Universal logic with encoded spin qubits in silicon.

Quantum computation features known examples of hardware acceleration for certain problems, but is challenging to realize because of its susceptibility to small errors from noise or imperfect control. The principles of fault tolerance may enable computational acceleration with imperfect hardware, but they place strict requirements on the character and correlation of errors1. For many qubit technologies2-21, some challenges to achieving fault tolerance can be traced to correlated errors arising from the need to control qubits by injecting microwave energy matching qubit resonances. Here we demonstrate an alternative approach to quantum computation that uses energy-degenerate encoded qubit states controlled by nearest-neighbour contact interactions that partially swap the spin states of electrons with those of their neighbours. Calibrated sequences of such partial swaps, implemented using only voltage pulses, allow universal quantum control while bypassing microwave-associated correlated error sources1,22-28. We use an array of six 28Si/SiGe quantum dots, built using a platform that is capable of extending in two dimensions following processes used in conventional microelectronics29. We quantify the operational fidelity of universal control of two encoded qubits using interleaved randomized benchmarking30, finding a fidelity of 96.3% ± 0.7% for encoded controlled NOT operations and 99.3% ± 0.5% for encoded SWAP. The quantum coherence offered by enriched silicon5-9,16,18,20,22,27,29,31-37, the all-electrical and low-crosstalk-control of partial swap operations1,22-28 and the configurable insensitivity of our encoding to certain error sources28,33,34,38 all combine to offer a strong pathway towards scalable fault tolerance and computational advantage.

The Fisher Subunit Anatomical Approach for Cleft Lip Revisions: An Evolution and Case Series.

ABSTRACT: Many techniques exist to reapproximate a cleft lip but can leave unsatisfactory results with nonanatomic scars and a short upper lip, creating a need for revision. Many revisions focus on adjacent tissue transfers and realignment of landmarks, but in the senior authors' experience, recreating the defect and utilizing the Fisher repair for revision have led to aesthetically pleasing results and less noticeable scars. A database was collected that included all cleft lip revisions performed at a large, comprehensive children's hospital from October 2018 to July 2021. Inclusion criteria included any cleft patient with a cleft lip revision performed by two craniofacial surgeons. Data collected included sex, characteristics of the cleft lip, age at initial and index repair, type of initial repair, previous revisions, type of revision with any additional tissue rearrangement, and any nose repair. Sixty-five patients were included in the study for analysis. The type of initial repair was known in sixty-four cases (98%), and fifty-four were Millard repairs (83%). Twenty-two patients (33%) had a previous revision prior to their index revision. Sixty patients (92%) underwent the Fisher repair technique for their index revision and forty-six patients (70%) underwent nasal revision. In follow-up, all patients demonstrated an improvement in lip aesthetics. This study demonstrates a large subset of patients that have undergone cleft lip revision using the Fisher technique. In the senior surgeons' experience, the Fisher repair technique in the setting of cleft lip revision is an ideal way to address the shortcomings of historical repair techniques.

Meta-Analytic Modeling of the Severity-Yield Relationships in Soybean Frogeye Leaf Spot Epidemics.

Frogeye leaf spot (FLS), caused by Cercospora sojina, is an important foliar disease affecting soybean in the United States. A meta-analytic approach including 39 fungicide trials conducted from 2012 to 2021 across eight states (Alabama, Arkansas, Illinois, Iowa, Kentucky, Louisiana, Mississippi, Tennessee) was used to assess the relationship between FLS severity and soybean yield. Correlation and regression analyses were performed separately to determine Fisher's transformation of correlation coefficients (Zr), intercept (ß0) and slope (ß1). Disease pressure (low severity, ≤34.5; high severity, >34.5%) and yield class (low, ≤3,352; high, >3,352 kg/ha) were included as categorical moderators. Pearson's [Formula: see text], obtained from back-transforming the [Formula: see text]r estimated by an overall random-effects model, showed a significant negative linear relationship between FLS severity and yield ([Formula: see text] = -0.60). The [Formula: see text]r was affected by disease pressure (P = 0.0003) but not by yield class (P = 0.8141). A random-coefficient model estimated a slope of -19 kg/ha for each percent severity for a mean attainable yield of 3,719.9 kg/ha. Based on the overall mean (95% CI) of the intercept and slope estimated by the random-coefficients model, the estimated overall relative damage coefficient was 0.51% (0.36 to 0.69), indicating that a percent increase in FLS severity reduced yield by 0.51%. The best model included yield class as a covariate, and population-average intercepts differed significantly between low (3,455.1 kg/ha) and high (3,842.7 kg/ha) yield classes. This highlights the potential impact of FLS on soybean yield if not managed and may help in disease management decisions.

Efficacy and Profitability of Fungicides for Managing Frogeye Leaf Spot on Soybean in the United States: A 10-Year Quantitative Summary.

Frogeye leaf spot (FLS), caused by Cercospora sojina, is an economically important disease of soybean in the United States. Data from 66 uniform fungicide trials (UFTs) conducted from 2012 to 2021 across eight states (Alabama, Arkansas, Illinois, Iowa, Kentucky, Louisiana, Mississippi, and Tennessee) were gathered and analyzed to determine the efficacy and profitability of the following fungicides applied at the beginning pod developmental stage (R3): azoxystrobin + difenoconazole (AZOX + DIFE), difenoconazole + pydiflumetofen (DIFE + PYDI), pyraclostrobin (PYRA), pyraclostrobin + fluxapyroxad + propiconazole (PYRA + FLUX + PROP), tetraconazole (TTRA), thiophanate-methyl (TMET), thiophanate-methyl + tebuconazole (TMET + TEBU), and trifloxystrobin + prothioconazole (TFLX + PROT). A network meta-analytic model was fitted to the log of the means of FLS severity data and to the nontransformed mean yield for each treatment, including the nontreated. The percent reduction in disease severity (%) and the yield response (kg/ha) relative to the nontreated was the lowest for PYRA (11%; 136 kg/ha) and the greatest for DIFE + PYDI (57%; 441 kg/ha). A significant decline in efficacy over time was detected for PYRA (18 percentage points [p.p.]), TTRA (27 p.p.), AZOX + DIFE (18 p.p.), and TMET + TEBU (19 p.p.) by using year as a continuous covariate in the model. Finally, probabilities of breaking even were the greatest (>65%) for the most effective fungicide DIFE + PYDI and the lowest (<55%) for PYRA. Results of this meta-analysis may be useful to support decisions when planning fungicide programs.

Selective Isotope Labeling and LC-Photo-CIDNP Enable NMR Spectroscopy at Low-Nanomolar Concentration.

NMR spectroscopy is a powerful tool to investigate molecular structure and dynamics. The poor sensitivity of this technique, however, limits its ability to tackle questions requiring dilute samples. Low-concentration photochemically induced dynamic nuclear polarization (LC-photo-CIDNP) is an optically enhanced NMR technology capable of addressing the above challenge by increasing the detection limit of aromatic amino acids in solution up to 1000-fold, either in isolation or within proteins. Here, we show that the absence of NMR-active nuclei close to a magnetically active site of interest (e.g., the structurally diagnostic 1Hα-13Cα pair of amino acids) is expected to significantly increase LC-photo-CIDNP hyperpolarization. Then, we exploit the spin-diluted tryptophan isotopolog Trp-α-13C-ß,ß,2,4,5,6,7-d7 and take advantage of the above prediction to experimentally achieve a ca 4-fold enhancement in NMR sensitivity over regular LC-photo-CIDNP. This advance enables the rapid (within seconds) detection of 20 nM concentrations or the molecule of interest, corresponding to a remarkable 3 ng detection limit. Finally, the above Trp isotopolog is amenable to incorporation within proteins and is readily detectable at a 1 µM concentration in complex cell-like media, including Escherichia coli cell-free extracts.

An AGS-associated mutation in ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the brain.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a severe neurodegenerative disease with clinical features of early-onset encephalopathy and progressive loss of intellectual abilities and motor control. Gene mutations in seven protein-coding genes have been found to be associated with AGS. However, the causative role of these mutations in the early-onset neuropathogenesis has not been demonstrated in animal models, and the mechanism of neurodegeneration of AGS remains ambiguous. METHODS: Via CRISPR/Cas-9 technology, we established a mutant mouse model in which a genetic mutation found in AGS patients at the ADAR1 coding gene (Adar) loci was introduced into the mouse genome. A mouse model carrying double gene mutations encoding ADAR1 and MDA-5 was prepared using a breeding strategy. Phenotype, gene expression, RNA sequencing, innate immune pathway activation, and pathologic studies including RNA in situ hybridization (ISH) and immunohistochemistry were used for characterization of the mouse models to determine potential disease mechanisms. RESULTS: We established a mouse model bearing a mutation in the catalytic domain of ADAR1, the D1113H mutation found in AGS patients. With this mouse model, we demonstrated a causative role of this mutation for the early-onset brain injuries in AGS and determined the signaling pathway underlying the neuropathogenesis. First, this mutation altered the RNA editing profile in neural transcripts and led to robust IFN-stimulated gene (ISG) expression in the brain. By ISH, the brains of mutant mice showed an unusual, multifocal increased expression of ISGs that was cell-type dependent. Early-onset astrocytosis and microgliosis and later stage calcification in the deep white matter areas were observed in the mutant mice. Brain ISG activation and neuroglial reaction were completely prevented in the Adar D1113H mutant mice by blocking RNA sensing through deletion of the cytosolic RNA receptor MDA-5. CONCLUSIONS: The Adar D1113H mutation in the ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the mouse brain.

Gamma Knife Radiosurgery in the Management of Hypothalamic Glioma: A Case Report with Long-Term Follow-Up.

BACKGROUND: Optic pathway/hypothalamic gliomas are rare pediatric brain tumors. The management paradigm for these challenging tumors includes chemotherapy, radiotherapy, or surgical resection, but the optimal management strategy remains elusive. Gamma knife radiosurgery (GKRS) has emerged as a promising treatment for such lesions as documented by a small number of cases in the literature. CASE PRESENTATION: We present a rare case of hypothalamic glioma in a 13-year-old girl who was referred to our service due to growth of an incidentally diagnosed hypothalamic lesion following head injury at the age of 8 years. The lesion demonstrated hypointensity on T1- and hyperintensity on T2-weighted imaging without contrast enhancement. Given the growth of the lesion on serial imaging, a stereotactic biopsy was performed demonstrating low-grade glioma. The patient underwent GKRS treatment with a marginal dose of 15 Gy at 50% isodose line for a tumor volume of 2.2 mL. Annual radiological surveillance over the next 17 years demonstrated a gradual shrinkage of the lesion until it completely disappeared. The patient is currently a healthy 31-year-old female without any visual, endocrine, or neurocognitive deficits. CONCLUSION: The outcome obtained after extended follow-up in our patient highlights the safety and efficacy of GKRS in the management of hypothalamic gliomas in pediatrics, which in turn can avoid potentially serious complications of surgery in this vulnerable patient population, especially in this sensitive location.

Detection of Pythium spp. in Golf Course Irrigation Systems.

Many Pythium spp. are causal agents of diseases of turfgrasses. Pythium spp. disseminate through irrigation systems in agricultural settings, and this study provides evidence that Pythium spp. also disseminate through golf course irrigation. Water samples were collected from irrigation heads and water sources at 10 golf courses in Missouri and Kansas, U.S.A. Samples were collected from 2018 to 2019 in April, July, and October. Phosphorus, nitrogen, and chloride concentrations were measured from irrigation head samples to determine if these parameters influence frequency of Pythium spp. detected. Pythium spp. were detected in samples through baiting and membrane filtration. Cultures were isolated on PARP media, and DNA was extracted from putative Pythium isolates. The internal transcribed spacer region was PCR-amplified and sequenced. Phylogenetic trees were constructed using representative sample sequences, sequences from seven morphologically identified reference isolates of Pythium, and similar GenBank accessions. Detected oomycete species include Lagenidium giganteum, Pythium biforme, Pythium insidiosum, Pythium marsipium, Pythium plurisporium, and Saprolegnia hypogyna. Twenty-one clades lacked species-level resolution, and 14 of these clades were associated with Pythium species. Clades A, C, D, E, I, and M contain Pythium species that cause root and crown rot on creeping bentgrass. Detected Pythium communities were dependent on the detection method used and sampling source. Pythium frequency and diversity were highest in April 2019. Sample temperature, sampling site, and chloride and nutrient concentrations did not influence Pythium frequency in samples. Irrigation systems using surface water sources contained at least three Pythium spp. over the course of 2 years.

Intra-rater reliability of goniometry to measure scapular protraction and retraction.

STUDY DESIGN: Observational, descriptive design. BACKGROUND: Despite scapular mobility being essential for the completion of activities of daily living (ADLs), there is currently no established, a reliable goniometric technique to measure scapular protraction and retraction. A proposed method has shown clinically significant inter-rater reliability for a goniometric technique for these measurements. PURPOSE: This observational descriptive study examined the intra-rater reliability of a goniometric technique to assess scapular protraction and retraction among a sample of healthy adults. METHODS: An occupational therapist who is a certified hand therapist (CHT) and an occupational therapy student used goniometry to measure the neutral (resting), protracted, and retracted positions of the right and left scapula for a sample of healthy young adults (n = 54; a total of 108 data points for each measurement). These measurements were compared to analyze intra-rater and inter-rater reliability. RESULTS: For measurements of the scapula in neutral, protraction, and retraction, the standard error of measure (SEM) for repeat measures by the expert and novice raters was < 4.5° and < 3.9° respectively and ICC values ranged from poor to moderate (0.37-0.63). The SEM for measures between evaluators was < 5.0° and the ICC was poor (0.16-0.35). Minimum detectable change (MDC) values as a percentage of the mean (% MDC) ranged between 15.9 and 43.7% for intra-rater reliability and 21.9-52.8% for inter-rater reliability. DISCUSSION: The results of the study were mixed; variance of less than 5° for repeat measures by the same rater and measures between raters suggest clinically acceptable reliability. However, variance as a proportion of available motion (%MDC) demonstrates a broader range both above and below the threshold of 30% suggested for rehabilitation assessments. CONCLUSION: There are few efficient, reliable techniques to measure scapular mobility in clinical practice. The absolute reliability of goniometry to measure scapular protraction and retraction is similar to measurements of other joints. However, additional research and possible refinement of the technique is recommended to further address relative reliability and validity.

Aicardi-Goutières syndrome-associated mutation at ADAR1 gene locus activates innate immune response in mouse brain.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a severe infant or juvenile-onset autoimmune disease characterized by inflammatory encephalopathy with an elevated type 1 interferon-stimulated gene (ISG) expression signature in the brain. Mutations in seven different protein-coding genes, all linked to DNA/RNA metabolism or sensing, have been identified in AGS patients, but none of them has been demonstrated to activate the IFN pathway in the brain of an animal. The molecular mechanism of inflammatory encephalopathy in AGS has not been well defined. Adenosine Deaminase Acting on RNA 1 (ADAR1) is one of the AGS-associated genes. It carries out A-to-I RNA editing that converts adenosine to inosine at double-stranded RNA regions. Whether an AGS-associated mutation in ADAR1 activates the IFN pathway and causes autoimmune pathogenesis in the brain is yet to be determined. METHODS: Mutations in the ADAR1 gene found in AGS patients were introduced into the mouse genome via CRISPR/Cas9 technology. Molecular activities of the specific p.K999N mutation were investigated by measuring the RNA editing levels in brain mRNA substrates of ADAR1 through RNA sequencing analysis. IFN pathway activation in the brain was assessed by measuring ISG expression at the mRNA and protein level through real-time RT-PCR and Luminex assays, respectively. The locations in the brain and neural cell types that express ISGs were determined by RNA in situ hybridization (ISH). Potential AGS-related brain morphologic changes were assessed with immunohistological analysis. Von Kossa and Luxol Fast Blue staining was performed on brain tissue to assess calcification and myelin, respectively. RESULTS: Mice bearing the ADAR1 p.K999N were viable though smaller than wild type sibs. RNA sequencing analysis of neuron-specific RNA substrates revealed altered RNA editing activities of the mutant ADAR1 protein. Mutant mice exhibited dramatically elevated levels of multiple ISGs within the brain. RNA ISH of brain sections showed selective activation of ISG expression in neurons and microglia in a patchy pattern. ISG-15 mRNA was upregulated in ADAR1 mutant brain neurons whereas CXCL10 mRNA was elevated in adjacent astroglia. No calcification or gliosis was detected in the mutant brain. CONCLUSIONS: We demonstrated that an AGS-associated mutation in ADAR1, specifically the p.K999N mutation, activates the IFN pathway in the mouse brain. The ADAR1 p.K999N mutant mouse replicates aspects of the brain interferonopathy of AGS. Neurons and microglia express different ISGs. Basal ganglia calcification and leukodystrophy seen in AGS patients were not observed in K999N mutant mice, indicating that development of the full clinical phenotype may need an additional stimulus besides AGS mutations. This mutant mouse presents a robust tool for the investigation of AGS and neuroinflammatory diseases including the modeling of potential "second hits" that enable severe phenotypes of clinically variable diseases.

Cardiac surgeons' concerns, perceptions, and responses during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact on health care and cardiac surgery. We report cardiac surgeons' concerns, perceptions, and responses during the COVID-19 pandemic. METHODS: A detailed survey was sent to recruit participating adult cardiac surgery centers in North America. Data regarding cardiac surgeons' perceptions and changes in practice were analyzed. RESULTS: Our study comprises 67 institutions with diverse geographic distribution across North America. Nurses were most likely to be redeployed (88%), followed by advanced care practitioners (69%), trainees (28%), and surgeons (25%). Examining surgeon concerns in regard to COVID-19, they were most worried with exposing their family to COVID-19 (81%), followed by contracting COVID-19 (68%), running out of personal protective equipment (PPE) (28%), and hospital resources (28%). In terms of PPE conservation strategies among users of N95 respirators, nearly half were recycling via decontamination with ultraviolet light (49%), followed by sterilization with heat (13%) and at home or with other modalities (13%). Reuse of N95 respirators for 1 day (22%), 1 week (21%) or 1 month (6%) was reported. There were differences in adoption of methods to conserve N95 respirators based on institutional pandemic phase and COVID-19 burden, with higher COVID-19 burden institutions more likely to resort to PPE conservation strategies. CONCLUSIONS: The present study demonstrates the impact of COVID-19 on North American cardiac surgeons. Our study should stimulate further discussions to identify optimal solutions to improve workforce preparedness for subsequent surges, as well as facilitate the navigation of future healthcare crises.

Design, Synthesis, and Validation of a Novel [11C]Promethazine PET Probe for Imaging Abeta Using Autoradiography.

Promethazine, an antihistamine drug used in the clinical treatment of nausea, has been demonstrated the ability to bind Abeta in a transgenic mouse model of Alzheimer's disease. However, so far, all of the studies were performed in vitro using extracted tissues. In this work, we report the design and synthesis of a novel [11C]promethazine PET radioligand for future in vivo studies. The [11C]promethazine was isolated by RP-HPLC with radiochemical purity >95% and molar activity of 48 TBq/mmol. The specificity of the probe was demonstrated using human hippocampal tissues via autoradiography.

Age-Related Pathology Associated with H1N1 A/California/07/2009 Influenza Virus Infection.

Influenza virus infection causes a spectrum of diseases, ranging from mild upper respiratory tract infection to severe lower respiratory tract infection, that can lead to diffuse alveolar damage, interstitial and airspace inflammation, or acute respiratory failure. Mechanisms instructing disease severity are not completely understood, but host, viral, and bacterial factors influence disease outcome. With age being one host factor associated with a higher risk of severe influenza, we investigated regional pulmonary distribution and severity of pneumonia after 2009 H1N1 influenza virus infection in newly weaned, adult, and aged ferrets to better understand age-dependent susceptibility and pathology. Aged ferrets exhibited greater weight loss and higher rates of mortality than adult ferrets, whereas most newly weaned ferrets did not lose weight but had a lack of weight gain. Newly weaned ferrets exhibited minimal pneumonia, whereas adult and aged ferrets had a spectrum of pneumonia severity. Influenza virus-induced pneumonia peaked earliest in adult ferrets, whereas aged ferrets had delayed presentation. Bronchial severity differed among groups, but bronchial pathology was comparable among all cohorts. Alveolar infection was strikingly different among groups. Newly weaned ferrets had little alveolar cell infection. Adult and aged ferrets had alveolar infection, but aged ferrets were unable to clear infection. These different age-related pneumonia and infection patterns suggest therapeutic strategies to treat influenza should be tailored contingent on age.

Giant polarization anisotropic optical response from anodic aluminum oxide templates embedded with plasmonic metamaterials.

Plasmonic metamaterials enable extraordinary manipulation of key constitutive properties of light at a subwavelength scale and thus have attracted significant interest. Here, we report a simple and convenient nanofabrication method for a novel meta-device by glancing deposition of gold into anodic aluminum oxide templates on glass substrates. A methodology with the assistance of ellipsometric measurements to examine the anisotropy and optical activity properties is presented. A tunable polarization conversion in both transmission and reflection is demonstrated. Specifically, giant broadband circular dichroism for reflection at visible wavelengths is experimentally realized by oblique incidence, due to the extrinsic chirality resulting from the mutual orientation of the metamaterials and the incident beam. This work paves the way for practical applications for large-area, low-cost polarization modulators, polarization imaging, displays, and bio-sensing.

Histologic Appearance of Iatrogenic Obstructive Hydrocephalus in the Fetal Lamb Model.

INTRODUCTION: Documentation of histologic findings associated with congenital hydrocephalus in the fetal lamb model is a critical step in evaluating the efficacy of ventriculoamniotic shunting in the human fetus. METHODS: Four fetal sheep had hydrocephalus induced at approximately 95 days' gestation. Two co-twins remained as controls. The ewes were euthanized at term. The lamb brains were fixed in formalin, paraffin-embedded, stained, and analyzed for markers of neuropathology. Astrocytosis, microgliosis, and axonal loss were assessed with immunocytochemistry for glial fibrillary acidic protein, ionized calcium-binding adapter, and neurofilament/amyloid precursor protein, respectively. Cortical gray matter extracellular matrix was assessed with staining for the lectin Wisteria Floribunda agglutinin. RESULTS: Hydrocephalic lamb brains demonstrated deep white matter damage with loss of projecting axonal tracts in regions physically distorted by hydrocephalus, similar to that seen in hydrocephalic humans. There was no evidence of abnormal neocortical neuronal migration; however, there was evidence for delayed maturation of the neocortical gray matter, possibly from increased intracerebral pressure and subsequent ischemia. Control lamb brains demonstrated none of the above findings. CONCLUSION: This histological approach can be used to further define the mechanism of brain damage associated with hydrocephalus and interpret the efficacy of ventriculoamniotic shunting on fetal lamb brain neuroanatomy.

Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues.

Zika virus (ZIKV), an emerging flavivirus, has recently spread explosively through the Western hemisphere. In addition to symptoms including fever, rash, arthralgia, and conjunctivitis, ZIKV infection of pregnant women can cause microcephaly and other developmental abnormalities in the fetus. We report herein the results of ZIKV infection of adult rhesus macaques. Following subcutaneous infection, animals developed transient plasma viremia and viruria from 1-7 days post infection (dpi) that was accompanied by the development of a rash, fever and conjunctivitis. Animals produced a robust adaptive immune response to ZIKV, although systemic cytokine response was minimal. At 7 dpi, virus was detected in peripheral nervous tissue, multiple lymphoid tissues, joints, and the uterus of the necropsied animals. Notably, viral RNA persisted in neuronal, lymphoid and joint/muscle tissues and the male and female reproductive tissues through 28 to 35 dpi. The tropism and persistence of ZIKV in the peripheral nerves and reproductive tract may provide a mechanism of subsequent neuropathogenesis and sexual transmission.

Correction: Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues.

[This corrects the article DOI: 10.1371/journal.ppat.1006219.].

Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques.

Human infections with highly pathogenic avian influenza A (H5N1) virus are frequently fatal but the mechanisms of disease remain ill-defined. H5N1 infection is associated with intense production of proinflammatory cytokines, but whether this cytokine storm is the main cause of fatality or is a consequence of extensive virus replication that itself drives disease remains controversial. Conventional intratracheal inoculation of a liquid suspension of H5N1 influenza virus in nonhuman primates likely results in efficient clearance of virus within the upper respiratory tract and rarely produces severe disease. We reasoned that small particle aerosols of virus would penetrate the lower respiratory tract and blanket alveoli where target cells reside. We show that inhalation of aerosolized H5N1 influenza virus in cynomolgus macaques results in fulminant pneumonia that rapidly progresses to acute respiratory distress syndrome with a fatal outcome reminiscent of human disease. Molecular imaging revealed intense lung inflammation coincident with massive increases in proinflammatory proteins and IFN-α in distal airways. Aerosolized H5N1 exposure decimated alveolar macrophages, which were widely infected and caused marked influx of interstitial macrophages and neutrophils. Extensive infection of alveolar epithelial cells caused apoptosis and leakage of albumin into airways, reflecting loss of epithelial barrier function. These data establish inhalation of aerosolized virus as a critical source of exposure for fatal human infection and reveal that direct viral effects in alveoli mediate H5N1 disease. This new nonhuman primate model will advance vaccine and therapeutic approaches to prevent and treat human disease caused by highly pathogenic avian influenza viruses.

Thiotepa-Based Intensified Reduced-Intensity Conditioning Adult Double-Unit Cord Blood Hematopoietic Stem Cell Transplantation Results in Decreased Relapse Rate and Improved Survival Compared with Transplantation Following Standard Reduced-Intensity Conditioning: A Retrospective Cohort Comparison.

The "Minnesota" reduced-intensity conditioning (RIC) cord blood transplantation (CBT) regimen (standard RIC) of fludarabine (Flu) (200 mg/m2), cyclophosphamide (Cy) (50 mg/kg), and 200- or 300-cGy total body irradiation (TBI) is the most published RIC CBT regimen. Though well tolerated, high relapse rates remain a concern with this regimen. Intensification of conditioning may reduce relapse without increasing transplant-related mortality (TRM). We performed a retrospective cohort comparison of outcomes in adult patients who underwent first double-unit CBT with standard RIC as compared with the intensified regimen of Flu 150 mg/m2, Cy 50 mg/kg, thiotepa 10 mg/kg, and 400-cGy TBI (intensified RIC). Of the 99 patients studied, 47 received intensified RIC. Acute myelogenous leukemia was the major indication for transplant. The median age at transplant was 67 years (range, 24 to 74 years) and 54 years (range, 25 to 67 years) in standard RIC and intensified RIC, respectively. Median hematopoietic stem cell transplantation comorbidity index was 3 (range, 0 to 5) and 1 (range, 0 to 6) in the standard RIC and intensified RIC groups, respectively. Median follow-up among survivors was 22 months (range, 3.7 to 79 months) following standard RIC and 15 months (range, 2.8 to 36 months) following intensified RIC. The cumulative incidence (CI) of relapse was significantly lower following intensified RIC compared with standard RIC (P = .0013); this finding maintained significance in multivariate analysis (P = .045). TRM was comparable between the 2 groups (P = .99). Overall survival (OS) was significantly improved following intensified RIC as compared with standard RIC (P = .03). Median OS was 17 months following standard RIC versus not reached followed intensified RIC. The CI of grade II to IV acute graft-versus-host disease (GVHD) was significantly higher in the intensified RIC cohort than the standard RIC-cohort (P = .007), while CI of grade III to IV acute GVHD, any chronic GVHD, and moderate-to-severe chronic GVHD was comparable in each cohort (P = .20, P = .21, and P = .61, respectively). This retrospective analysis shows an improvement in OS and decreased relapse without increase in TRM in patients receiving intensified RIC as compared with standard RIC. Our data suggest that consideration of thiotepa-based intensified RIC may improve outcomes in fit, older patients undergoing double-unit CBT.

Aged Chinese-origin rhesus macaques infected with SIV develop marked viremia in absence of clinical disease, inflammation or cognitive impairment.

BACKGROUND: Damage to the central nervous system during HIV infection can lead to variable neurobehavioral dysfunction termed HIV-associated neurocognitive disorders (HAND). There is no clear consensus regarding the neuropathological or cellular basis of HAND. We sought to study the potential contribution of aging to the pathogenesis of HAND. Aged (range = 14.7-24.8 year) rhesus macaques of Chinese origin (RM-Ch) (n = 23) were trained to perform cognitive tasks. Macaques were then divided into four groups to assess the impact of SIVmac251 infection (n = 12) and combined antiretroviral therapy (CART) (5 infected; 5 mock-infected) on the execution of these tasks. RESULTS: Aged SIV-infected RM-Ch demonstrated significant plasma viremia and modest CSF viral loads but showed few clinical signs, no elevations of systemic temperature, and no changes in activity levels, platelet counts or weight. Concentrations of biomarkers of acute and chronic inflammation such as soluble CD14, CXCL10, IL-6 and TNF-α are known to be elevated following SIV infection of young adult macaques of several species, but concentrations of these biomarkers did not shift after SIV infection in aged RM-Ch and remained similar to mock-infected macaques. Neither acute nor chronic SIV infection or CART had a significant impact on accuracy, speed or percent completion in a sensorimotor test. CONCLUSIONS: Viremia in the absence of a chronic elevated inflammatory response seen in some aged RM-Ch is reminiscent of SIV infection in natural disease resistant hosts. The absence of cognitive impairment during SIV infection in aged RM-Ch might be in part attributed to diminishment of some facets of the immunological response. Additional study encompassing species and age differences is necessary to substantiate this hypothesis.