impairs the antibody response to SARS-CoV-2 vaccines. Specific vaccination schemes should be urgently tailored in this setting, particularly in patients with CD4 cell counts <200 cells/μL. Adenoviral-vectored vaccines should be avoided in PLWH whenever possible.     

Diffusion‐weighted MRI of the prostate without susceptibility artifacts: Undersampled multi‐shot turbo‐STEAM with rotated radial trajectories

The aim of this study was to develop and evaluate a clinically feasible approach to diffusion‐weighted (DW) MRI of the prostate without susceptibility‐induced artifacts. The proposed method relies on an undersampled multi‐shot DW turbo‐STEAM sequence with rotated radial trajectories and a multi‐step inverse reconstruction with denoised multi‐shot phase maps. The total acquisition time was below 6 min for a resolution of 1.4 × 1.4 × 3.5 mm³ and six directions at b = 600 s mm^?2. Studies of eight healthy subjects and two patients with prostate cancer were performed at 3 T employing an 18‐channel body‐array coil and elements of the spine coil. The method was compared with conventional DW echo‐planar imaging (EPI) of the prostate. The results confirm that DW STEAM MRI avoids geometric distortions and false image intensities, which were present for both single‐shot EPI (ssEPI) and readout‐segmented EPI, particularly near the intestinal wall of the prostate. Quantitative accuracy of the apparent diffusion coefficient (ADC) was validated with use of a numerical phantom providing ground truth. ADC values in the central prostate gland of healthy subjects were consistent with those measured using ssEPI and with literature data. Preliminary results for patients with prostate cancer revealed a correct anatomical localization of lesions with respect to T₂‐weighted MRI in both mean DW STEAM images and ADC maps. In summary, DW STEAM MRI of the prostate offers clinically relevant advantages for the diagnosis of prostate cancer compared with state‐of‐the‐art EPI‐based approaches. The method warrants extended clinical trials.     

Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre‐clinical assessment of Shigella vaccine formulations

Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood‐ and mucus‐streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre‐clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 10⁸, 2 × 10⁹ and 2 × 10¹⁰ colony forming unit (CFU)] was determined. In addition, the monkeys were re‐infected. The identified optimal challenge dose was 2 × 10⁹ CFU; this dose elicited 60% protection in monkeys when they were re‐challenged with a one log higher dose (2 × 10¹⁰ CFU). The challenge dose, 2 × 10¹⁰ CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re‐challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre‐clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re‐challenges with homologous strains.     

The influences of time-of-day and sleep deprivation on postural control

The aim of this study was to check the combined and/or dissociated influences of time-of-day and sleep deprivation on postural control. Twenty subjects participated in test sessions which took place at 6:00 am, 10:00 am, 2:00 pm and 6:00 pm either after a normal night’s sleep or after a night of total sleep deprivation. Postural control was evaluated by COP surface area, LFS ratio and Romberg’s index. The results showed that postural control fluctuates diurnally according to three different periods, pronounced by sleep deprivation: (1) at 6:00 am, there was no modification by sleep deprivation; (2) at 10:00 am and 2:00 pm, an interaction effect was observed for COP surface area and LFS ratio after sleep deprivation. Values of COP surface area were significantly higher (P < 0.01) following the night of sleep deprivation than after the normal night’s sleep (139.36 ± 63.82 mm² vs. 221.72 ± 137.13 mm² and 143.78 ± 75.31 mm² vs. 228.65 ± 125.09 mm², respectively); (3) at 6:00 pm, the LFS ratio was higher than during the two other periods (P < 0.001) whereas COP surface area decreased to the level observed at 6:00 am. At this time-of-day, only the LFS ratio was significantly increased (P < 0.05) by the night of sleep deprivation (0.89 ± 0.14 vs. 1.03 ± 0.30). This temporal evolution in postural control does not seem to be related to any deterioration in visual input as Romberg’s index (150.09 ± 97.91) was not modified, regardless of the test session.     

Two new Myxidium species (Myxosporea: Myxidiidae) infecting the gallbladder of African flying fish, Cheilopogon nigricans and Suez fusilier, Caesio suevicus from the Red Sea, Egypt: a morphological and morphometric study

Myxidium maamouni sp. n. and Myxidium aydai sp. n. were described from the gallbladder of the African flying fish Cheilopogon nigricans and Suez fusilier Caesio suevicus, respectively. Fishes were collected from the Red Sea at Al-Quseir, Egypt. M. maamouni have irregular to mostly rounded polysporous plasmodia with diameter of 27 μm. Spores were sigmoid or S-shaped and sometimes spindle-shaped in the frontal view with smooth valves. They measured 13.5 × 8.0 × 8.2 μm in size. Their polar capsules were equal pyriform and measured 7.0 × 3.2 μm in size with nine to 12 coils. Spores of M. aydai were spindle-shaped in the frontal view with thin smooth valves. They measured 23.0 × 5.6 × 5.5 μm in size. Their polar capsules were pyriform and measured 7.2 × 3.4 μm in size with eight to nine coils.