Impact and return on investment of the take kare safe space program—a harm reduction strategy implemented in Sydney, Australia

Safe spaces are increasingly utilized to reduce alcohol-related harm, violence, crime and improve public safety in nightlife settings. This study aimed to determine the impact and return on investment of the Take Kare Safe Space (TKSS) program—a harm reduction program implemented to address alcohol-related violence and disorder in three locations in Sydney’s night-time economy between 2014 and 2019. TKSS ambassadors provided support at static safe spaces and patrolled designated nightlife precincts to provide practical assistance to vulnerable and intoxicated people. Ambassadors recorded information relating to these interactions including ‘client’ age, gender, perceived level of intoxication, time and length of engagement with the program. Costs of program implementation and benefits of major incidents averted were obtained to allow calculation of return on investment. From December 2014 to April 2019, 66,455 people were supported by TKSS ambassadors. Most users were male (62%) and aged 18–25 years (66%). Of 3633 interventions by ambassadors, serious risk of harm was averted in 735 cases (20%). The program’s return on investment is estimated at 2.67, suggesting that a $1 investment results in$2.67 in benefits. Safe Spaces are extensively utilized, particularly by young males with high levels of intoxication, and represent a positive return on investment. Despite the growth of such services, there remains a notable absence of rigorous, independent evaluation regarding the outcomes and/or social benefit of safe space programs. From a policy perspective, there is a need for more high-quality economic evaluations to better inform decisions about competing uses of limited resources

Reduced mechanical efficiency in left-ventricular trabeculae of the spontaneously hypertensive rat.

Long-term systemic arterial hypertension, and its associated compensatory response of left-ventricular hypertrophy, is fatal. This disease leads to cardiac failure and culminates in death. The spontaneously hypertensive rat (SHR) is an excellent animal model for studying this pathology, suffering from ventricular failure beginning at about 18 months of age. In this study, we isolated left-ventricular trabeculae from SHR-F hearts and contrasted their mechanoenergetic performance with those from nonfailing SHR (SHR-NF) and normotensive Wistar rats. Our results show that, whereas the performance of the SHR-F differed little from that of the SHR-NF, both SHR groups performed less stress-length work than that of Wistar trabeculae. Their lower work output arose from reduced ability to produce sufficient force and shortening. Neither their heat production nor their enthalpy output (the sum of work and heat), particularly the energy cost of Ca(2+) cycling, differed from that of the Wistar controls. Consequently, mechanical efficiency (the ratio of work to change of enthalpy) of both SHR groups was lower than that of the Wistar trabeculae. Our data suggest that in hypertension-induced left-ventricular hypertrophy, the mechanical performance of the tissue is compromised such that myocardial efficiency is reduced

“It’s like a safety net for when things go wrong”: key stakeholder and program user perspectives on a peer-led safe space program in Sydney, Australia

Background: Safe Spaces are a harm reduction approach commonly utilised in nightlife and festival settings to address alcohol and other drug-related harms. Despite increasing use, there has been little independent evaluation of safe space programs. This study aimed to explore (1) program user satisfaction with and use of a safe space program implemented in Sydney, Australia (The Take Kare Safe Space (TKSS)), and (2) the strengths and weaknesses of TKSS from the perspective of key stakeholders. Methods: Semi-structured, in-depth, interviews lasting between 30 min to 1 h were conducted with 38 key program stakeholders, including staff from police (n = 4), ambulance (n = 4), a local hospital accident and emergency room (n = 4), local council (n = 2), city ‘rangers’ (n = 2), the TKSS program (n = 4), licensed venues and other nightlife service providers (n = 4), and program users (n = 14). Purposive sampling was used to identify key stakeholders to participate in interviews. Results: Stakeholders stated that the TKSS program had a number of core benefits, including that it filled a service gap in nightlife settings; improved the efficiency and effectiveness of emergency services and other stakeholders operating in nightlife precincts; provided welfare services through proactive and non-judgmental interventions; and facilitated a means to de-escalate conflict without engaging police. Perceived weaknesses of the program included a lack of public awareness about the program; staff and volunteer levels; and misunderstandings regarding the scope and function of the TKSS program by some stakeholders. Conclusion: This study demonstrates the complex relationships that exist around the delivery of harm reduction in nightlife settings. In particular, it highlights the relative lack of servicing of public nightlife settings and the value of safe spaces/peer-to-peer safety ambassador programs in linking up care and filling this service gap. Further, it documents the extended benefit across key stakeholder groups of delivering proactive and non-judgemental harm reduction services and, in doing so, provides critical evidence around their efficacy in reducing AOD-related harms in the night-time economy

The Outstanding Decisions of the United States Supreme Court in 1954

We perform a kinematic and morphological analysis of 44 star-forming galaxies at z ̃ 2 in the COSMOS legacy field using near-infrared spectroscopy from Keck/MOSFIRE and F160W imaging from CANDELS/3D-HST as part of the ZFIRE survey. Our sample consists of cluster and field galaxies from 2.0 < z < 2.5 with K-band multi-object slit spectroscopic measurements of their Hα emission lines. Hα rotational velocities and gas velocity dispersions are measured using the Heidelberg Emission Line Algorithm (HELA), which compares directly to simulated 3D data cubes. Using a suite of simulated emission lines, we determine that HELA reliably recovers input S 0.5 and angular momentum at small offsets, but V 2.2/σ g values are offset and highly scattered. We examine the role of regular and irregular morphology in the stellar mass kinematic scaling relations, deriving the kinematic measurement S 0.5, and finding {log}({S}0.5)=(0.38+/- 0.07){log}(M/{M}☉ -10)+(2.04+/- 0.03) with no significant offset between morphological populations and similar levels of scatter (̃0.16 dex). Additionally, we identify a correlation between M ⋆ and V 2.2/σ g for the total sample, showing an increasing level of rotation dominance with increasing M ⋆, and a high level of scatter for both regular and irregular galaxies. We estimate the specific angular momenta (j disk) of these galaxies and find a slope of 0.36 ± 0.12, shallower than predicted without mass-dependent disk growth, but this result is possibly due to measurement uncertainty at M ⋆ < 9.5 However, through a Kolmogorov-Smirnov test we find irregular galaxies to have marginally higher j disk values than regular galaxies, and high scatter at low masses in both populations

Pteridine-2,4-diamine derivatives as radical scavengers and inhibitors of lipoxygenase that can possess anti-inflammatory properties

BACKGROUND: Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. The complex nature of inflammation and of oxidative stress suggests that dual-target agents may be effective in combating diseases involving reactive oxygen species. RESULTS: A novel series of N-substituted 2,4-diaminopteridines has been synthesized and evaluated as antioxidants in several assays. Many exhibited potent lipid antioxidant properties, and some are inhibitors of soybean lipoxygenase, IC50 values extending down to 100 nM for both targets. Several pteridine derivatives showed efficacy at 0.01 mmol/kg with little tissue damage in a rat model of colitis. 2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)pteridin-4-amine (18f) at 0.01 mmol/kg exhibited potent anti-inflammatory activity (reduction by 41%). CONCLUSION: The 2,4-diaminopteridine core represents a new scaffold for lipoxygenase inhibition as well as sustaining anti-inflammatory properties

On the Gas Content, Star Formation Efficiency, and Environmental Quenching of Massive Galaxies in Protoclusters at z ≈ 2.0–2.5

We present ALMA Band 6 (ν = 233 GHz, λ = 1.3 mm) continuum observations toward 68 "normal" star-forming galaxies within two Coma-like progenitor structures at z = 2.10 and 2.47, from which ISM masses are derived, providing the largest census of molecular gas mass in overdense environments at these redshifts. Our sample comprises galaxies with a stellar mass range of 1 × 10⁹ M_⊙–4 × 10¹¹ M_⊙ with a mean M_★ ≈ 6 × 10¹⁰ M_⊙. Combining these measurements with multiwavelength observations and spectral energy distribution modeling, we characterize the gas mass fraction and the star formation efficiency, and infer the impact of the environment on galaxies' evolution. Most of our detected galaxies (≳70%) have star formation efficiencies and gas fractions similar to those found for coeval field galaxies and in agreement with the field scaling relations. However, we do find that the protoclusters contain an increased fraction of massive, gas-poor galaxies, with low gas fractions (f_(gas) ≾ 6%–10%) and red rest-frame ultraviolet/optical colors typical of post-starburst and passive galaxies. The relatively high abundance of passive galaxies suggests an accelerated evolution of massive galaxies in protocluster environments. The large fraction of quenched galaxies in these overdense structures also implies that environmental quenching takes place during the early phases of cluster assembly, even before virialization. From our data, we derive a quenching efficiency of ϵ_q ≈ 0.45 and an upper limit on the quenching timescale of τ_q < 1 Gyr

Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4⁺CD25⁺ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor

CD4+CD25+Foxp3+T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4+CD25+T cells generated from CD4+CD25- T cells’ activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4+CD25+T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than naïve/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressed foxp3, irf4, gata3 and il5. In vivo, we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4+CD25+T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived ≥60d whereas sham treated rats fully rejected by day 31 (p60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg including Irf4, gata3 and Il5. These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg

New first trimester crown-rump length's equations optimized by structured data collection from a French general population

--- Objectives --- Prior to foetal karyotyping, the likelihood of Down's syndrome is often determined combining maternal age, serum free beta-HCG, PAPP-A levels and embryonic measurements of crown-rump length and nuchal translucency for gestational ages between 11 and 13 weeks. It appeared important to get a precise knowledge of these scan parameters' normal values during the first trimester. This paper focused on crown-rump length. --- METHODS --- 402 pregnancies from in-vitro fertilization allowing a precise estimation of foetal ages (FA) were used to determine the best model that describes crown-rump length (CRL) as a function of FA. Scan measures by a single operator from 3846 spontaneous pregnancies representative of the general population from Northern France were used to build a mathematical model linking FA and CRL in a context as close as possible to normal scan screening used in Down's syndrome likelihood determination. We modeled both CRL as a function of FA and FA as a function of CRL. For this, we used a clear methodology and performed regressions with heteroskedastic corrections and robust regressions. The results were compared by cross-validation to retain the equations with the best predictive power. We also studied the errors between observed and predicted values. --- Results --- Data from 513 spontaneous pregnancies allowed to model CRL as a function of age of foetal age. The best model was a polynomial of degree 2. Datation with our equation that models spontaneous pregnancies from a general population was in quite agreement with objective datations obtained from 402 IVF pregnancies and thus support the validity of our model. The most precise measure of CRL was when the SD was minimal (1.83mm), for a CRL of 23.6 mm where our model predicted a 49.4 days of foetal age. Our study allowed to model the SD from 30 to 90 days of foetal age and offers the opportunity of using Zscores in the future to detect growth abnormalities. --- Conclusion --- With powerful statistical tools we report a good modeling of the first trimester embryonic growth in the general population allowing a better knowledge of the date of fertilization useful in the ultrasound screening of Down's syndrome. The optimal period to measure CRL and predict foetal age was 49.4 days (9 weeks of gestational age). Our results open the way to the detection of foetal growth abnormalities using CRL Zscores throughout the first trimester

Alloactivation of naïve CD4⁺ CD8⁻ CD25⁺T regulatory cells: Expression of CD8α identifies potent suppressor cells that can promote transplant tolerance induction

Therapy with alloantigen-specific CD4+ CD25+ T regulatory cells (Treg) for induction of transplant tolerance is desirable, as naïve thymic Treg (tTreg) are not alloantigen-specific and are weak suppressor cells. Naïve tTreg from DA rats cultured with fully allogeneic PVG stimulator cells in the presence of rIL-2 express IFN-gamma receptor (IFNGR) and IL-12 receptor beta2 (IL-12Rβ2) and are more potent alloantigen-specific regulators that we call Ts1 cells. This study examined additional markers that could identify the activated alloantigen-specific Treg as a subpopulation within the CD4+ CD25+ Foxp3+ Treg. After culture of naïve DA CD4+ CD8− CD25+ T cells with rIL-2 and PVG alloantigen, or rIL-2 without alloantigen, CD8α was expressed on 10–20% and CD8β on <5% of these cells. These cells expressed ifngr and Il12rb2. CD8α+ cells had increased Ifngr that characterizes Ts1 cells as well was Irf4, a transcription factor induced by TCR activation. Proliferation induced by re-culture with rIL-12 and alloantigen was greater with CD4+ CD8α+ CD25+ Treg consistent with the CD8α+ cells expressing IL-12R. In MLC, the CD8α+ fraction suppressed responses against allogeneic stimulators more than the mixed Ts1 population, whereas the CD4+ CD8− CD25+ T cells were less potent. In an adoptive transfer assay, rIL-2 and alloantigen activated Treg suppress rejection at a ratio of 1:10 with naïve effector cells, whereas alloantigen and rIL-2 activated tTreg depleted of the CD8α+ cells were much less effective. This study demonstrated that expression of CD8α by rIL-2 and alloantigen activation of CD4+ CD8− CD25+ Foxp3+ T cells was a marker of activated and potent Treg that included alloantigen-specific Treg

Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD

Our previous studies have shown that nutritional zinc restriction exacerbates airway inflammation accompanied by an increase in caspase-3 activation and an accumulation of apoptotic epithelial cells in the bronchioles of the mice. Normally, apoptotic cells are rapidly cleared by macrophage efferocytosis, limiting any secondary necrosis and inflammation. We therefore hypothesized that zinc deficiency is not only pro-apoptotic but also impairs macrophage efferocytosis. Impaired efferocytic clearance of apoptotic epithelial cells by alveolar macrophages occurs in chronic obstructive pulmonary disease (COPD), cigarette-smoking and other lung inflammatory diseases. We now show that zinc is a factor in impaired macrophage efferocytosis in COPD. Concentrations of zinc were significantly reduced in the supernatant of bronchoalveolar lavage fluid of patients with COPD who were current smokers, compared to healthy controls, smokers or COPD patients not actively smoking. Lavage zinc was positively correlated with AM efferocytosis and there was decreased efferocytosis in macrophages depleted of Zn in vitro by treatment with the membrane-permeable zinc chelator TPEN. Organ and cell Zn homeostasis are mediated by two families of membrane ZIP and ZnT proteins. Macrophages of mice null for ZIP1 had significantly lower intracellular zinc and efferocytosis capability, suggesting ZIP1 may play an important role. We investigated further using the human THP-1 derived macrophage cell line, with and without zinc chelation by TPEN to mimic zinc deficiency. There was no change in ZIP1 mRNA levels by TPEN but a significant 3-fold increase in expression of another influx transporter ZIP2, consistent with a role for ZIP2 in maintaining macrophage Zn levels. Both ZIP1 and ZIP2 proteins were localized to the plasma membrane and cytoplasm in normal human lung alveolar macrophages. We propose that zinc homeostasis in macrophages involves the coordinated action of ZIP1 and ZIP2 transporters responding differently to zinc deficiency signals and that these play important roles in macrophage efferocytosis