Reactions of [(dmpe)2MnH(C2H4)] with hydrogermanes to form germylene, germyl, hydrogermane, and germanide complexes.

Reactions of the ethylene hydride complex trans-[(dmpe)2MnH(C2H4)] (1) with secondary hydrogermanes H2GeR2 at 55-60 °C afforded the base-free terminal germylene hydride complexes trans-[(dmpe)2MnH(GeR2)] (R = Ph; 2a, R = Et; 2b). Room temperature reactions of 2a or 2b with an excess of the primary hydrogermanes H3GeR' (R' = Ph or nBu) afforded trans-[(dmpe)2MnH(GeHR')] (R' = Ph; 3a, R' = nBu; 3b) in rapid equilibrium with small amounts of 2a/b, as well as the digermyl hydride complex mer-[(dmpe)2MnH(GeH2R')2] {R' = Ph (4a) or nBu (4b)} and the trans-hydrogermane germyl complex trans-[(dmpe)2Mn(GeH2R')(HGeH2R')] {R' = Ph (5a) or nBu (5b)}. Pure 3b was isolated from the reaction of 2b with H3GenBu, whereas 3a decomposed readily in solution in the absence of free H3GePh, and a pure bulk sample was not obtained. Reactions of 1 with H3GeR' (R' = Ph or nBu) also proceeded at 55-60 °C to afford mixtures of 3a/b, 4a/b and 5a/b, accompanied by remaining 1. However, upon continued heating to consume 1, various unidentified manganese-containing intermediates were formed, ultimately affording the germanide complex [{(dmpe)2MnH}2(µ-Ge)] (6) in 17-49% spectroscopic yield. Pure trans,trans-6 was isolated in 27% yield from the reaction of 1 with H3GenBu, and it is notable that this reaction involves stripping of all four substituents from the hydrogermane. Complexes 2a, 3a, and 6 were crystallographically characterized, and the nature of the MnGe bonding in these species (as well as in 2b and 3b) was probed computationally.

Human Alcohol-Microbiota Mice have Increased Susceptibility to Bacterial Pneumonia.

Preclinical studies have shown that chronic alcohol abuse leads to alterations in the gastrointestinal microbiota that are associated with behavior changes, physiological alterations, and immunological effects. However, such studies have been limited in their ability to evaluate the direct effects of alcohol-associated dysbiosis. To address this, we developed a humanized alcohol-microbiota mouse model to systematically evaluate the immunological effects of chronic alcohol abuse mediated by intestinal dysbiosis. Germ-free mice were colonized with human fecal microbiota from individuals with high and low Alcohol Use Disorders Identification Test (AUDIT) scores and bred to produce human alcohol-associated microbiota or human control-microbiota F1 progenies. F1 offspring colonized with fecal microbiota from individuals with high AUDIT scores had increased susceptibility to Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia, as determined by increased mortality rates, pulmonary bacterial burden, and post-infection lung damage. These findings highlight the importance of considering both the direct effects of alcohol and alcohol-induced dysbiosis when investigating the mechanisms behind alcohol-related disorders and treatment strategies.

Critical contributions of protein cargos to the functions of macrophage-derived extracellular vesicles.

BACKGROUND: Macrophages are highly plastic innate immune cells that play key roles in host defense, tissue repair, and homeostasis maintenance. In response to divergent stimuli, macrophages rapidly alter their functions and manifest a wide polarization spectrum with two extremes: M1 or classical activation and M2 or alternative activation. Extracellular vesicles (EVs) secreted from differentially activated macrophages have been shown to have diverse functions, which are primarily attributed to their microRNA cargos. The role of protein cargos in these EVs remains largely unexplored. Therefore, in this study, we focused on the protein cargos in macrophage-derived EVs. RESULTS: Naïve murine bone marrow-derived macrophages were treated with lipopolysaccharide or interlukin-4 to induce M1 or M2 macrophages, respectively. The proteins of EVs and their parental macrophages were subjected to quantitative proteomics analyses, followed by bioinformatic analyses. The enriched proteins of M1-EVs were involved in proinflammatory pathways and those of M2-EVs were associated with immunomodulation and tissue remodeling. The signature proteins of EVs shared a limited subset of the proteins of their respective progenitor macrophages, but they covered many of the typical pathways and functions of their parental cells, suggesting their respective M1-like and M2-like phenotypes and functions. Experimental examination validated that protein cargos in M1- or M2-EVs induced M1 or M2 polarization, respectively. More importantly, proteins in M1-EVs promoted viability, proliferation, and activation of T lymphocytes, whereas proteins in M2-EVs potently protected the tight junction structure and barrier integrity of epithelial cells from disruption. Intravenous administration of M2-EVs in colitis mice led to their accumulation in the colon, alleviation of colonic inflammation, promotion of M2 macrophage polarization, and improvement of gut barrier functions. Protein cargos in M2-EVs played a key role in their protective function in colitis. CONCLUSION: This study has yielded a comprehensive unbiased dataset of protein cargos in macrophage-derived EVs, provided a systemic view of their potential functions, and highlighted the important engagement of protein cargos in the pathophysiological functions of these EVs.

Diet-microbiome-immune interplay in multiple sclerosis: Understanding the impact of phytoestrogen metabolizing gut bacteria.

Multiple sclerosis (MS) is a chronic and progressive autoimmune disease of the central nervous system (CNS), with both genetic and environmental factors contributing to the pathobiology of the disease. Although HLA genes have emerged as the strongest genetic factor linked to MS, consensus on the environmental risk factors is lacking. Recently, the gut microbiota has garnered increasing attention as a potential environmental factor in MS, as mounting evidence suggests that individuals with MS exhibit microbial dysbiosis (changes in the gut microbiome). Thus, there has been a strong emphasis on understanding the role of the gut microbiome in the pathobiology of MS, specifically, factors regulating the gut microbiota and the mechanism(s) through which gut microbes may contribute to MS. Among all factors, diet has emerged to have the strongest influence on the composition and function of gut microbiota. As MS patients lack gut bacteria capable of metabolizing dietary phytoestrogen, we will specifically discuss the role of a phytoestrogen diet and phytoestrogen metabolizing gut bacteria in the pathobiology of MS. A better understanding of these mechanisms will help to harness the enormous potential of the gut microbiota as potential therapeutics to treat MS and other autoimmune diseases.

Rare earth dialkyl cations and monoalkyl dications supported by a rigid neutral pincer ligand: synthesis and ethylene polymerization.

A palladium-catalyzed coupling reaction between 4,5-dibromo-2,7-di-tert-butyl-9,9-dimethylxanthene and 2 equiv. of 1,3-diisopropylimidazolin-2-imine afforded the rigid neutral 2,7-di-tert-butyl-4,5-bis(1,3-diisopropylimidazolin-2-imino)-9,9-dimethylxanthene (XII2) pincer ligand. Reaction of XII2 with YCl3(THF)3.5 provided [(XII2)YCl3] (1). However, compound 1 failed to react cleanly with 3 equiv. of LiCH2SiMe3, and the reaction of XII2 with [Y(CH2SiMe3)3(THF)2] afforded a complex mixture of products. To access group 3 alkyl complexes without the intermediacy of [(XII2)M(CH2SiMe3)3], the XII2 ligand was protonated using [H(OEt2)2][B(C6F5)4] to form [H(XII2)][B(C6F5)4], and subsequent reaction with [M(CH2SiMe3)3(THF)2] (M = Y, Sc) directly afforded the cationic scandium and yttrium dialkyl complexes [(XII2)M(CH2SiMe3)2][B(C6F5)4] {M = Y (2) and Sc (3)}. Reaction of 3 with B(C6F5)3 in C6D5Br afforded dicationic [(XII2)Sc(CH2SiMe2CH2SiMe3)][MeB(C6F5)3][B(C6F5)4] (4) featuring a CH2SiMe2CH2SiMe3 ligand, formed as a result of methyl anion abstraction from silicon, with concomitant migration of the neighbouring CH2SiMe3 group from scandium to silicon. The MeB(C6F5)3 anion in 4 forms a contact ion pair. By contrast, reaction of 1 with [CPh3][B(C6F5)3] in C6D5Br/toluene or o-C6H4F2/toluene afforded dicationic [(XII2)Sc(CH2SiMe3)(ηx-toluene)n][B(C6F5)4]2 (5). Compounds 2-4 showed negligible ethylene polymerization activity, whereas 5 is highly active (up to 870 kg mol-1 h-1 atm-1 in o-C6H4F2/toluene under 1 atm of ethylene at room temperature).

Pseudopathologic findings on panoramic radiographs and utility of follow-up cone beam computed tomographic scans: a case series.

Conventional radiography is the mainstay for evaluation of developmental and pathologic disorders of oral and maxillofacial structures. Occasionally, clinicians may experience diagnostic pitfalls during interpretation of these imaging modalities. The aim of this article is to present 4 cases of pseudopathologic disorders found on intraoral and panoramic radiographs. Subsequent use of cone beam computed tomographic (CBCT) imaging determined that the initial concerning findings represented anatomical or radiographic anomalies rather than pathologic processes. Supplemental use of CBCT scans may enhance diagnostic assessment, possibly reducing the need for surgical intervention, and elucidate structurally compromised regions of the jaw that could predispose it to fracture.

Effect of Spatial and Spectral Scaling on Joint Characterization of the Spectral Mixture Residual: Comparative Analysis of AVIRIS and WorldView-3 SWIR for Geologic Mapping in Anza-Borrego Desert State Park.

A geologic map is both a visual depiction of the lithologies and structures occurring at the Earth's surface and a representation of a conceptual model for the geologic history in a region. The work needed to capture such multifaced information in an accurate geologic map is time consuming. Remote sensing can complement traditional primary field observations, geochemistry, chronometry, and subsurface geophysical data in providing useful information to assist with the geologic mapping process. Two novel sources of remote sensing data are particularly relevant for geologic mapping applications: decameter-resolution imaging spectroscopy (spectroscopic imaging) and meter-resolution multispectral shortwave infrared (SWIR) imaging. Decameter spectroscopic imagery can capture important mineral absorptions but is frequently unable to spatially resolve important geologic features. Meter-resolution multispectral SWIR images are better able to resolve fine spatial features but offer reduced spectral information. Such disparate but complementary datasets can be challenging to integrate into the geologic mapping process. Here, we conduct a comparative analysis of spatial and spectral scaling for two such datasets: one Airborne Visible/Infrared Imaging Spectrometer-Classic (AVIRIS-classic) flightline, and one WorldView-3 (WV3) scene, for a geologically complex landscape in Anza-Borrego Desert State Park, California. To do so, we use a two-stage framework that synthesizes recent advances in the spectral mixture residual and joint characterization. The mixture residual uses the wavelength-explicit misfit of a linear spectral mixture model to capture low variance spectral signals. Joint characterization utilizes nonlinear dimensionality reduction (manifold learning) to visualize spectral feature space topology and identify clusters of statistically similar spectra. For this study area, the spectral mixture residual clearly reveals greater spectral dimensionality in AVIRIS than WorldView (99% of variance in 39 versus 5 residual dimensions). Additionally, joint characterization shows more complex spectral feature space topology for AVIRIS than WorldView, revealing information useful to the geologic mapping process in the form of mineralogical variability both within and among mapped geologic units. These results illustrate the potential of recent and planned imaging spectroscopy missions to complement high-resolution multispectral imagery-along with field and lab observations-in planning, collecting, and interpreting the results from geologic field work.

The Inherited Intestinal Microbiota from Myeloid-Specific ZIP8KO Mice Impairs Pulmonary Host Defense against Pneumococcal Pneumonia.

Intestinal dysbiosis increases susceptibility to infection through the alteration of metabolic profiles, which increases morbidity. Zinc (Zn) homeostasis in mammals is tightly regulated by 24 Zn transporters. ZIP8 is unique in that it is required by myeloid cells to maintain proper host defense against bacterial pneumonia. In addition, a frequently occurring ZIP8 defective variant (SLC39A8 rs13107325) is strongly associated with inflammation-based disorders and bacterial infection. In this study, we developed a novel model to study the effects of ZIP8-mediated intestinal dysbiosis on pulmonary host defense independent of the genetic effects. Cecal microbial communities from a myeloid-specific Zip8 knockout mouse model were transplanted into germ-free mice. Conventionalized ZIP8KO-microbiota mice were then bred to produce F1 and F2 generations of ZIP8KO-microbiota mice. F1 ZIP8KO-microbiota mice were also infected with S. pneumoniae, and pulmonary host defense was assessed. Strikingly, the instillation of pneumococcus into the lung of F1 ZIP8KO-microbiota mice resulted in a significant increase in weight loss, inflammation, and mortality when compared to F1 wild-type (WT)-microbiota recipients. Similar defects in pulmonary host defense were observed in both genders, although consistently greater in females. From these results, we conclude that myeloid Zn homeostasis is not only critical for myeloid function but also plays a significant role in the maintenance and control of gut microbiota composition. Further, these data demonstrate that the intestinal microbiota, independent of host genetics, play a critical role in governing host defense in the lung against infection. Finally, these data strongly support future microbiome-based interventional studies, given the high incidence of zinc deficiency and the rs13107325 allele in humans.

Home-site advantage for host species-specific gut microbiota.

Mammalian species harbor compositionally distinct gut microbial communities, but the mechanisms that maintain specificity of symbionts to host species remain unclear. Here, we show that natural selection within house mice (Mus musculus domesticus) drives deterministic assembly of the house-mouse gut microbiota from mixtures of native and non-native microbiotas. Competing microbiotas from wild-derived lines of house mice and other mouse species (Mus and Peromyscus spp.) within germ-free wild-type (WT) and Rag1-knockout (Rag1-/-) house mice revealed widespread fitness advantages for native gut bacteria. Native bacterial lineages significantly outcompeted non-native lineages in both WT and Rag1-/- mice, indicating home-site advantage for native microbiota independent of host adaptive immunity. However, a minority of native Bacteriodetes and Firmicutes favored by selection in WT hosts were not favored or disfavored in Rag1-/- hosts, indicating that Rag1 mediates fitness advantages of these strains. This study demonstrates home-site advantage for native gut bacteria, consistent with local adaptation of gut microbiota to their mammalian species.

Visual and circadian regulation of Drosophila BDBT and BDBT effects on DBT and PER localization.

BRIDE OF DOUBLETIME (BDBT) interacts with the circadian kinase DOUBLETIME (DBT) and accumulates in eye foci during the dark of a light:dark cycle. BDBT foci are shown here to be broadly expressed in constant dark and low in constant light. Analysis of circadian photoreceptor cry and visual photoreceptor ninaE mutants showed that disappearance of eye BDBT foci requires both the CRYPTOCHROME and the RHODOPSIN-1 pathways. The arr1 and arr2 mutants, which affect rhodopsin quenching, eliminated BDBT foci under dark conditions. arr1 and arr2 mutants also caused increased nuclear PER protein. The changes in BDBT foci do not result from altered BDBT levels in the eye but from changes in its immunodetection. Knockdown of BDBT specifically in the eye produced constitutively nuclear PER and constitutively cytosolic DBT. The results show that BDBT is necessary for co-transport of DBT and PER into the nucleus and suggest that this process is regulated by a light-dependent mechanism.

Trans Ligand Determines the Stability of Paramagnetic Manganese(II) Hydrides of the Type trans-[MnH(L)(dmpe)2]+ Where L is PMe3, C2H4, or CO.

Paramagnetic metal hydride (PMH) complexes play important roles in catalytic applications and bioinorganic chemistry. 3d PMH chemistry has largely focused on Ti, Mn, Fe, and Co. Various MnII PMHs have been proposed as intermediates in catalysis, but isolated MnII PMHs are limited to dimeric high-spin MnII structures with bridging hydrides. In this paper, a series of the first low-spin monomeric MnII PMH complexes are generated by chemical oxidation of their MnI analogues. This series is of the type trans-[MnH(L)(dmpe)2]+/0 where the trans ligand L is PMe3, C2H4, or CO [dmpe is 1,2-bis(dimethylphosphino)ethane], and the thermal stability of the MnII hydride complexes was found to be strongly dependent on the identity of the trans ligand. When L is PMe3, the complex is the first example of an isolated monomeric MnII hydride complex. In contrast, when L is C2H4 or CO, the complexes are only stable at low temperatures; upon warming to room temperature, the former decomposed to afford [Mn(dmpe)3]+, accompanied by ethane and ethylene, whereas the latter eliminated H2, generating [Mn(MeCN)(CO)(dmpe)2]+ or a mixture of products including [Mn(κ1-PF6)(CO)(dmpe)2], depending on the reaction conditions. All PMHs were characterized by low-temperature electron paramagnetic resonance (EPR) spectroscopy, and stable [MnH(PMe3)(dmpe)2]+ was further characterized by UV-vis and IR spectroscopy, Superconducting Quantum Interference Device magnetometry, and single-crystal X-ray diffraction. Noteworthy spectral properties are the significant EPR superhyperfine coupling to the hydride (∼85 MHz) and an increase (+33 cm-1) in the Mn-H IR stretch upon oxidation. Density functional theory calculations were also employed to gain insights into the acidity and bond strengths of the complexes. MnII-H bond dissociation free energies are estimated to decrease in the series of complexes from 60 (L = PMe3) to 47 kcal/mol (L = CO).

Incidental findings in cone beam computed tomography volumes: Calcified head-and-neck atheromas detected during dental evaluation.

PURPOSE: Atheromas can be detected incidentally in routine dental cone beam computed tomography (CBCT) images. This study aims to assess prevalence and risk factors associated with these vascular lesions. MATERIALS AND METHODS: The maxillofacial CBCTs of 458 subjects were evaluated and divided into 4 groups based on the presence of calcified atheroma: subjects with no calcified atheroma, subjects with intracranial calcified atheroma (ICA), subjects with extracranial calcified atheroma (ECA), and subjects exhibiting combined lesions. Age, sex, medical conditions, family history, and size were documented. Analysis of variance followed by a multiple comparison test was used for data satisfying parametric test assumptions. Chi-squared tests were used to assess categorical data. The Spearman Rho test was used to assess the correlation between the incidence of calcified atheroma and subjects' medical condition. RESULTS: Of the 458 CBCTs evaluated, 29.90% presented with calcified atheroma. Calcified atheroma prevalence was significantly higher in older patients versus younger patients (p = 0.004) and in males compared to females (p = 0.004). Males were more likely to have the combination of ICA and ECA, whereas females were more likely to have ICA alone (p ≤ 0.040). Patients with calcified atheroma were significantly more likely to have a history of hyperlipidemia (p = 0.001), hypertension (p = 0.001), and myocardial infarction/coronary artery diseases (p = 0.001). Overall, patients exhibiting both intracranial and extracranial lesions were more likely to have cardiovascular risk factors (p = 0.001). CONCLUSION: Incidentally detected calcified atheromas in CBCTs are common. Subjects with combined atheroma lesions are at higher risk for cardiovascular disease. The diagnosis of incidental calcified atheromas in CBCT's warrants early referral to medical specialists, especially if there is no medical history of existing cardiovascular disease.

Uranium(iv) alkyl cations: synthesis, structures, comparison with thorium(iv) analogues, and the influence of arene-coordination on thermal stability and ethylene polymerization activity.

Reaction of [(XA2)U(CH2SiMe3)2] (1; XA2 = 4,5-bis(2,6-diisopropylanilido)-2,7-di-tert-butyl-9,9-dimethylxanthene) with 1 equivalent of [Ph3C][B(C6F5)4] in arene solvents afforded the arene-coordinated uranium alkyl cations, [(XA2)U(CH2SiMe3)(η n -arene)][B(C6F5)4] {arene = benzene (2), toluene (3), bromobenzene (4) and fluorobenzene (5)}. Compounds 2, 3, and 5 were crystallographically characterized, and in all cases the arene is π-coordinated. Solution NMR studies of 2-5 suggest that the binding preferences of the [(XA2)U(CH2SiMe3)]+ cation follow the order: toluene ≈ benzene > bromobenzene > fluorobenzene. Compounds 2-4 generated in C6H5R (R = H, Me or Br, respectively) showed no polymerization activity under 1 atm of ethylene. By contrast, 5 and 5-Th (the thorium analogue of 5) in fluorobenzene at 20 and 70 °C achieved ethylene polymerization activities between 16 800 and 139 200 g mol-1 h-1 atm-1, highlighting the extent to which common arene solvents such as toluene can suppress ethylene polymerization activity in sterically open f-element complexes. However, activation of [(XA2)An(CH2SiMe3)2] {M = U (1) or Th (1-Th)} with [Ph3C][B(C6F5)4] in n-alkane solvents did not afford an active polymerization catalyst due to catalyst decomposition, illustrating the critical role of PhX (X = H, Me, Br or F) coordination for alkyl cation stabilization. Gas phase DFT calculations, including fragment interaction calculations with energy decomposition and ETS-NOCV analysis, were carried out on the cationic portion of 2'-Th, 2', 3' and 5' (analogues of 2-Th, 2, 3 and 5 with hydrogen atoms in place of ligand backbone methyl and tert-butyl groups), providing insight into the nature of actinide-arene bonding, which decreases in strength in the order 2'-Th > 2' ≈ 3' > 5'.

DBT affects sleep in both circadian and non-circadian neurons.

Sleep is a very important behavior observed in almost all animals. Importantly, sleep is subject to both circadian and homeostatic regulation. The circadian rhythm determines the daily alternation of the sleep-wake cycle, while homeostasis mediates the rise and dissipation of sleep pressure during the wake and sleep period. As an important kinase, dbt plays a central role in both circadian rhythms and development. We investigated the sleep patterns of several ethyl methanesulfonate-induced dbt mutants and discuss the possible reasons why different sleep phenotypes were shown in these mutants. In order to reduce DBT in all neurons in which it is expressed, CRISPR-Cas9 was used to produce flies that expressed GAL4 in frame with the dbt gene at its endogenous locus, and knock-down of DBT with this construct produced elevated sleep during the day and reduced sleep at night. Loss of sleep at night is mediated by dbt loss during the sleep/wake cycle in the adult, while the increased sleep during the day is produced by reductions in dbt during development and not by reductions in the adult. Additionally, using targeted RNA interference, we uncovered the contribution of dbt on sleep in different subsets of neurons in which dbt is normally expressed. Reduction of dbt in circadian neurons produced less sleep at night, while lower expression of dbt in noncircadian neurons produced increased sleep during the day. Importantly, independently of the types of neurons where dbt affects sleep, we demonstrate that the PER protein is involved in DBT mediated sleep regulation.

High-content analysis and Kinetic Image Cytometry identify toxicity and epigenetic effects of HIV antiretrovirals on human iPSC-neurons and primary neural precursor cells.

INTRODUCTION: Despite viral suppression due to combination antiretroviral therapy (cART), HIV-associated neurocognitive disorders (HAND) continue to affect half of people with HIV, suggesting that certain antiretrovirals (ARVs) may contribute to HAND. METHODS: We examined the effects of nucleoside/nucleotide reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) and the integrase inhibitors dolutegravir (DTG) and elvitegravir (EVG) on viability, structure, and function of glutamatergic neurons (a subtype of CNS neuron involved in cognition) derived from human induced pluripotent stem cells (hiPSC-neurons), and primary human neural precursor cells (hNPCs), which are responsible for neurogenesis. RESULTS: Using automated digital microscopy and image analysis (high content analysis, HCA), we found that DTG, EVG, and TDF decreased hiPSC-neuron viability, neurites, and synapses after 7 days of treatment. Analysis of hiPSC-neuron calcium activity using Kinetic Image Cytometry (KIC) demonstrated that DTG and EVG also decreased the frequency and magnitude of intracellular calcium transients. Longer ARV exposures and simultaneous exposure to multiple ARVs increased the magnitude of these neurotoxic effects. Using the Microscopic Imaging of Epigenetic Landscapes (MIEL) assay, we found that TDF decreased hNPC viability and changed the distribution of histone modifications that regulate chromatin packing, suggesting that TDF may reduce neuroprogenitor pools important for CNS development and maintenance of cognition in adults. CONCLUSION: This study establishes human preclinical assays that can screen potential ARVs for CNS toxicity to develop safer cART regimens and HAND therapeutics.

A Multi­Center, Open­Label, Single­Arm Trial to Evaluate the Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency.

PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.

Uranium(IV) Thio- and Selenoether Complexes: Syntheses, Structures, and Computational Investigation of U-ER2 Interactions.

Rigid thioether- and selenoether-containing pincer proligands H[AS2 Ph 2 ] (1) and H[ASe2 Ph 2 ] (2) were synthesized, and deprotonation provided the potassium salts [K(AS2 Ph 2 )(dme)] (3) and [K(ASe2 Ph 2 )(dme)2 ] (4). Reaction of two equivalents of 3 or 4 with [UI4 (dioxane)2 ] afforded the uranium thioether complex [(AS2 Ph 2 )2 UI2 ] (5) and the first example of a uranium-selenoether complex, [(ASe2 Ph 2 )2 UI2 ] (6). X-ray structures revealed distorted square antiprismatic geometries in which the AE2 Ph 2 ligands are κ3 -coordinated. The nature of the U-ER2 bonding in 5 and 6, as well as methyl-free analogues of 5 and 6 and a hypothetical ether analogue, was investigated computationally (including NBO, AIM, and ELF calculations) illustrating increasing covalency from O to S to Se.

Reactions of [(dmpe)2MnH(C2H4)]: synthesis and characterization of manganese(i) borohydride and hydride complexes.

Reactions of trans-[(dmpe)2MnH(C2H4)] (1) with BH3(NMe3), 9-BBN, and HBMes2 yielded the manganese(i) borohydride complexes [(dmpe)2Mn(µ-H)2BR2] (3: R = H, 4: R2 = C8H14, 5: R = Mes). The reaction of 1 with BH3(NMe3) proceeds via ethylene substitution. By contrast, a detuerium labelling study indicates that the reaction of 1 with HBMes2 involves initial isomerization of 1 to an unobserved 5-coordinate ethyl intermediate, [(dmpe)2MnEt], which reacts with the hydroborane to afford EtBR2 and [(dmpe)2MnH], followed by reaction with a second equivalent of hydroborane to generate 5 (an analogous pathway is likely followed for other base-free hydroboranes such as 9-BBN). Identification of 3-5 as κ2-borohydride complexes, as opposed to boryl dihydride or hydroborane hydride isomers, is supported by 11B NMR spectroscopy, X-ray diffraction, and Atoms in Molecules calculations. Two byproducts were observed in the syntheses of 3-5: [{(dmpe)2MnH}2(µ-dmpe)] (6) and [(dmpe)2MnH(κ1-dmpe)] (7). These complexes were independently prepared by exposure of 1 to free dmpe under an atmosphere of Ar or H2, and the generality of this synthetic route was demonstrated by the reaction of 1 with PMe3 (under H2) to form [(dmpe)2MnH(PMe3)] (8). Complexes 6-8 can exist as isomers with either a trans or a cis relationship between the hydride and κ1-coordinated phosphine ligands on manganese. trans to cis isomerization of 6-8 is photochemically induced, whereas the reverse reaction occurs under thermal conditions. X-ray crystal structures were obtained for 3-5, trans,trans-6, cis,cis-6, trans-7, and trans-8.

Polyvalent Human Immune Globulin: A Prospective, Open-Label Study Assessing Anti-Hepatitis A Virus (HAV) Antibody Levels, Pharmacokinetics, and Safety in HAV-Seronegative Healthy Subjects.

BACKGROUND: Analytical data suggesting that immunoglobulin given intramuscularly (IGIM) may have reduced protection against hepatitis A virus (HAV) infection led to an update in the recommended IGIM dose (0.2 ml/kg). METHODS: This prospective, open-label, single-arm clinical study evaluated whether a single 0.2 ml/kg dose of IGIM provided protective levels of anti-HAV antibodies (≥ 10 mIU/ml for up to 60 days) in HAV-seronegative healthy adults. RESULTS: Of the 28 subjects enrolled and dosed, 26 (93%) completed the study. Mean uncorrected anti-HAV antibody titers peaked at 109 mIU/ml on day 5 and stayed above 10 mIU/ml through day 60 (N = 26). The mean uncorrected anti-HAV antibody titers had a median Tmax of 95.33 h, a mean Cmax of 118 mIU/ml, and a mean observed Thalf of 63.3 days; baseline-corrected titers had a median Tmax of 95.33 h, a mean Cmax of 114 mIU/ml, and a mean observed Thalf of 47.1 days (N = 27). All subjects (28/28) experienced at least 1 treatment-emergent adverse event (TEAE), with a total of 83 TEAEs reported; none was serious, and 96% (80/83) resolved without sequelae. Most (63%) events judged definitely and possibly related to study treatment involved localized pain due to intramuscular injections. There were no serious adverse events and no deaths or discontinuations due to TEAEs. CONCLUSIONS: A single 0.2 ml/kg dose of IGIM provided protective anti-HAV levels for at least 60 days, with acceptable safety and tolerability profiles in healthy subjects. Uncorrected and baseline-corrected pharmacokinetic findings were similar and consistent with the corresponding sampling points in previous research. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT03351933.