East Bay Coalition for the Homeless: Branding Study and Marketing Strategy

There are a number of potential positioning strategies. The two which make the most sense for the EBCH are to “position the EBCH away from others in the category” and to “position the EBCH as unique.” These strategies have the advantage of setting the EBCH apart from the other organizations that address homelessness. Occupying its own “position” in the minds of potential and current donors is not only an effective communications/marketing strategy but also a less costly one because it avoids head-to-head competition and comparisons

Clinical leadership in service redesign using Clinical Commissioning Groups: a mixed-methods study

Background: A core component of the Health and Social Care Act 2012 (Great Britain. Health and Social Care Act 2012. London: HMSO; 2012) was the idea of devolving to general practitioners (GPs) a health service leadership role for service redesign. For this purpose, new Clinical Commissioning Groups (CCGs) were formed in the English NHS.Objectives: This research examined the extent to which, and the methods by which, clinicians stepped forward to take up a leadership role in service redesign using CCGs as a platform.Design: The project proceeded in five phases: (1) a scoping study across 15 CCGs, (2) the design and administration of a national survey of all members of CCG governing bodies in 2014, (3) six main in-depth case studies, (4) a second national survey of governing body members in 2016, which allowed longitudinal comparisons, and (5) international comparisons.Participants: In addition to GPs serving in clinical lead roles for CCGs, the research included insights from accountable officers and other managers and perspectives from secondary care and other provider organisations (local authority councillors and staff, patients and the public, and other relevant bodies).Results: Instances of the exercise of clinical leadership utilising the mechanism of the CCGs were strikingly varied. Some CCG teams had made little of the opportunity. However, we found other examples of clinicians stepping forward to bring about meaningful improvements in services. The most notable cases involved the design of integrated care for frail elderly patients and others with long-term conditions. The leadership of these service redesigns required cross-boundary working with primary care, secondary care, community care and social work. The processes enabling such breakthroughs required interlocking processes of leadership across three arenas: (1) strategy-level work at CCG board level, (2) mid-range operational planning and negotiation at programme board level and (3) the arena of practical implementation leadership at the point of delivery. The arena of the CCG board provided the legitimacy for strategic change; the programme boards worked through the competing logics of markets, hierarchy and networks; and the practice arena allowed the exercise of clinical leadership in practical problemsolving, detailed learning and routinisation of new ways of working at a common-sense everyday level.Limitations: Although the research was conducted over a 3-year period, it could be argued that a much longer period is required for CCGs to mature and realise their potential.Conclusions: Despite the variation in practice, we found significant examples of clinical leaders forging new modes of service design and delivery. A great deal of the service redesign effort was directed at compensating for the fragmented nature of the NHS – part of which had been created by the 2012 reforms. This is the first study to reveal details of such work in a systematic way

Toward A Brain-Based Theory of Beauty

We wanted to learn whether activity in the same area(s) of the brain correlate with the experience of beauty derived from different sources. 21 subjects took part in a brain-scanning experiment using functional magnetic resonance imaging. Prior to the experiment, they viewed pictures of paintings and listened to musical excerpts, both of which they rated on a scale of 1-9, with 9 being the most beautiful. This allowed us to select three sets of stimuli-beautiful, indifferent and ugly-which subjects viewed and heard in the scanner, and rated at the end of each presentation. The results of a conjunction analysis of brain activity showed that, of the several areas that were active with each type of stimulus, only one cortical area, located in the medial orbito-frontal cortex (mOFC), was active during the experience of musical and visual beauty, with the activity produced by the experience of beauty derived from either source overlapping almost completely within it. The strength of activation in this part of the mOFC was proportional to the strength of the declared intensity of the experience of beauty. We conclude that, as far as activity in the brain is concerned, there is a faculty of beauty that is not dependent on the modality through which it is conveyed but which can be activated by at least two sources-musical and visual-and probably by other sources as well. This has led us to formulate a brain-based theory of beauty

The role of the amygdala in face perception and evaluation

Faces are one of the most significant social stimuli and the processes underlying face perception are at the intersection of cognition, affect, and motivation. Vision scientists have had a tremendous success of mapping the regions for perceptual analysis of faces in posterior cortex. Based on evidence from (a) single unit recording studies in monkeys and humans; (b) human functional localizer studies; and (c) meta-analyses of neuroimaging studies, I argue that faces automatically evoke responses not only in these regions but also in the amygdala. I also argue that (a) a key property of faces represented in the amygdala is their typicality; and (b) one of the functions of the amygdala is to bias attention to atypical faces, which are associated with higher uncertainty. This framework is consistent with a number of other amygdala findings not involving faces, suggesting a general account for the role of the amygdala in perception

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

DNA twisting flexibility and the formation of sharply looped protein–DNA complexes

Gene-regulatory complexes often require that pairs of DNA-bound proteins interact by looping-out short (often ≈100-bp) stretches of DNA. The loops can vary in detailed length and sequence and, thus, in total helical twist, which radically alters their geometry. How this variability is accommodated structurally is not known. Here we show that the inherent twistability of 89- to 105-bp DNA circles exceeds theoretical expectation by up to 400-fold. These results can be explained only by greatly enhanced DNA flexibility, not by permanent bends. They invalidate the use of classic theories of flexibility for understanding sharp DNA looping but support predictions of two recent theories. Our findings imply an active role for DNA flexibility in loop formation and suggest that variability in the detailed helical twist of regulatory loops is accommodated naturally by the inherent twistability of the DNA

Kaposi Sarcoma-associated Herpesvirus Latency-associated Nuclear Antigen Inhibits Interferon (IFN) β Expression by Competing with IFN Regulatory Factor-3 for Binding to IFNB Promoter*

Host cells respond to viral infections by synthesizing and producing antiviral molecules such as type I interferons (IFN). The Kaposi sarcoma-associated herpesvirus (KSHV) encodes multiple proteins expressed during the lytic replication cycle that alter the antiviral response of the host. Considering that in Kaposi sarcoma lesions and primary effusion lymphoma cells KSHV is latent in the vast majority of cells, we were interested in determining whether latently expressed viral proteins have the ability to modulate IFN synthesis. The latency-associated nuclear antigen (LANA-1) is a large nuclear protein that plays a role in the establishment and maintenance of latent KSHV episome in the nucleus of infected cells. LANA-1 is also described to modulate the cellular transcription. Here, we report that LANA-1 inhibits IFN-β transcription and synthesis by competing with the binding of interferon regulatory factor-3 (IRF3) to the IFNB promoter. Using mutants of LANA-1, we have identified the central acidic repeated region as the domain essential for interfering with the binding of IRF3 to the positive regulatory domains I–III of the IFNB promoter. In addition, the nuclear localization of LANA-1 proved essential for IFN-β inhibition. Thus, LANA-1 interferes with the formation of IFN-β enhanceosome by competing with the fixation of IRF3 and by inhibiting the expression of the CREB-binding protein. The ability of LANA-1 to inhibit IFNB gene expression highlights a new role for this protein in cellular gene modulation and immune evasion strategies