Mucosal adenovirus vaccine boosting elicits IgA and durably prevents XBB.1.16 infection in nonhuman primates.

A mucosal route of vaccination could prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication at the site of infection and limit transmission. We compared protection against heterologous XBB.1.16 challenge in nonhuman primates (NHPs) ~5 months following intramuscular boosting with bivalent mRNA encoding WA1 and BA.5 spike proteins or mucosal boosting with a WA1-BA.5 bivalent chimpanzee adenoviral-vectored vaccine delivered by intranasal or aerosol device. NHPs boosted by either mucosal route had minimal virus replication in the nose and lungs, respectively. By contrast, protection by intramuscular mRNA was limited to the lower airways. The mucosally delivered vaccine elicited durable airway IgG and IgA responses and, unlike the intramuscular mRNA vaccine, induced spike-specific B cells in the lungs. IgG, IgA and T cell responses correlated with protection in the lungs, whereas mucosal IgA alone correlated with upper airway protection. This study highlights differential mucosal and serum correlates of protection and how mucosal vaccines can durably prevent infection against SARS-CoV-2.

Variant-proof high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways.

SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool that would maintain its efficacy despite the ongoing emergence of new variants. Here, we challenge male rhesus macaques with SARS-CoV-2 Delta-the most pathogenic variant in a highly susceptible animal model. At the time of challenge, we also treat the macaques with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment equivalently suppresses virus replication in both upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 does not block the development of virus-specific T- and B-cell responses and does not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Investigating Fryette's mechanics in computed tomography scans: an analysis of vertebrae spinal physiology using open-sourced datasets and three-dimensional vertebral orientation.

CONTEXT: Fryette's mechanics is taught as a simplistic model of coupled vertebral movement, fundamental in osteopathic practice. This study seeks to better understand the likelihood of Fryette's model by calculating vertebral orientation in computed tomography (CT) scans. Given previous findings of low angular coupled movements during overall spinal motion, static calculations provide a unique perspective on the likelihood of Fryette's mechanics. OBJECTIVES: This analysis aims to evaluate the efficacy of Fryette's principles in predicting vertebral positioning in CT scans by comparing their 3-dimensional (3D) orientation to movements described by Fryette. METHODS: 3D models of 953 thoracic and lumbar vertebrae were obtained from 82 CT scans within the VerSe`20 open-source dataset. A stepwise algorithm generated three unique symmetry planes for each vertebra, offering 3D angular orientation with respect to the vertebral level below. A total of 422 vertebrae were omitted from the analysis due to the presence of pathologies significant enough to affect their motion, inaccurate symmetry plane calculations, or absence of vertebral level below. The remaining 531 vertebra were analyzed to compare quantitative coupled positioning against expected coupled spinal movements in line with Fryette's mechanics. One-sample proportional z-scoring was implemented for all vertebral levels with an ∝=0.05 and a null hypothesis of Fryette's primed positioning occurring by chance of 50 %. Further analysis was performed with individual z-scoring for each individual level to see which levels were statistically significant. RESULTS: Data from the VerSe`20 dataset revealed that 56.9 % of successfully analyzed vertebrae demonstrated positions compatible with Fryette's mechanics (p=0.0014, power=89 %). The 302 vertebral levels that did display coupled positioning consisted of Type I (166 vertebrae) and Type II (136 vertebrae) compatible with Fryette's mechanics. Levels that demonstrated statistical significance consisted of T5 (p=0, power=99 %), T6 (p=0.0023, power=77 %), T7 (p=0.041, power=46 %), and T10 (p=0.017, power=60 %). CONCLUSIONS: Our analysis suggests that the static positions of vertebrae in CT scans may align with Fryette's descriptions, although not very often. Notably, vertebral levels T5-T7 and T10 exhibit strong evidence of their static positions aligning with expected movements, warranting further investigation into the Fryette phenomenon at these levels. Future studies should explore the dynamic implications of these findings to enhance our understanding of spinal biomechanics.

Kinetically controlled synthesis of rotaxane geometric isomers.

Geometric isomerism in mechanically interlocked systems-which arises when the axle of a mechanically interlocked molecule is oriented, and the macrocyclic component is facially dissymmetric-can provide enhanced functionality for directional transport and polymerization catalysis. We now introduce a kinetically controlled strategy to control geometric isomerism in [2]rotaxanes. Our synthesis provides the major geometric isomer with high selectivity, broadening synthetic access to such interlocked structures. Starting from a readily accessible [2]rotaxane with a symmetrical axle, one of the two stoppers is activated selectively for stopper exchange by the substituents on the ring component. High selectivities are achieved in these reactions, based on coupling the selective formation reactions leading to the major products with inversely selective depletion reactions for the minor products. Specifically, in our reaction system, the desired (major) product forms faster in the first step, while the undesired (minor) product subsequently reacts away faster in the second step. Quantitative 1H NMR data, fit to a detailed kinetic model, demonstrates that this effect (which is conceptually closely related to minor enantiomer recycling and related processes) can significantly improve the intrinsic selectivity of the reactions. Our results serve as proof of principle for how multiple selective reaction steps can work together to enhance the stereoselectivity of synthetic processes forming complex mechanically interlocked molecules.

Long-Chain Omega-3 Fatty Acid Supplementation and Exercise-Induced Muscle Damage: EPA or DHA?

PURPOSE: Long-chain omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) may enhance recovery from exercise-induced muscle damage (EIMD). However, it is unclear if the effects are due to EPA, DHA, or both. The purpose of this investigation was to examine the effect of EPA + DHA, EPA, and DHA compared with placebo (PL) on muscular recovery. METHODS: Thirty males were randomized to 4 g·d -1 EPA + DHA ( n = 8), EPA ( n = 8), DHA ( n = 7), or PL ( n = 7). After 7-wk supplementation, a downhill running (20 min, 70% V̇O 2max , -16% gradient) plus jumping lunges (5 × 20 reps, 2-min rest intervals) muscle damage protocol was performed. Indices of muscle damage, soreness, muscle function, and inflammation were measured at baseline and throughout recovery. The omega-3 index (O3i; %EPA + %DHA in erythrocytes) was used to track tissue EPA and DHA status. RESULTS: After supplementation, the O3i was significantly higher than PL in all experimental groups ( P < 0.001). Leg press performance was lower in the PL group at 24 h compared with EPA ( P = 0 .019) and at 72 h for EPA ( P = 0.004) and DHA ( P = 0 .046). Compared with PL, muscle soreness was lower in the DHA ( P = 0.015) and EPA ( P = 0.027) groups at 48 h. Albeit nonsignificant, EPA + DHA tended to attenuate muscle soreness ( d = 1.37) and leg strength decrements ( d = 0.75) compared with PL. Jump performance and power metrics improved more rapidly in the EPA and DHA groups (time effects: P < 0.001). Measures of inflammation, range of motion, and muscle swelling were similar between groups ( P > 0.05). CONCLUSIONS: Compared with PL, 4 g·d -1 of EPA or DHA for 52 d improves certain aspects of recovery from EIMD. EPA + DHA did not clearly enhance recovery. Equivalent dosing of EPA + DHA may blunt the performance effects observed in EPA or DHA alone.

Alicyclic-Amine-Derived Imine-BF3 Complexes: Easy-to-Make Building Blocks for the Synthesis of Valuable α-Functionalized Azacycles.

A new strategy to access α-functionalized alicyclic amines via their corresponding imine-BF3 complexes is reported. Isolable imine-BF3 complexes, readily prepared via dehydrohalogenation of N-bromoamines in a base-promoted/18-crown-6 catalyzed process followed by addition of boron trifluoride etherate, undergo reactions with a wide range of organometallic nucleophiles to afford α-functionalized azacycles. Organozinc and organomagnesium nucleophiles add at ambient temperatures, obviating the need for cryogenic conditions. In situ preparation of imine-BF3 complexes provides access to α-functionalized morpholines and piperazines directly from their parent amines in a single operation. α-Functionalized morpholines can be elaborated further, for instance by installing a second substituent in the α'-position.

Durable immunity to SARS-CoV-2 in both lower and upper airways achieved with a gorilla adenovirus (GRAd) S-2P vaccine in non-human primates.

SARS-CoV-2 continues to pose a global threat, and current vaccines, while effective against severe illness, fall short in preventing transmission. To address this challenge, there's a need for vaccines that induce mucosal immunity and can rapidly control the virus. In this study, we demonstrate that a single immunization with a novel gorilla adenovirus-based vaccine (GRAd) carrying the pre-fusion stabilized Spike protein (S-2P) in non-human primates provided protective immunity for over one year against the BA.5 variant of SARS-CoV-2. A prime-boost regimen using GRAd followed by adjuvanted S-2P (GRAd+S-2P) accelerated viral clearance in both the lower and upper airways. GRAd delivered via aerosol (GRAd(AE)+S-2P) modestly improved protection compared to its matched intramuscular regimen, but showed dramatically superior boosting by mRNA and, importantly, total virus clearance in the upper airway by day 4 post infection. GrAd vaccination regimens elicited robust and durable systemic and mucosal antibody responses to multiple SARS-CoV-2 variants, but only GRAd(AE)+S-2P generated long-lasting T cell responses in the lung. This research underscores the flexibility of the GRAd vaccine platform to provide durable immunity against SARS-CoV-2 in both the lower and upper airways.

Mucosal Adenoviral-vectored Vaccine Boosting Durably Prevents XBB.1.16 Infection in Nonhuman Primates.

Waning immunity and continued virus evolution have limited the durability of protection from symptomatic infection mediated by intramuscularly (IM)-delivered mRNA vaccines against COVID-19 although protection from severe disease remains high. Mucosal vaccination has been proposed as a strategy to increase protection at the site of SARS-CoV-2 infection by enhancing airway immunity, potentially reducing rates of infection and transmission. Here, we compared protection against XBB.1.16 virus challenge 5 months following IM or mucosal boosting in non-human primates (NHP) that had previously received a two-dose mRNA-1273 primary vaccine regimen. The mucosal boost was composed of a bivalent chimpanzee adenoviral-vectored vaccine encoding for both SARS-CoV-2 WA1 and BA.5 spike proteins (ChAd-SARS-CoV-2-S) and delivered either by an intranasal mist or an inhaled aerosol. An additional group of animals was boosted by the IM route with bivalent WA1/BA.5 spike-matched mRNA (mRNA-1273.222) as a benchmark control. NHP were challenged in the upper and lower airways 18 weeks after boosting with XBB.1.16, a heterologous Omicron lineage strain. Cohorts boosted with ChAd-SARS-CoV-2-S by an aerosolized or intranasal route had low to undetectable virus replication as assessed by levels of subgenomic SARS-CoV-2 RNA in the lungs and nose, respectively. In contrast, animals that received the mRNA-1273.222 boost by the IM route showed minimal protection against virus replication in the upper airway but substantial reduction of virus RNA levels in the lower airway. Immune analysis showed that the mucosal vaccines elicited more durable antibody and T cell responses than the IM vaccine. Protection elicited by the aerosolized vaccine was associated with mucosal IgG and IgA responses, whereas protection elicited by intranasal delivery was mediated primarily by mucosal IgA. Thus, durable immunity and effective protection against a highly transmissible heterologous variant in both the upper and lower airways can be achieved by mucosal delivery of a virus-vectored vaccine. Our study provides a template for the development of mucosal vaccines that limit infection and transmission against respiratory pathogens.

Nano-Bio Interactions between DNA Nanocages and Human Serum Albumin.

DNA nanostructures have emerged as promising nanomedical tools due to their biocompatibility and tunable behavior. Recent work has shown that DNA nanocages decorated with organic dendrimers strongly bind human serum albumin (HSA), yet the dynamic structures of these complexes remain uncharacterized. This theoretical and computational investigation elucidates the fuzzy interactions between dendritically functionalized cubic DNA nanocages and HSA. The dendrimer-HSA interactions occur via nonspecific binding with the protein thermodynamically and kinetically free to cross the open faces of the cubic scaffold. However, the rigidity of the DNA scaffold prevents the binding energetics from scaling with the number of dendrimers. These discoveries not only provide a useful framework by which to model general interactions of DNA nanostructures complexed with serum proteins but also give valuable molecular insight into the design of next-generation DNA nanomedicines.

Alternating styrene-propylene and styrene-ethylene copolymers prepared by photocatalytic decarboxylation.

Synthesis of olefin-styrene copolymers with defined architecture is challenging due to the limitations associated with the inherent reactivity ratios for these monomers in radical or metal-catalyzed polymerizations. Herein, we developed a straightforward approach to alternating styrene-propylene and styrene-ethylene copolymers by combining radical polymerizations and powerful post-polymerization modification reactions. We employed reversible addition-fragmentation chain transfer (RAFT) copolymerization between styrene derivatives and saccharin (meth)acrylamide to generate alternating copolymers. Once polymerized, the amide bond of the saccharin monomers was highly reactive toward hydrolysis, an observation exploited to obtain alternating styrene-acrylic acid/methacrylic acid copolymers. Subsequent mild decarboxylation of the (meth)acrylic acid groups in the presence of a photocatalyst and a hydrogen source under visible light resulted in the styrene-alt-ethylene/propylene copolymers. Alternating copolymers comprised of either propylene or ethylene units alternating with functional styrene derivatives were also prepared, illustrating the compatibility of this approach for functional polymer synthesis. Finally, the thermal properties of the alternating copolymers were compared to those from statistical copolymer analogs to elucidate the effect of microarchitecture and styrene substituents on the glass transition temperature.

RBD-based high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways.

SARS-CoV-2 has the capacity to evolve mutations to escape vaccine-and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool. Here, we challenged rhesus macaques with SARS-CoV-2 Delta and simultaneously treated them with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment gave equivalent protection in upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 did not block the development of memory responses to Delta and did not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Advanced Systemic Mastocytosis with associated haematological neoplasm: Treatment with avapritinib can facilitate successful bridge to allogeneic haematopoietic cell transplant.

Advanced systemic mastocytosis (AdvSM) is a rare, life-limiting mast cell (MC) neoplasm, with approximately 70% patients having an associated haematological neoplasm (AHN). Avapritinib, a selective tyrosine kinase inhibitor targeting KIT D816V, has shown potent activity translating clinically into durable responses in the phase 1 EXPLORER (NCT02561988) and phase 2 PATHFINDER (NCT03580655) studies. We report three patients with AdvSM-AHN on avapritinib who achieved complete remission (CR) of SM and were successfully bridged to allogeneic haematopoietic cell transplant (allo-HCT). Two cases additionally highlight the risk of clonal evolution within the AHN component and requirement for close monitoring while on targeted therapy.

Cytochalasans produced by Xylaria karyophthora and their biological activities.

The recent description of the putative fungal pathogen of greenheart trees, Xylaria karyophthora (Xylariaceae, Ascomycota), prompted a study of its secondary metabolism to access its ability to produce cytochalasans in culture. Solid-state fermentation of the ex-type strain on rice medium resulted in the isolation of a series of 19,20-epoxidated cytochalasins by means of preparative high-performance liquid chromatography (HPLC). Nine out of 10 compounds could be assigned to previously described structures, with one compound being new to science after structural assignment via nuclear magnetic resonance (NMR) assisted by high-resolution mass spectrometry (HRMS). We propose the trivial name "karyochalasin" for the unprecedented metabolite. The compounds were used in our ongoing screening campaign to study the structure-activity relationship of this family of compounds. This was done by examining their cytotoxicity against eukaryotic cells and impact on the organization of networks built by their main target, actin-a protein indispensable for processes mediating cellular shape changes and movement. Moreover, the cytochalasins' ability to inhibit the biofilm formation of Candida albicans and Staphylococcus aureus was examined.

The effect of fish oil supplementation on resistance training-induced adaptations.

BACKGROUND: Resistance exercise training (RET) is a common and well-established method to induce hypertrophy and improvement in strength. Interestingly, fish oil supplementation (FOS) may augment RET-induced adaptations. However, few studies have been conducted on young, healthy adults. METHODS: A randomized, placebo-controlled design was used to determine the effect of FOS, a concentrated source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), compared to placebo (PL) on RET-induced adaptations following a 10-week RET program (3 days·week-1). Body composition was measured by dual-energy x-ray absorptiometry (LBM, fat mass [FM], percent body fat [%BF]) and strength was measured by 1-repetition maximum barbell back squat (1RMSQT) and bench press (1RMBP) at PRE (week 0) and POST (10 weeks). Supplement compliance was assessed via self-report and bottle collection every two weeks and via fatty acid dried blood spot collection at PRE and POST. An a priori α-level of 0.05 was used to determine statistical significance and Cohen's d was used to quantify effect sizes (ES). RESULTS: Twenty-one of 28 male and female participants (FOS, n = 10 [4 withdrawals]; PL, n = 11 [3 withdrawals]) completed the 10-week progressive RET program and PRE/POST measurements. After 10-weeks, blood EPA+DHA substantially increased in the FOS group (+109.7%, p< .001) and did not change in the PL group (+1.3%, p = .938). Similar between-group changes in LBM (FOS: +3.4%, PL: +2.4%, p = .457), FM (FOS: -5.2%, PL: 0.0%, p = .092), and %BF (FOS: -5.9%, PL: -2.5%, p = .136) were observed, although, the between-group ES was considered large for FM (d = 0.84). Absolute and relative (kg·kg [body mass]-1) 1RMBP was significantly higher in the FOS group compared to PL (FOS: +17.7% vs. PL: +9.7%, p = .047; FOS: +17.6% vs. PL: +7.3%, p = .011; respectively), whereas absolute 1RMSQT was similar between conditions (FOS: +28.8% vs. PL: +20.5%, p = .191). Relative 1RMSQT was higher in the FOS group (FOS: +29.3% vs. PL: +17.9%, p = .045). CONCLUSIONS: When combined with RET, FOS improves absolute and relative 1RM upper-body and relative 1RM lower-body strength to a greater extent than that observed in the PL group of young, recreationally trained adults.

The Impacts of Combined Blood Flow Restriction Training and Betaine Supplementation on One-Leg Press Muscular Endurance, Exercise-Associated Lactate Concentrations, Serum Metabolic Biomarkers, and Hypoxia-Inducible Factor-1α Gene Expression.

The purpose of this investigation was to compare the impacts of a potential blood flow restriction (BFR)-betaine synergy on one-leg press performance, lactate concentrations, and exercise-associated biomarkers. Eighteen recreationally trained males (25 ± 5 y) were randomized to supplement 6 g/day of either betaine anhydrous (BET) or cellulose placebo (PLA) for 14 days. Subsequently, subjects performed four standardized sets of one-leg press and two additional sets to muscular failure on both legs (BFR [LL-BFR; 20% 1RM at 80% arterial occlusion pressure] and high-load [HL; 70% 1RM]). Toe-tip lactate concentrations were sampled before (PRE), as well as immediately (POST0), 30 min (POST30M), and 3 h (POST3H) post-exercise. Serum homocysteine (HCY), growth hormone (GH) and insulin-like growth factor-1 concentrations were additionally assessed at PRE and POST30M. Analysis failed to detect any significant between-supplement differences for total repetitions completed. Baseline lactate changes (∆) were significantly elevated from POST0 to POST30 and from POST30 to POST3H (p < 0.05), whereby HL additionally demonstrated significantly higher ∆Lactate versus LL-BFR (p < 0.001) at POST3H. Although serum ∆GH was not significantly impacted by supplement or condition, serum ∆IGF-1 was significantly (p = 0.042) higher in BET versus PLA and serum ∆HCY was greater in HL relative to LL-BFR (p = 0.044). Although these data fail to support a BFR-betaine synergy, they otherwise support betaine's anabolic potential.

LGD-4033 and MK-677 use impacts body composition, circulating biomarkers, and skeletal muscle androgenic hormone and receptor content: A case report.

NEW FINDINGS: What is the main observation in this case? Co-administration of LGD-4033 and MK-677 increased body mass, lean mass and fat mass, while negatively impacting bone, serum lipids, liver enzymes, testosterone (total and free) and, probably, follicle-stimulating hormone. What insights does it reveal? Our cross-sectional data imply that these compounds might alter intramuscular androgenic hormone and receptor concentrations along with promoting muscular strength, when compared with previously published data from trained males. ABSTRACT: LGD-4033, a selective androgen receptor modulator, and MK-677, a growth hormone secretagogue, are being used increasingly amongst recreationally active demographics. However, limited data exist describing their effects on health- and androgen-related biomarkers. The purpose of this case study was to determine changes in body composition and biomarkers during and after continued co-administration of LGD-4033 and MK-677. We also aimed to examine muscular strength and intramuscular androgen-associated biomarkers relative to non-users. A 25-year-old male ingested LGD-4033 (10 mg) and MK-677 (15 mg) daily for 5 weeks. Blood and body composition metrics were obtained pre-, on- and post-cycle. One-repetition maximum leg and bench press, in addition to intramuscular androgens and androgen receptor content, were analysed on-cycle. We observed pre- to on-cycle changes in body composition (body mass, +6.0%; total lean body mass, +3.1%; trunk lean body mass, +6.6%; appendicular lean body mass, +4.3%; total fat mass, +15.4%; trunk fat mass, +2.8%; and appendicular fat mass, +14.8%), bone (bone mineral content, -3.60%; area, -1.1%; and bone mineral density, -2.1%), serum lipid-associated biomarkers (cholesterol, +14.8%; triglycerides, +39.2%; low-density lipoprotein-cholesterol, +40.0%; and high-density lipoprotein-cholesterol, -36.4%), liver-associated biomarkers (aspartate aminotransferase, +95.8%; and alanine aminotransferase, +205.0%) and androgen-associated biomarkers (free testosterone, -85.7%; total testosterone, -62.3%; and sex hormone-binding globulin, -79.6%); however, all variables returned to pre-cycle values post-cycle, apart from total fat mass, appendicular fat mass, bone area, total cholesterol and low-density lipoprotein-cholesterol. Follicle-stimulating hormone was below clinical reference values on- (1.2 IU/L) and post-cycle (1.3 IU/L). Intramuscular androgen receptor (-44.6%), testosterone (+47.8%) and dihydrotestosterone (+34.4%), in addition to one-repetition maximum leg press and bench press (+39.2 and +32.0%, respectively), were different in the case subject compared with non-users. These data demonstrate that LGD-4033 and MK-677 increase several body composition parameters, whilst negatively impacting bone and several serum biomarkers. Given the sparsity of data in recreationally using demographics, further research is warranted to elucidate the acute and chronic physiological effects of these anabolic agents.

Ceftolozane/tazobactam for the treatment of bacteremia: a systematic literature review (SLR).

BACKGROUND: Bloodstream infections (BSIs), or bacteremia, are responsible for considerable disease burden. Increasing rates of antibiotic resistance and delays in selection of appropriate treatment lead to increased morbidity, mortality, and costs. Due to limitations of current standard treatments, especially for bacteremia caused by resistant pathogens, a systematic literature review (SLR) was conducted to understand the utilization of ceftolozane/tazobactam (C/T) in bacteremia. METHODS: Electronic database searches of EMBASE®, MEDLINE®, CCTR and Northern Lights, as well as hand searches of conference proceedings from the last two annual meetings (i.e., 2018, 2019) of the European Congress of Clinical Microbiological and Infectious Diseases (ECCMID) and the Infectious Diseases Society of America's annual meeting (IDWeek) were conducted. A total of 23 studies reporting on patients with bacteremia receiving C/T were included in the review. RESULTS: Most studies were observational (k = 20 studies), though few interventional studies were also identified (k = 3). Heterogeneity was ubiquitous with respect to source of bacteremia (i.e., primary or secondary), source of infection (for secondary bacteremia), pathogen type, antibiotic resistance, C/T dose, and outcome definitions. This heterogeneity, along with limited data, and small sample sizes (n = 1 to 31) made it difficult to draw any substantial conclusions, though overall results were favorable to C/T with respect to the outcomes of interest. Nineteen studies reported clinical cure or success (primary bacteremia: k = 6, reported range: 33.3% to 100%; secondary bacteremia: k = 8, 60% to 100%; mixed/unspecified bacteremia: k = 10, 50% to 91.7%). Eight studies reported microbiological cure or eradication rates (primary: k = 3, all reporting 100%; secondary: k = 4, 68% to 80%; mixed/unspecified: k = 5, 60% to 80%). Thirteen studies reported mortality (primary: k = 4, 0% to 14%; secondary: k = 7, 0% to 100%; or mixed/unspecified bacteremia: k = 7, 0% to 51.6%). One study each also reported composite clinical response, relapse, hospital re-admission, and hospital length of stay. CONCLUSIONS: Although the available evidence and observed trends for C/T in bacteremia should be interpreted with caution, the direction of effect would support the utilization of C/T for these difficult to treat infections. Future research should supplement the existing evidence by considering the impact of key treatment effect modifiers without contributing to the observed heterogeneity.

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19.

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as "COVID toes," remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits similar B cell expansion, neutralizing responses, and protection from Omicron.

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing titers against D614G were 4,760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (preboost), respectively, and 320 and 110 for Omicron. 2 weeks after the boost, titers against D614G and Omicron increased to 5,360 and 2,980 for mRNA-1273 boost and 2,670 and 1,930 for mRNA-Omicron, respectively. Similar increases against BA.2 were observed. Following either boost, 70%-80% of spike-specific B cells were cross-reactive against WA1 and Omicron. Equivalent control of virus replication in lower airways was observed following Omicron challenge 1 month after either boost. These data show that mRNA-1273 and mRNA-Omicron elicit comparable immunity and protection shortly after the boost.

Human Serum Betaine and Associated Biomarker Concentrations Following a 14 Day Supplemental Betaine Loading Protocol and during a 28 Day Washout Period: A Pilot Investigation.

Several previous investigations have employed betaine supplementation in randomized controlled crossover designs to assess its ostensible ergogenic potential. Nevertheless, prior methodology is predicated on limited pharmacokinetic data and an appropriate betaine-specific washout period is hitherto undescribed. The purpose of the present pilot investigation was therein to determine whether a 28 day washout period was sufficient to return serum betaine concentrations to baseline following a supplementation protocol. Five resistance-trained men (26 ± 6 y) supplemented with 6 g/day betaine anhydrous for 14 days and subsequently visited the lab 10 additional times during a 28 day washout period. Participants underwent venipuncture to assess serum betaine and several other parameters before (PRE) and periodically throughout the washout timeframe (POST0, -4, -7, -10, -13, -16, -19, -22, -25 and -28). All analyses were performed at a significance level of p < 0.05. While analyses failed to detect any differences in any other serum biomarker (p > 0.05), serum betaine was significantly elevated from PRE-to-POST0 (p = 0.047; 2.31 ± 1.05 to 11.1 ± 4.91 µg·mL−1) and was statistically indistinguishable from baseline at POST4 (p = 1.00). Nevertheless, visual data assessment and an inability to assess skeletal muscle concentrations would otherwise suggest that a more conservative 7 day washout period is sufficient to truly return both serum-and-skeletal muscle betaine content to pre-supplementation levels.