Targeted neurostimulation reverses a spatiotemporal biomarker of treatment-resistant depression

Major depressive disorder (MDD) is widely hypothesized to result from disordered communication across brain-wide networks. Yet, prior resting-state-functional MRI (rs-fMRI) studies of MDD have studied zero-lag temporal synchrony (functional connectivity) in brain activity absent directional information. We utilize the recent discovery of stereotyped brain-wide directed signaling patterns in humans to investigate the relationship between directed rs-fMRI activity, MDD, and treatment response to FDA-approved neurostimulation paradigm termed Stanford neuromodulation therapy (SNT). We find that SNT over the left dorsolateral prefrontal cortex (DLPFC) induces directed signaling shifts in the left DLPFC and bilateral anterior cingulate cortex (ACC). Directional signaling shifts in the ACC, but not the DLPFC, predict improvement in depression symptoms, and moreover, pretreatment ACC signaling predicts both depression severity and the likelihood of SNT treatment response. Taken together, our findings suggest that ACC-based directed signaling patterns in rs-fMRI are a potential biomarker of MDD

A Galactic O-Star Catalog

We have produced a catalog of 378 Galactic O stars with accurate spectral classifications which is complete for V<8 but includes many fainter stars. The catalog provides cross-identifications with other sources; coordinates (obtained in most cases from Tycho-2 data); astrometric distances for 24 of the nearest stars; optical (Tycho-2, Johnson, and Stromgren) and NIR photometry; group membership, runaway character, and multiplicity information; and a web-based version with links to online services.Comment: 76 pages, 13 tables, and 3 figures. Accepted for publication in Astrophysical Journal. Online version of the catalog available at http://www.stsci.edu/~jmaiz/GOSmain.htm

No difference in radiologic outcomes for natalizumab patients treated with extended interval dosing compared with standard interval dosing: Real-world evidence from MS PATHS

BACKGROUND: Extended interval dosing (EID; average dosing interval approximately every 6 weeks) of natalizumab is associated with significantly lower risk of progressive multifocal leukoencephalopathy than standard interval dosing (SID; every 4 weeks) in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies, though limited, suggest that natalizumab effectiveness is generally maintained in patients who switch to EID after initiation of stable treatment with SID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a collaborative, multicenter learning health system that generates real-world clinical and MRI data using highly standardized acquisition protocols. We compared MRI outcomes in MS PATHS patients treated with natalizumab EID versus SID. We also compared MRI outcomes in patients treated with natalizumab (EID and/or SID) versus injectable MS platform therapy. METHODS: Natalizumab infusion data from the TOUCH Prescribing Program database and MS PATHS MRI assessment data from seven US sites as of July 23, 2020, were used to identify patients with relapsing-remitting MS who had received natalizumab EID or SID in the interval between two MRI scans (an MRI segment). Patients who received injectable platform MS therapy between two MRI scans were also identified. MRI data were used to determine the incidence rate and odds of developing new or enlarging T2 lesions, annualized percentage change in T2 lesion volume (T2LV), and annualized percentage change in brain parenchymal fraction (BPF). MRI outcomes were compared for 1) natalizumab EID treatment versus natalizumab SID treatment, 2) natalizumab treatment (EID + SID) versus platform therapy, and 3) natalizumab EID versus platform therapy. Propensity score-based weighting or matching were used to balance covariates at the start of MRI segments for all comparisons. RESULTS: The MRI outcomes observed with natalizumab EID treatment did not differ significantly from those observed with natalizumab SID treatment. The odds ratio for any new or enlarging T2 lesion was 1.07 (95% confidence interval [CI]: 0.93, 1.24; p = 0.355), and the rate ratio (95% CI) for new or enlarging T2 lesions was 1.62 (0.93, 2.82; p = 0.090). Differences (95% CI) between EID and SID patients in mean annualized percentage change in T2LV and BPF were 1.56% (-3.77%, 6.90%; p = 0.566) and -0.11% (-0.25%, -0.10%; p = 0.096), respectively. Conversely, when MRI outcomes in natalizumab and platform therapy patients were compared, there were significant differences favoring natalizumab in all assessments: the odds of any new or enlarging T2 lesion (odds ratio: 0.69 [95% CI: 0.64, 0.75]; p\u3c0.001), the incidence rate of new or enlarging T2 lesions (rate ratio: 0.47 [95% CI: 0.37, 0.61]; p\u3c0.001), annualized percentage change (decrease) in T2LV (difference: -3.68% [95% CI: -7.06%, -0.30%]; p = 0.033), and annualized percentage change (increase) in BPF (difference: 0.22% [95% CI: 0.16%, 0.29%]; p\u3c0.001). Results of the subgroup comparison of natalizumab EID patients with platform therapy patients were similar to those of the overall-natalizumab-group-versus-platform-therapy comparison. CONCLUSIONS: The results indicate that natalizumab EID and SID provide comparable real-world effectiveness on quantitative MRI metrics. These data further demonstrate that natalizumab EID can provide superior real-world effectiveness to injectable platform therapy on quantitative MRI metrics

The INTEGRAL ground segment and its science operations centre

The INTEGRAL ground segment is divided into operational and scientific components. The operational component consists of the Mission Operations Centre, the ground stations and communications lines while the scientific component comprises of a Science Operations Centre and Science Data Centre. The overall architecture of the ground segment is described paying particular attention to the tasks and functionalities of the INTEGRAL Science Operations Centre.Comment: 4 pages, 2 figures, accepted for publication in A&

Anti-α4 Antibody Treatment Blocks Virus Traffic to the Brain and Gut Early, and Stabilizes CNS Injury Late in Infection

Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab) once a week for three weeks beginning on 28 days post-infection (late). Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS), and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+) in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early) for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV – RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity

Zfhx3-mediated genetic ablation of the SCN abolishes light entrainable circadian activity while sparing food anticipatory activity.

Circadian rhythms persist in almost all organisms and are crucial for maintaining appropriate timing in physiology and behaviour. Here, we describe a mouse mutant where the central mammalian pacemaker, the suprachiasmatic nucleus (SCN), has been genetically ablated by conditional deletion of the transcription factor Zfhx3 in the developing hypothalamus. Mutants were arrhythmic over the light-dark cycle and in constant darkness. Moreover, rhythms of metabolic parameters were ablated in vivo although molecular oscillations in the liver maintained some rhythmicity. Despite disruptions to SCN cell identity and circuitry, mutants could still anticipate food availability, yet other zeitgebers - including social cues from cage-mates - were ineffective in restoring rhythmicity although activity levels in mutants were altered. This work highlights a critical role for Zfhx3 in the development of a functional SCN, while its genetic ablation further defines the contribution of SCN circuitry in orchestrating physiological and behavioral responses to environmental signals

The capabilities approach and critical social policy: lessons from the majority world?

The capabilities approach (CA) most closely associated with the thinner and thicker versions of Sen and Nussbaum has the potential to provide a paradigm shift for critical social policy, encompassing but also transcending some of the limitations associated with the Marshallian social citizenship approach. The article argues, however, that it cannot simply be imported from the majority world, rather there is a need to bear in mind the critical literature that developed around it. This is generally discussed and then critically applied to case studies of CA in the developed capitalist world, particularly the Equalities Review conducted for the Equality and Human Rights Commission

Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma

Relapsed Mantle cell lymphoma (MCL) is often treated with Bruton\u27s tyrosine kinase inhibitors (BTKi); however, post-BTKi relapse can be challenging. Adding venetoclax (VEN) to ibrutinib (IBR) has shown synergy in preclinical MCL models. Prior MCL studies of the combination show promising efficacy but have conducted limited dose finding. We sought to identify the optimal dosing combination, based on efficacy and toxicity, utilizing a continual reassessment method of 6 combinations of IBR (280 mg, 420 mg, and 560 mg by mouth daily) and VEN (max dose of 200 mg and 400 mg by mouth daily). Eligible participants were not previously exposed to BTKi and not high risk for tumor lysis syndrome (TLS). VEN, initiated first at 100 mg, then at 20 mg by mouth daily after a TLS event, was started prior to adding IBR and ramped-up based on the dose level assigned. Combination treatment continued for six 28-day cycles. Thirty-five participants were enrolled and treated. One TLS event occurred with starting dose of 100 mg VEN; no TLS was seen with 20 mg. The optimal dosing combination was considered to be VEN 200 mg and IBR 420 mg with an overall response rate (ORR) of 93.8% (95% CI: 73.6% to 99.7%) and DLT incidence of 6.2% (95% CI: 0.3% to 26.4%). ORR for all arms was 82.3% (28/34; 95% CI: 65.5% to 93.2%) with a complete response (CR) rate of 42.4% (14/33; 95% CI: 25.5% to 60.8%). A participant was not allocated to IBR 560 mg and VEN 400 mg. ORR benefit was not seen with higher dosing combinations and toxicity was higher; a comparison made within the limitations of small cohorts. Resistance was seen in nearly all arms. This trial was registered at www.clinicaltrials.gov #NCT02419560

Cosmological expansion and local systems: a Lema\^{i}tre-Tolman-Bondi model

We propose a Lema\^{i}tre-Tolman-Bondi system mimicking a two-body system to address the problem of the cosmological expansion versus local dynamics. This system is strongly bound but participates in the cosmic expansion and is exactly comoving with the cosmic substratum