Highlights ► Both MMP-2 and MMP-9 were upregulated and activated in the early ischemic brain. ► MMP-9 KO decreased hemorrhagic volume in the cortex, but not in the striatum. ► MMP-2 KO and MMP-2/9 ...dKO reduced hemorrhagic volume in both cortex and striatum. ► MMP-2 KO and MMP-2/9 dKO was more protective than MMP-9 KO against brain HT. ► MMP-2 and/or -9 KO protected against brain infarct and neurological deficits.
IMPORTANCE: The potential association of schizophrenia with distinct retinal changes is of clinical interest but has been challenging to investigate because of a lack of sufficiently large and ...detailed cohorts. OBJECTIVE: To investigate the association between retinal biomarkers from multimodal imaging (oculomics) and schizophrenia in a large real-world population. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis used data from a retrospective cohort of 154 830 patients 40 years and older from the AlzEye study, which linked ophthalmic data with hospital admission data across England. Patients attended Moorfields Eye Hospital, a secondary care ophthalmic hospital with a principal central site, 4 district hubs, and 5 satellite clinics in and around London, United Kingdom, and had retinal imaging during the study period (January 2008 and April 2018). Data were analyzed from January 2022 to July 2022. MAIN OUTCOMES AND MEASURES: Retinovascular and optic nerve indices were computed from color fundus photography. Macular retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layer (mGC-IPL) thicknesses were extracted from optical coherence tomography. Linear mixed-effects models were used to examine the association between schizophrenia and retinal biomarkers. RESULTS: A total of 485 individuals (747 eyes) with schizophrenia (mean SD age, 64.9 years 12.2; 258 53.2% female) and 100 931 individuals (165 400 eyes) without schizophrenia (mean age, 65.9 years 13.7; 53 253 52.8% female) were included after images underwent quality control and potentially confounding conditions were excluded. Individuals with schizophrenia were more likely to have hypertension (407 83.9% vs 49 971 48.0%) and diabetes (364 75.1% vs 28 762 27.6%). The schizophrenia group had thinner mGC-IPL (−4.05 μm, 95% CI, −5.40 to −2.69; P = 5.4 × 10−9), which persisted when investigating only patients without diabetes (−3.99 μm; 95% CI, −6.67 to −1.30; P = .004) or just those 55 years and younger (−2.90 μm; 95% CI, −5.55 to −0.24; P = .03). On adjusted analysis, retinal fractal dimension among vascular variables was reduced in individuals with schizophrenia (−0.14 units; 95% CI, −0.22 to −0.05; P = .001), although this was not present when excluding patients with diabetes. CONCLUSIONS AND RELEVANCE: In this study, patients with schizophrenia had measurable differences in neural and vascular integrity of the retina. Differences in retinal vasculature were mostly secondary to the higher prevalence of diabetes and hypertension in patients with schizophrenia. The role of retinal features as adjunct outcomes in patients with schizophrenia warrants further investigation.
The purpose of this study was to explore the reliability and construct validity of the EPDS-US.
To enhance the perinatal mental health screen, we adapted the Edinburgh Postnatal Depression Screen ...(EPDS) for application in the United States, and evaluated reliability and construct validity of the EPDS-US in a sample of 100 postpartum individuals. We explored reliability by estimating internal consistency of the scale and evaluating concurrent validity with correlations to the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder Assessment (GAD-7); and construct validity using factor analysis and discriminant validity with correlations to the Perceived Stress Scale (PSS).
We present both a one-factor (Cronbach's alpha of 0.83) and two-factor model consisting of depressive (Cronbach's alpha 0.76) and anxiety symptoms (Cronbach's alpha 0.78) of the EPDS-US. Related to discriminant validity, the EPDS-US and PSS exhibited a moderate correlation of 0.71. For measures of concurrent validity, correlations with the PHQ-9 and GAD-7 were moderate; 0.63 and 0.68, respectively.
The EPDS-US was adapted to enhance the perinatal mental health screening experience for populations in the US while maintaining the reliability and validity of the original Edinburgh Postnatal Depression Scale. These findings contribute to the evidence of reliability and validity of the EPDS-US in perinatal populations in the United States; presenting initial evidence supporting construct validity and concurrent validity of this newly adapted 10-item scale.
•The EPDS-US is an adaptioation to enhance the PMH screening experience for populations in the US while maintaining the reliability and validity of the original Edinburgh Postnatal Depression Scale.•This psychometric evaluation of the EPDS-US evaluated construct validity via factor analysis, discriminant validity via correlation with PSS-10 (stress) and concurrent validity via correlations with PHQ-9 (depressive symtpoms) and GAD-7 (anxiety symptoms).•The findings from this study contribute to the evidence of reliability and validity of the EPDS-US in perinatal populations in the US; presenting initial evidence supporting construct validity and concurrent validity of thie newly adapted 10 item scale.
Treatment with moderate, systemic hypothermia reduces the rates of cerebral edema and death after injury to the cerebral cortex in laboratory animals.
1
–
4
The results of early studies of ...hypothermia in humans with brain injury were inconclusive.
5
–
9
Subsequent testing established 32°C as the safe limit for hypothermia in humans with brain injury.
10
In two 1993 reports of trials in patients with brain injury, moderate hypothermia maintained for 48
11
and 24
12
hours resulted in a 15 percent and an 18 percent increase (i.e., difference between the hypothermia and normothermia groups), respectively, in the percentage of patients who had a favorable . . .
Context.
Accreting planetary-mass objects have been detected at H
α
, but targeted searches have mainly resulted in non-detections. Accretion tracers in the planetary-mass regime could originate from ...the shock itself, making them particularly susceptible to extinction by the accreting material. High-resolution (
R
> 50 000) spectrographs operating at H
α
should soon enable one to study how the incoming material shapes the line profile.
Aims.
We calculate how much the gas and dust accreting onto a planet reduce the H
α
flux from the shock at the planetary surface and how they affect the line shape. We also study the absorption-modified relationship between the H
α
luminosity and accretion rate.
Methods.
We computed the high-resolution radiative transfer of the H
α
line using a one-dimensional velocity–density–temperature structure for the inflowing matter in three representative accretion geometries: spherical symmetry, polar inflow, and magnetospheric accretion. For each, we explored the wide relevant ranges of the accretion rate and planet mass. We used detailed gas opacities and carefully estimated possible dust opacities.
Results.
At accretion rates of
Ṁ
≲ 3 × 10
−6
M
J
yr
−1
, gas extinction is negligible for spherical or polar inflow and at most
A
H
α
≲ 0.5 mag for magnetospheric accretion. Up to
Ṁ
≈ 3 × 10
−4
M
J
yr
−1
, the gas contributes
A
H
α
≲ 4 mag. This contribution decreases with mass. We estimate realistic dust opacities at H
α
to be
κ
~ 0.01–10 cm
2
g
−1
, which is 10–10
4
times lower than in the interstellar medium. Extinction flattens the
L
H
α
–
Ṁ
relationship, which becomes non-monotonic with a maximum luminosity
L
H
α
~ 10
−4
L
⊙
towards
Ṁ
≈ 10
−4
M
J
yr
−1
for a planet mass ~10
M
J
. In magnetospheric accretion, the gas can introduce features in the line profile, while the velocity gradient smears them out in other geometries.
Conclusions.
For a wide part of parameter space, extinction by the accreting matter should be negligible, simplifying the interpretation of observations, especially for planets in gaps. At high
Ṁ
, strong absorption reduces the H
α
flux, and some measurements can be interpreted as two
Ṁ
values. Highly resolved line profiles (
R
~ 10
5
) can provide (complex) constraints on the thermal and dynamical structure of the accretion flow.
Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA).
...This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434.
Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 29% of 72 patients) than with placebo (37 53% of 70 patients; hazard ratio 0·46, 95% CI 0·27–0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study.
The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections.
Pfizer.
Atmospheric secondary organic aerosol (SOA) is likely to exist in a semi-solid or glassy state, particularly at low temperatures and humidities. Previously, it has been shown that glassy aqueous ...citric acid aerosol is able to nucleate ice heterogeneously under conditions relevant to cirrus in the tropical tropopause layer (TTL). In this study we test if glassy aerosol distributions with a range of chemical compositions heterogeneously nucleate ice under cirrus conditions. Three single component aqueous solution aerosols (raffinose, 4-hydroxy-3-methoxy-DL-mandelic acid (HMMA) and levoglucosan) and one multi component aqueous solution aerosol (raffinose mixed with five dicarboxylic acids and ammonium sulphate) were studied in both the liquid and glassy states at a large cloud simulation chamber. The investigated organic compounds have similar functionality to oxidised organic material found in atmospheric aerosol and have estimated temperature/humidity induced glass transition thresholds that fall within the range predicted for atmospheric SOA. A small fraction of aerosol particles of all compositions were found to nucleate ice heterogeneously in the deposition mode at temperatures relevant to the TTL (<200 K). Raffinose and HMMA, which form glasses at higher temperatures, nucleated ice heterogeneously at temperatures as high as 214.6 and 218.5 K respectively. We present the calculated ice active surface site density, ns, of the aerosols tested here and also of glassy citric acid aerosol as a function of relative humidity with respect to ice (RHi). We also propose a parameterisation which can be used to estimate heterogeneous ice nucleation by glassy aerosol for use in cirrus cloud models up to ~220 K. Finally, we show that heterogeneous nucleation by glassy aerosol may compete with ice nucleation on mineral dust particles in mid-latitudes cirrus.
Protein glycosylation events that happen early in the secretory pathway are often dysregulated during tumorigenesis. These events can be probed, in principle, by monosaccharides with bioorthogonal ...tags that would ideally be specific for distinct glycan subtypes. However, metabolic interconversion into other monosaccharides drastically reduces such specificity in the living cell. Here, we use a structure-based design process to develop the monosaccharide probe NE-(S)-azidopropionylgalactosamine (GalNAzMe) that is specific for cancer-relevant Ser/Thr(O)–linked N-acetylgalactosamine (GalNAc) glycosylation. By virtue of a branched N-acylamide side chain, GalNAzMe is not interconverted by epimerization to the corresponding N-acetylglucosamine analog by the epimerase N-acetylgalactosamine–4-epimerase (GALE) like conventional GalNAc–based probes. GalNAzMe enters O-GalNAc glycosylation but does not enter other major cell surface glycan types including Asn(N)-linked glycans. We transfect cells with the engineered pyrophosphorylase mut-AGX1 to biosynthesize the nucleotidesugar donor uridine diphosphate (UDP)-GalNAzMe from a sugar-1-phosphate precursor. Tagged with a bioorthogonal azide group, GalNAzMe serves as an O-glycan–specific reporter in superresolution microscopy, chemical glycoproteomics, a genome-wide CRISPR-knockout (CRISPR-KO) screen, and imaging of intestinal organoids. Additional ectopic expression of an engineered glycosyltransferase, “bump-and-hole” (BH)–GalNAc-T2, boosts labeling in a programmable fashion by increasing incorporation of GalNAzMe into the cell surface glycoproteome. Alleviating the need for GALE-KO cells in metabolic labeling experiments, GalNAzMe is a precision tool that allows a detailed view into the biology of a major type of cancer-relevant protein glycosylation.
There has been increasing evidence that chronic low-grade inflammation is associated with mood disorders. However, the findings have been inconsistent because of heterogeneity across studies and ...methodological limitations. Our aim is to prospectively evaluate the bi-directional associations between inflammatory markers including interleukin (IL)-6, tumor necrosis factor (TNF)-α and high sensitivity C-reactive protein (hsCRP) with mood disorders.
The sample consisted of 3118 participants (53.7% women; mean age: 51.0, s.d. 8.8 years), randomly selected from the general population, who underwent comprehensive somatic and psychiatric evaluations at baseline and follow-up (mean follow-up duration = 5.5 years, s.d. 0.6). Current and remitted mood disorders including bipolar and major depressive disorders (MDD) and its subtypes (atypical, melancholic, combined atypical and melancholic, and unspecified) were based on semi-structured diagnostic interviews. Inflammatory biomarkers were analyzed in fasting blood samples. Associations were tested by multiple linear and logistic regression models.
Current combined MDD β = 0.29, 95% confidence interval (CI) 0.03-0.55 and current atypical MDD (β = 0.32, 95% CI 0.10-0.55) at baseline were associated with increased levels of hsCRP at follow-up. There was little evidence for inflammation markers at baseline predicting mood disorders at follow-up.
The prospective unidirectional association between current MDD subtype with atypical features and hsCRP levels at follow-up suggests that inflammation may be a consequence of this condition. The role of inflammation, particularly hsCRP that is critically involved in cardiovascular diseases, warrants further study. Future research that examines potential influences of medications on inflammatory processes is indicated.
Acceleration of high energy ions was observed in z-pinches and dense plasma foci as early as the 1950s. Even though many theories have been suggested, the ion acceleration mechanism remains a source ...of controversy. Recently, the experiments on the GIT-12 generator demonstrated acceleration of ions up to 30 MeV from a deuterium gas-puff z-pinch. High deuteron energies enable us to obtain unique information about spatial, spectral and temporal properties of accelerated ions. In particular, the off-axis ion emission from concentric circles of a ∼1 cm diameter and the radial lines in an ion beam profile are germane for the discussion of acceleration mechanisms. The acceleration of 30 MeV deuterons can be explained by the fast increase of an impedance with a sub-nanosecond e-folding time. The high (>10 ) impedance is attributed to a space-charge limited flow after the effective ejection of plasmas from m = 0 constrictions. Detailed knowledge of the ion acceleration mechanism is used with a neutron-producing catcher to increase neutron yields above 1013 at a current of 2.7 MA.
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