Robust and Realtime Large Deformation Ultrasound Registration Using End-to-End Differentiable Displacement Optimisation.

Image registration for temporal ultrasound sequences can be very beneficial for image-guided diagnostics and interventions. Cooperative human-machine systems that enable seamless assistance for both inexperienced and expert users during ultrasound examinations rely on robust, realtime motion estimation. Yet rapid and irregular motion patterns, varying image contrast and domain shifts in imaging devices pose a severe challenge to conventional realtime registration approaches. While learning-based registration networks have the promise of abstracting relevant features and delivering very fast inference times, they come at the potential risk of limited generalisation and robustness for unseen data; in particular, when trained with limited supervision. In this work, we demonstrate that these issues can be overcome by using end-to-end differentiable displacement optimisation. Our method involves a trainable feature backbone, a correlation layer that evaluates a large range of displacement options simultaneously and a differentiable regularisation module that ensures smooth and plausible deformation. In extensive experiments on public and private ultrasound datasets with very sparse ground truth annotation the method showed better generalisation abilities and overall accuracy than a VoxelMorph network with the same feature backbone, while being two times faster at inference.

Effect of altitude and acetazolamide on sleep and nocturnal breathing in healthy lowlanders 40 y of age or older. Data from a randomized trial.

STUDY OBJECTIVES: To assess altitude-induced sleep and nocturnal breathing disturbances in healthy lowlanders 40 y of age or older and the effects of preventive acetazolamide treatment. METHODS: Clinical examinations and polysomnography were performed at 760 m and in the first night after ascent to 3100 m in a subsample of participants of a larger trial evaluating altitude illness. Participants were randomized 1:1 to treatment with acetazolamide (375 mg/day) or placebo, starting 24 h before and while staying at 3100 m. The main outcomes were indices of sleep structure, oxygenation, and apnea/hypopnea index (AHI). RESULTS: Per protocol analysis included 86 participants (mean ± SE 53 ± 7 y old, 66% female). In 43 individuals randomized to placebo, mean nocturnal pulse oximetry (SpO2) was 94.0 ± 0.4% at 760 m and 86.7 ± 0.4% at 3100 m, with mean change (95%CI) -7.3% (-8.0 to -6.5); oxygen desaturation index (ODI) was 5.0 ± 2.3 at 760 m and 29.2 ± 2.3 at 3100 m, change 24.2/h (18.8 to 24.5); AHI was 11.3 ± 2.4/h at 760 m and 23.5 ± 2.4/h at 3100 m, change 12.2/h (7.3 to 17.0). In 43 individuals randomized to acetazolamide, altitude-induced changes were mitigated. Mean differences (Δ, 95%CI) in altitude-induced changes were: ΔSpO2 2.3% (1.3 to 3.4), ΔODI -15.0/h (-22.6 to -7.4), ΔAHI -11.4/h (-18.3 to -4.6). Total sleep time, sleep efficiency, and N3-sleep fraction decreased with an ascent to 3100 m under placebo by 40 min (17 to 60), 5% (2 to 8), and 6% (2 to 11), respectively. Acetazolamide did not significantly change these outcomes. CONCLUSIONS: During a night at 3100 m, healthy lowlanders aged 40 y or older revealed hypoxemia, sleep apnea, and disturbed sleep. Preventive acetazolamide treatment improved oxygenation and nocturnal breathing but had no effect on sleep duration and structure. TRIAL REGISTRATION: The trial is registered at Clinical Trials, https://clinicaltrials.gov, NCT03561675.

Increased Polymerase Activity of Zoonotic H7N9 Allows Partial Escape from MxA.

The interferon-induced myxovirus resistance protein A (MxA) is a potent restriction factor that prevents zoonotic infection from influenza A virus (IAV) subtype H7N9. Individuals expressing antivirally inactive MxA variants are highly susceptible to these infections. However, human-adapted IAVs have acquired specific mutations in the viral nucleoprotein (NP) that allow escape from MxA-mediated restriction but that have not been observed in MxA-sensitive, human H7N9 isolates. To date, it is unknown whether H7N9 can adapt to escape MxA-mediated restriction. To study this, we infected Rag2-knockout (Rag2-/-) mice with a defect in T and B cell maturation carrying a human MxA transgene (MxAtg/-Rag2-/-). In these mice, the virus could replicate for several weeks facilitating host adaptation. In MxAtg/-Rag2-/-, but not in Rag2-/- mice, the well-described mammalian adaptation E627K in the viral polymerase subunit PB2 was acquired, but no variants with MxA escape mutations in NP were detected. Utilizing reverse genetics, we could show that acquisition of PB2 E627K allowed partial evasion from MxA restriction in MxAtg/tg mice. However, pretreatment with type I interferon decreased viral replication in these mice, suggesting that PB2 E627K is not a true MxA escape mutation. Based on these results, we speculate that it might be difficult for H7N9 to acquire MxA escape mutations in the viral NP. This is consistent with previous findings showing that MxA escape mutations cause severe attenuation of IAVs of avian origin.

Are pigs overestimated as a source of zoonotic influenza viruses?

BACKGROUND: Swine influenza caused by influenza A viruses (IAV) directly affects respiratory health and indirectly impairs reproduction rates in pigs causing production losses. In Europe, and elsewhere, production systems have intensified featuring fewer holdings but, in turn, increased breeding herd and litter sizes. This seems to foster swine IAV (swIAV) infections with respect to the entrenchment within and spread between holdings. Disease management of swine influenza is difficult and relies on biosecurity and vaccination measures. Recently discovered and widely proliferating forms of self-sustaining modes of swIAV infections in large swine holdings challenge these preventive concepts by generating vaccine-escape mutants in rolling circles of infection. MAIN BODY: The most recent human IAV pandemic of 2009 rooted at least partly in IAV of porcine origin highlighting the zoonotic potential of swIAV. Pigs constitute a mixing vessel of IAV from different species including avian and human hosts. However, other host species such as turkey and quail but also humans themselves may also act in this way; thus, pigs are not essentially required for the generation of IAV reassortants with a multispecies origin. Since 1918, all human pandemic influenza viruses except the H2N2 virus of 1958 have been transmitted in a reverse zoonotic mode from human into swine populations. Swine populations act as long-term reservoirs of these viruses. Human-derived IAV constitute a major driver of swIAV epidemiology in pigs. Swine-to-human IAV transmissions occurred rarely and mainly sporadically as compared to avian-to-human spill-over events of avian IAV. Yet, new swIAV variants that harbor zoonotic components continue to be detected. This increases the risk that such components might eventually reassort into viruses with pandemic potential. CONCLUSIONS: Domestic pig populations should not be globally stigmatized as the only or most important reservoir of potentially zoonotic IAV. The likely emergence from swine of the most recent human IAV pandemic in 2009, however, emphasized the principal risks of swine populations in which IAV circulate unimpededly. Implementation of regular and close-meshed IAV surveillance of domestic swine populations to follow the dynamics of swIAV evolution is clearly demanded. Improved algorithms for directly inferring zoonotic potential from whole IAV genome sequences as well as improved vaccines are still being sought.

Paradoxical immunodeficiencies-When failures of innate immunity cause immunopathology.

Innate immunity facilitates immediate defense against invading pathogens throughout all organs and tissues but also mediates tissue homeostasis and repair, thereby playing a key role in health and development. Recognition of pathogens is mediated by germline-encoded PRRs. Depending on the specific PRRs triggered, ligand binding leads to phagocytosis and pathogen killing and the controlled release of immune-modulatory factors such as IFNs, cytokines, or chemokines. PRR-mediated and other innate immune responses do not only prevent uncontrolled replication of intruding pathogens but also contribute to the tailoring of an effective adaptive immune response. Therefore, hereditary or acquired immunodeficiencies impairing innate responses may paradoxically cause severe immunopathology in patients. This can occur in the context of, but also independently of an increased microbial burden. It can include pathogen-dependent organ damage, autoinflammatory syndromes, and neurodevelopmental or neurodegenerative diseases. Here, we discuss the current state of research of several different such immune paradoxes. Understanding the underlying mechanisms causing immunopathology as a consequence of failures of innate immunity may help to prevent life-threatening disease.

A prospective cohort study about the effect of repeated living high and working higher on cerebral autoregulation in unacclimatized lowlanders.

Cerebral autoregulation (CA) is impaired during acute high-altitude (HA) exposure, however, effects of temporarily living high and working higher on CA require further investigation. In 18 healthy lowlanders (11 women), we hypothesized that the cerebral autoregulation index (ARI) assessed by the percentage change in middle cerebral artery peak blood velocity (Δ%MCAv)/percentage change in mean arterial blood pressure (Δ%MAP) induced by a sit-to-stand maneuver, is (i) reduced on Day1 at 5050 m compared to 520 m, (ii) is improved after 6 days at 5050 m, and (iii) is less impaired during re-exposure to 5050 m after 7 days at 520 m compared to Cycle1. Participants spent 4-8 h/day at 5050 m and slept at 2900 m similar to real-life working shifts. High/low ARI indicate impaired/intact CA, respectively. With the sit-to-stand at 520 m, mean (95% CI) in ΔMAP and ΔMCAv were - 26% (- 41 to - 10) and - 13% (- 19 to - 7), P < 0.001 both comparisons; mean ± SD in ARI was 0.58 ± 2.44Δ%/Δ%, respectively. On Day1 at 5050 m, ARI worsened compared to 520 m (3.29 ± 2.42Δ%/Δ%), P = 0.006 but improved with acclimatization (1.44 ± 2.43Δ%/Δ%, P = 0.039). ARI was less affected during re-exposure to 5050 m (1.22 ± 2.52Δ%/Δ%, P = 0.027 altitude-induced change between sojourns). This study showed that CA (i) is impaired during acute HA exposure, (ii) improves with living high, working higher and (iii) is ameliorated during re-exposure to HA.

Epidemiological characteristics of the B.1.526 SARS-CoV-2 variant.

To characterize the epidemiological properties of the B.1.526 SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) variant of interest, here we used nine epidemiological and population datasets and model-inference methods to reconstruct SARS-CoV-2 transmission dynamics in New York City, where B.1.526 emerged. We estimated that B.1.526 had a moderate increase (15 to 25%) in transmissibility, could escape immunity in 0 to 10% of previously infected individuals, and substantially increased the infection fatality risk (IFR) among adults 65 or older by >60% during November 2020 to April 2021, compared to estimates for preexisting variants. Overall, findings suggest that new variants like B.1.526 likely spread in the population weeks before detection and that partial immune escape (e.g., resistance to therapeutic antibodies) could offset prior medical advances and increase IFR. Early preparedness for and close monitoring of SARS-CoV-2 variants, their epidemiological characteristics, and disease severity are thus crucial to COVID-19 (coronavirus disease 2019) response.

Comparison of metal artifact reduction techniques in magnetic resonance imaging of carbon-reinforced PEEK and titanium spinal implants.

BACKGROUND: Carbon-reinforced PEEK (C-FRP) implants are non-magnetic and have increasingly been used for the fixation of spinal instabilities. PURPOSE: To compare the effect of different metal artifact reduction (MAR) techniques in magnetic resonance imaging (MRI) on titanium and C-FRP spinal implants. MATERIAL AND METHODS: Rod-pedicle screw constructs were mounted on ovine cadaver spine specimens and instrumented with either eight titanium pedicle screws or pedicle screws made of C-FRP and marked with an ultrathin titanium shell. MR scans were performed of each configuration on a 3-T scanner. MR sequences included transaxial conventional T1-weighted turbo spin echo (TSE) sequences, T2-weighted TSE, and short-tau inversion recovery (STIR) sequences and two different MAR-techniques: high-bandwidth (HB) and view-angle-tilting (VAT) with slice encoding for metal artifact correction (SEMAC). Metal artifact degree was assessed by qualitative and quantitative measures. RESULTS: There was a much stronger effect on artifact reduction with using C-FRP implants compared to using specific MRI MAR-techniques (screw shank: P < 0.001; screw tulip: P < 0.001; rod: P < 0.001). VAT-SEMAC sequences were able to reduce screw-related signal loss artifacts in constructs with titanium screws to a certain degree. Constructs with C-FRP screws showed less artifact-related implant diameter amplification when compared to constructs with titanium screws (P < 0.001). CONCLUSION: Constructs with C-FRP screws are associated with significantly less artifacts compared to constructs with titanium screws including dedicated MAR techniques. Artifact-reducing sequences are able to reduce implant-related artifacts. This effect is stronger in constructs with titanium screws than in constructs with C-FRP screws.

Rare variant MX1 alleles increase human susceptibility to zoonotic H7N9 influenza virus.

Zoonotic avian influenza A virus (IAV) infections are rare. Sustained transmission of these IAVs between humans has not been observed, suggesting a role for host genes. We used whole-genome sequencing to compare avian IAV H7N9 patients with healthy controls and observed a strong association between H7N9 infection and rare, heterozygous single-nucleotide variants in the MX1 gene. MX1 codes for myxovirus resistance protein A (MxA), an interferon-induced antiviral guanosine triphosphatase known to control IAV infections in transgenic mice. Most of the MxA variants identified lost the ability to inhibit avian IAVs, including H7N9, in transfected human cell lines. Nearly all of the inactive MxA variants exerted a dominant-negative effect on the antiviral function of wild-type MxA, suggesting an MxA null phenotype in heterozygous carriers. Our study provides genetic evidence for a crucial role of the MX1-based antiviral defense in controlling zoonotic IAV infections in humans.

Comparison of different CT metal artifact reduction strategies for standard titanium and carbon-fiber reinforced polymer implants in sheep cadavers.

BACKGROUND: CT artifacts induced by orthopedic implants can limit image quality and diagnostic yield. As a number of different strategies to reduce artifact extent exist, the aim of this study was to systematically compare ex vivo the impact of different CT metal artifact reduction (MAR) strategies on spine implants made of either standard titanium or carbon-fiber-reinforced-polyetheretherketone (CFR-PEEK). METHODS: Spine surgeons fluoroscopically-guided prepared six sheep spine cadavers with pedicle screws and rods of either titanium or CFR-PEEK. Samples were subjected to single- and dual-energy (DE) CT-imaging. Different tube voltages (80, DE mixed, 120 and tin-filtered 150 kVp) at comparable radiation dose and iterative reconstruction versus monoenergetic extrapolation (ME) techniques were compared. Also, the influence of image reconstruction kernels (soft vs. bone tissue) was investigated. Qualitative (Likert scores) and quantitative parameters (attenuation changes induced by implant artifact, implant diameter and image noise) were evaluated by two independent radiologists. Artifact degree of different MAR-strategies and implant materials were compared by multiple ANOVA analysis. RESULTS: CFR-PEEK implants induced markedly less artifacts than standard titanium implants (p < .001). This effect was substantially larger than any other tested MAR technique. Reconstruction algorithms had small impact in CFR-PEEK implants and differed significantly in MAR efficiency (p < .001) with best MAR performance for DECT ME 130 keV (bone kernel). Significant differences in image noise between reconstruction kernels were seen (p < .001) with minor impact on artifact degree. CONCLUSIONS: CFR-PEEK spine implants induce significantly less artifacts than standard titanium compositions with higher MAR efficiency than any alternate scanning or image reconstruction strategy. DECT ME 130 keV image reconstructions showed least metal artifacts. Reconstruction kernels primarily modulate image noise with minor impact on artifact degree.

Nowcasting for Real-Time COVID-19 Tracking in New York City: An Evaluation Using Reportable Disease Data From Early in the Pandemic.

BACKGROUND: Nowcasting approaches enhance the utility of reportable disease data for trend monitoring by correcting for delays, but implementation details affect accuracy. OBJECTIVE: To support real-time COVID-19 situational awareness, the New York City Department of Health and Mental Hygiene used nowcasting to account for testing and reporting delays. We conducted an evaluation to determine which implementation details would yield the most accurate estimated case counts. METHODS: A time-correlated Bayesian approach called Nowcasting by Bayesian Smoothing (NobBS) was applied in real time to line lists of reportable disease surveillance data, accounting for the delay from diagnosis to reporting and the shape of the epidemic curve. We retrospectively evaluated nowcasting performance for confirmed case counts among residents diagnosed during the period from March to May 2020, a period when the median reporting delay was 2 days. RESULTS: Nowcasts with a 2-week moving window and a negative binomial distribution had lower mean absolute error, lower relative root mean square error, and higher 95% prediction interval coverage than nowcasts conducted with a 3-week moving window or with a Poisson distribution. Nowcasts conducted toward the end of the week outperformed nowcasts performed earlier in the week, given fewer patients diagnosed on weekends and lack of day-of-week adjustments. When estimating case counts for weekdays only, metrics were similar across days when the nowcasts were conducted, with Mondays having the lowest mean absolute error of 183 cases in the context of an average daily weekday case count of 2914. CONCLUSIONS: Nowcasting using NobBS can effectively support COVID-19 trend monitoring. Accounting for overdispersion, shortening the moving window, and suppressing diagnoses on weekends-when fewer patients submitted specimens for testing-improved the accuracy of estimated case counts. Nowcasting ensured that recent decreases in observed case counts were not overinterpreted as true declines and supported officials in anticipating the magnitude and timing of hospitalizations and deaths and allocating resources geographically.

Tick-transmitted thogotovirus gains high virulence by a single MxA escape mutation in the viral nucleoprotein.

Infections with emerging and re-emerging arboviruses are of increasing concern for global health. Tick-transmitted RNA viruses of the genus Thogotovirus in the Orthomyxoviridae family have considerable zoonotic potential, as indicated by the recent emergence of Bourbon virus in the USA. To successfully infect humans, arboviruses have to escape the restrictive power of the interferon defense system. This is exemplified by the high sensitivity of thogotoviruses to the antiviral action of the interferon-induced myxovirus resistance protein A (MxA) that inhibits the polymerase activity of incoming viral ribonucleoprotein complexes. Acquiring resistance to human MxA would be expected to enhance the zoonotic potential of these pathogens. Therefore, we screened a panel of 10 different thogotovirus isolates obtained from various parts of the world for their sensitivity to MxA. A single isolate from Nigeria, Jos virus, showed resistance to the antiviral action of MxA in cell culture and in MxA-transgenic mice, whereas the prototypic Sicilian isolate SiAr126 was fully MxA-sensitive. Further analysis identified two amino acid substitutions (G327R and R328V) in the viral nucleoprotein as determinants for MxA resistance. Importantly, when introduced into SiAr126, the R328V mutation resulted in complete MxA escape of the recombinant virus, without causing any viral fitness loss. The escape mutation abolished viral nucleoprotein recognition by MxA and allowed unhindered viral growth in MxA-expressing cells and in MxA-transgenic mice. These findings demonstrate that thogotoviruses can overcome the species barrier by escaping MxA restriction and reveal that these tick-transmitted viruses may have a greater zoonotic potential than previously suspected.

COVID-19 Outbreak - New York City, February 29-June 1, 2020.

New York City (NYC) was an epicenter of the coronavirus disease 2019 (COVID-19) outbreak in the United States during spring 2020 (1). During March-May 2020, approximately 203,000 laboratory-confirmed COVID-19 cases were reported to the NYC Department of Health and Mental Hygiene (DOHMH). To obtain more complete data, DOHMH used supplementary information sources and relied on direct data importation and matching of patient identifiers for data on hospitalization status, the occurrence of death, race/ethnicity, and presence of underlying medical conditions. The highest rates of cases, hospitalizations, and deaths were concentrated in communities of color, high-poverty areas, and among persons aged ≥75 years or with underlying conditions. The crude fatality rate was 9.2% overall and 32.1% among hospitalized patients. Using these data to prevent additional infections among NYC residents during subsequent waves of the pandemic, particularly among those at highest risk for hospitalization and death, is critical. Mitigating COVID-19 transmission among vulnerable groups at high risk for hospitalization and death is an urgent priority. Similar to NYC, other jurisdictions might find the use of supplementary information sources valuable in their efforts to prevent COVID-19 infections.

Evaluation of Nowcasting for Real-Time COVID-19 Tracking - New York City, March-May 2020.

To account for delays between specimen collection and report, the New York City Department of Health and Mental Hygiene used a time-correlated Bayesian nowcasting approach to support real-time COVID-19 situational awareness. We retrospectively evaluated nowcasting performance for case counts among residents diagnosed during March-May 2020, a period when the median reporting delay was 2 days. Nowcasts with a 2-week moving window and a negative binomial distribution had lower mean absolute error, lower relative root mean square error, and higher 95% prediction interval coverage than nowcasts conducted with a 3-week moving window or with a Poisson distribution. Nowcasts conducted toward the end of the week outperformed nowcasts performed earlier in the week, given fewer patients diagnosed on weekends and lack of day-of-week adjustments. When estimating case counts for weekdays only, metrics were similar across days the nowcasts were conducted, with Mondays having the lowest mean absolute error, of 183 cases in the context of an average daily weekday case count of 2,914. Nowcasting ensured that recent decreases in observed case counts were not overinterpreted as true declines and supported health department leadership in anticipating the magnitude and timing of hospitalizations and deaths and allocating resources geographically.

Combinatorial mutagenesis of rapidly evolving residues yields super-restrictor antiviral proteins.

Antagonistic interactions drive host-virus evolutionary arms races, which often manifest as recurrent amino acid changes (i.e., positive selection) at their protein-protein interaction interfaces. Here, we investigated whether combinatorial mutagenesis of positions under positive selection in a host antiviral protein could enhance its restrictive properties. We tested approximately 700 variants of human MxA, generated by combinatorial mutagenesis, for their ability to restrict Thogotovirus (THOV). We identified MxA super-restrictors with increased binding to the THOV nucleoprotein (NP) target protein and 10-fold higher anti-THOV restriction relative to wild-type human MxA, the most potent naturally occurring anti-THOV restrictor identified. Our findings reveal a means to elicit super-restrictor antiviral proteins by leveraging signatures of positive selection. Although some MxA super-restrictors of THOV were impaired in their restriction of H5N1 influenza A virus (IAV), other super-restrictor variants increased THOV restriction without impairment of IAV restriction. Thus, broadly acting antiviral proteins such as MxA mitigate breadth-versus-specificity trade-offs that could otherwise constrain their adaptive landscape.

Analysis of Early Phase HIV-1 Replication and Integration Events by Using Real-time PCR.

Upon entry into a host cell, the HIV-1 virus undergoes a series of critical early replication events including reverse transcription, nuclear import, and integration of its cDNA into the host genome. Molecular assays used to detect and analyze changes in HIV-1 early phase replication events are valuable tools in developing potential antiretroviral drugs, as well as studying the pathogenesis of HIV. Described here are the molecular assays utilized to detect and quantify HIV-1 early, intermediate, and late reverse transcription (RT) products. In addition to this, protocols for quantifying HIV-1 2-LTR circle DNA and proviral DNA after integration are also included. In these protocols, the optimized TaqMan Real-time PCR reagent is used to increase assay sensitivity and reproducibility. Furthermore, a nested PCR is applied to HIV-1 integration quantification with increased accuracy.

Human MxB Protein Is a Pan-herpesvirus Restriction Factor.

Herpesvirus infections are highly prevalent in the human population and persist for life. They are often acquired subclinically but potentially progress to life-threatening diseases in immunocompromised individuals. The interferon system is indispensable for the control of herpesviral replication. However, the responsible antiviral effector mechanisms are not well characterized. The type I interferon-induced, human myxovirus resistance 2 (MX2) gene product MxB, a dynamin-like large GTPase, has recently been identified as a potent inhibitor of HIV-1. We now show that MxB also interferes with an early step of herpesvirus replication, affecting alpha-, beta-, and gammaherpesviruses before or at the time of immediate early gene expression. Defined MxB mutants influencing GTP binding and hydrolysis revealed that the effector mechanism against herpesviruses is thoroughly different from that against HIV-1. Overall, our findings demonstrate that MxB serves as a broadly acting intracellular restriction factor that controls the establishment of not only retrovirus but also herpesvirus infection of all three subfamilies.IMPORTANCE Human herpesviruses pose a constant threat to human health. Reactivation of persisting herpesvirus infections, particularly in immunocompromised individuals and the elderly, can cause severe diseases, such as zoster, pneumonia, encephalitis, or cancer. The interferon system is relevant for the control of herpesvirus replication as exemplified by fatal disease outcomes in patients with primary immunodeficiencies. Here, we describe the interferon-induced, human MX2 gene product MxB as an efficient restriction factor of alpha-, beta-, and gammaherpesviruses. MxB has previously been described as an inhibitor of HIV-1. Importantly, our mutational analyses of MxB reveal an antiviral mechanism of herpesvirus restriction distinct from that against HIV-1. Thus, the dynamin-like MxB GTPase serves as a broadly acting intracellular restriction factor that controls retrovirus as well as herpesvirus infections.