The influenza virus is a global threat to human health causing unpredictable yet recurring pandemics, the last four emerging over the course of a hundred years. As our knowledge of influenza virus ...evolution, distribution, and transmission has increased, paths to pandemic preparedness have become apparent. In the 1950s, the World Health Organization (WHO) established a global influenza surveillance network that is now composed of institutions in 122 member states. This and other surveillance networks monitor circulating influenza strains in humans and animal reservoirs and are primed to detect influenza strains with pandemic potential. Both the United States Centers for Disease Control and Prevention and the WHO have also developed pandemic risk assessment tools that evaluate specific aspects of emerging influenza strains to develop a systematic process of determining research and funding priorities according to the risk of emergence and potential impact. Here, we review the history of influenza pandemic preparedness and the current state of preparedness, and we propose additional measures for improvement. We also comment on the intersection between the influenza pandemic preparedness network and the current SARS-CoV-2 crisis. We must continually evaluate and revise our risk assessment and pandemic preparedness plans and incorporate new information gathered from research and global crises.
Both Ireland and the Pacific Northwest are known for their climates, and have historically been associated with the rose. This collection of essays explores the exchange Ireland has had with the ...Northwest using the rose as an example by examining the beautiful and the harsh, the petals and the thorns. It is the culmination of the work of established and emerging historians and writers who have traversed the boundary between the Northwest and Ireland several times. The timely contributions gathered here include essays about the imperialist mindset, biased court systems, the victims of social hatred, and organized resistance. Timeless themes include grief, poetry and the oral tradition, and the effect plants have upon a given population. The book is a much-needed contribution to often overlooked aspects of colonialism and boundaries.
Objective
This study examined general medical illnesses and their association with clinical features of bipolar disorder.
Method
Data were cross‐sectional and derived from the Lithium Treatment – ...Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n = 264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥4 and <4 respectively.
Results
The baseline prevalence of significant medical comorbidity was 53% (n = 139). Patients with high medical burden were more likely to present in a major depressive episode (P = .04), meet criteria for obsessive–compulsive disorder (P = .02), and experience a greater number of lifetime mood episodes (P = 0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P = .002). Sixty‐nine per cent of the sample was overweight or obese as defined by body mass index (BMI), with African Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥35; 31%, n = 14).
Conclusion
The burden of comorbid medical illnesses was high in this generalizable sample of treatment‐seeking patients and appears associated with worsened course of illness and psychotropic medication patterns.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Non-coding “ultraconserved” regions containing hundreds of consecutive bases of perfect sequence conservation across mammalian genomes can function as distant-acting enhancers. However, initial ...deletion studies in mice revealed that loss of such extraordinarily constrained sequences had no immediate impact on viability. Here, we show that ultraconserved enhancers are required for normal development. Focusing on some of the longest ultraconserved sites genome wide, located near the essential neuronal transcription factor Arx, we used genome editing to create an expanded series of knockout mice lacking individual or combinations of ultraconserved enhancers. Mice with single or pairwise deletions of ultraconserved enhancers were viable and fertile but in nearly all cases showed neurological or growth abnormalities, including substantial alterations of neuron populations and structural brain defects. Our results demonstrate the functional importance of ultraconserved enhancers and indicate that remarkably strong sequence conservation likely results from fitness deficits that appear subtle in a laboratory setting.
Display omitted
•The Arx locus has a high density of very long ultraconserved forebrain enhancers•Single or pairwise deletion of these enhancers results in viable mice in all cases•In most cases, individual enhancer loss results in developmental anomalies•Selection against these fitness deficits likely contributes to ultraconservation
Although initial studies suggested that loss of ultraconserved enhancers had no impact on viability, these sequences are now shown to be required for normal development.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Focal traumatic brain injury (TBI) induces astrogliosis, a process essential to protecting uninjured brain areas from secondary damage. However, astrogliosis can cause loss of astrocyte homeostatic ...functions and possibly contributes to comorbidities such as posttraumatic epilepsy (PTE). Scar-forming astrocytes seal focal injuries off from healthy brain tissue. It is these glial scars that are associated with epilepsy originating in the cerebral cortex and hippocampus. However, the vast majority of human TBIs also present with diffuse brain injury caused by acceleration-deceleration forces leading to tissue shearing. The resulting diffuse tissue damage may be intrinsically different from focal lesions that would trigger glial scar formation. Here, we used mice of both sexes in a model of repetitive mild/concussive closed-head TBI, which only induced diffuse injury, to test the hypothesis that astrocytes respond uniquely to diffuse TBI and that diffuse TBI is sufficient to cause PTE. Astrocytes did not form scars and classic astrogliosis characterized by upregulation of glial fibrillary acidic protein was limited. Surprisingly, an unrelated population of atypical reactive astrocytes was characterized by the lack of glial fibrillary acidic protein expression, rapid and sustained downregulation of homeostatic proteins and impaired astrocyte coupling. After a latency period, a subset of mice developed spontaneous recurrent seizures reminiscent of PTE in human TBI patients. Seizing mice had larger areas of atypical astrocytes compared with nonseizing mice, suggesting that these atypical astrocytes might contribute to epileptogenesis after diffuse TBI.
Traumatic brain injury (TBI) is a leading cause of acquired epilepsies. Reactive astrocytes have long been associated with seizures and epilepsy in patients, particularly after focal/lesional brain injury. However, most TBIs also include nonfocal, diffuse injuries. Here, we showed that repetitive diffuse TBI is sufficient for the development of spontaneous recurrent seizures in a subset of mice. We identified an atypical response of astrocytes induced by diffuse TBI characterized by the rapid loss of homeostatic proteins and lack of astrocyte coupling while reactive astrocyte markers or glial scar formation was absent. Areas with atypical astrocytes were larger in animals that later developed seizures suggesting that this response may be one root cause of epileptogenesis after diffuse TBI.
We present measurements of the E-mode polarization angular auto-power spectrum (EE) and temperature-E-mode cross-power spectrum (TE) of the cosmic microwave background (CMB) using 150 GHz data from ...three seasons of SPTpol observations. We report the power spectra over the spherical harmonic multipole range and detect nine acoustic peaks in the EE spectrum with high signal-to-noise ratio. These measurements are the most sensitive to date of the EE and TE power spectra at and , respectively. The observations cover 500 , a fivefold increase in area compared to previous SPTpol analyses, which increases our sensitivity to the photon diffusion damping tail of the CMB power spectra enabling tighter constraints on ΛCDM model extensions. After masking all sources with unpolarized flux mJy, we place a 95% confidence upper limit on residual polarized point-source power of at , suggesting that the EE damping tail dominates foregrounds to at least with modest source masking. We find that the SPTpol data set is in mild tension with the ΛCDM model ( ), and different data splits prefer parameter values that differ at the level. When fitting SPTpol data at , we find cosmological parameter constraints consistent with those for Planck temperature. Including SPTpol data at results in a preference for a higher value of the expansion rate ( ) and a lower value for present-day density fluctuations ( ).
Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b underwent an explosive geographic expansion in 2021 among wild birds and domestic poultry across Asia, Europe, and Africa. By the ...end of 2021, 2.3.4.4b viruses were detected in North America, signifying further intercontinental spread. Here we show that the western movement of clade 2.3.4.4b was quickly followed by reassortment with viruses circulating in wild birds in North America, resulting in the acquisition of different combinations of ribonucleoprotein genes. These reassortant A(H5N1) viruses are genotypically and phenotypically diverse, with many causing severe disease with dramatic neurologic involvement in mammals. The proclivity of the current A(H5N1) 2.3.4.4b virus lineage to reassort and target the central nervous system warrants concerted planning to combat the spread and evolution of the virus within the continent and to mitigate the impact of a potential influenza pandemic that could originate from similar A(H5N1) reassortants.
Objective
Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder.
Method
The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic ...Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6‐month trial comparing lithium‐ and quetiapine‐based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models.
Results
At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome.
Conclusion
Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium‐ or quetiapine‐based treatment.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT We present a measurement of the B-mode polarization power spectrum (the BB spectrum) from 100 of sky observed with SPTpol, a polarization-sensitive receiver currently installed on the South ...Pole Telescope. The observations used in this work were taken during 2012 and early 2013 and include data in spectral bands centered at 95 and 150 GHz. We report the BB spectrum in five bins in multipole space, spanning the range , and for three spectral combinations: 95 GHz × 95 GHz, 95 GHz × 150 GHz, and 150 GHz × 150 GHz. We subtract small (<0.5 in units of statistical uncertainty) biases from these spectra and account for the uncertainty in those biases. The resulting power spectra are inconsistent with zero power but consistent with predictions for the BB spectrum arising from the gravitational lensing of E-mode polarization. If we assume no other source of BB power besides lensed B modes, we determine a preference for lensed B modes of 4.9 . After marginalizing over tensor power and foregrounds, namely, polarized emission from galactic dust and extragalactic sources, this significance is 4.3 . Fitting for a single parameter, , that multiplies the predicted lensed B-mode spectrum, and marginalizing over tensor power and foregrounds, we find , indicating that our measured spectra are consistent with the signal expected from gravitational lensing. The data presented here provide the best measurement to date of the B-mode power spectrum on these angular scales.
Abstract
Background
Baloxavir marboxil is an antiviral drug that targets the endonuclease activity of the influenza virus polymerase acidic (PA) protein. PA I38T/M/F substitutions reduce its ...antiviral efficacy.
Objectives
To understand the effects of the 19 possible amino acid (AA) substitutions at PA 38 on influenza A(H1N1)pdm09 polymerase activity and inhibition by baloxavir acid, the active metabolite of baloxavir marboxil.
Methods
Influenza A(H1N1)pdm09 viral polymerase complexes containing all 19 I38X AA substitutions were reconstituted in HEK293T cells in a mini-replicon assay. Polymerase complex activity and baloxavir inhibitory activity were measured in the presence or absence of 50 nM baloxavir acid.
Results
Only three substitutions (R, K, P) reduced polymerase activity to <79% of I38-WT. When compared with the prototypical baloxavir marboxil resistance marker T38, 5 substitutions conferred 10%–35% reductions in baloxavir acid inhibitory activity (M, L, F, Y, C) and 11 substitutions conferred >50% reductions (R, K, S, N, G, W, A, Q, E, D, H), while two substitutions (V, P) maintained baloxavir acid inhibitory activity.
Conclusions
Most PA 38 substitutions permit a functional replication complex retaining some drug resistance in the mini-replicon assay. This study provides a targeted approach for virus rescue and analysis of novel baloxavir marboxil reduced-susceptibility markers, supports the consideration of a broader range of these markers during antiviral surveillance and adds to the growing knowledge of baloxavir marboxil resistance profiles.
PDF
