Explore the vast range of titles available.

Significance The innate immune system provides a first line of defense against invading pathogens. The inflammasome is an innate immune complex that activates inflammatory caspases upon infection, causing cell death and IL-1 cytokine release, which initiate defense against gram-negative bacterial pathogens but also mediate septic shock. Many inflammasome studies have been performed using cells from mice, but mice and humans differ in their complement of inflammatory caspases. Instead of caspase-11, humans encode the putative orthologs caspase-4 and caspase-5. Here, we show that caspase-4 plays a conserved role in inflammasome activation in response to virulent gram-negative pathogens in primary human macrophages. Our findings provide important insight into how inflammasomes are regulated in human cells. Inflammasomes are critical for host defense against bacterial pathogens. In murine macrophages infected by gram-negative bacteria, the canonical inflammasome activates caspase-1 to mediate pyroptotic cell death and release of IL-1 family cytokines. Additionally, a noncanonical inflammasome controlled by caspase-11 induces cell death and IL-1 release. However, humans do not encode caspase-11. Instead, humans encode two putative orthologs: caspase-4 and caspase-5. Whether either ortholog functions similar to caspase-11 is poorly defined. Therefore, we sought to define the inflammatory caspases in primary human macrophages that regulate inflammasome responses to gram-negative bacteria. We find that human macrophages activate inflammasomes specifically in response to diverse gram-negative bacterial pathogens that introduce bacterial products into the host cytosol using specialized secretion systems. In primary human macrophages, IL-1β secretion requires the caspase-1 inflammasome, whereas IL-1α release and cell death are caspase-1–independent. Instead, caspase-4 mediates IL-1α release and cell death. Our findings implicate human caspase-4 as a critical regulator of noncanonical inflammasome activation that initiates defense against bacterial pathogens in primary human macrophages.

To determine the geographic variability of Medicaid acceptance among allergists in the US. Geospatial analysis predicted Medicaid acceptance across space, and a multivariable regression identified area-level population demographic variables associated with acceptance. We used the National Plan & Provider Enumeration System database to identify allergists. Medicaid acceptance was determined from lists or search engines from state Medicaid offices and calls to provider offices. Spatial analysis was performed using the empirical Bayesian kriging tool. Multivariate logistic regression was used to identify county-level characteristics associated with provider Medicaid acceptance. Of 5694 allergists, 55.5% accepted Medicaid. Acceptance in each state ranged from 13% to 90%. Washington, Arizona, and the Northeast had lowest predicted proportion of both Medicaid acceptance and Medicaid acceptance per 10,000 enrollees. Overall, county-level characteristics were not associated with the likelihood of accepting Medicaid in multivariate analyses. Only the percentage of individuals living in poverty was associated with a higher likelihood of providers accepting Medicaid (OR, 1.245; 95% CI, 1.156-1.340; P < .001). A barrier to accessing allergy-related health care is finding a provider who accepts a patient's insurance, which is largely variable by state. Lack of access to allergy care likely affects health outcomes for children with prevalent atopic conditions such as food allergy.

A male infant presented at term with neonatal respiratory failure and pulmonary hypertension. His respiratory symptoms improved initially, but he exhibited a biphasic clinical course, re-presenting at 15 months of age with tachypnea, interstitial lung disease, and progressive pulmonary hypertension. We identified an intronic TBX4 gene variant in close proximity to the canonical donor splice site of exon 3 (hg 19; chr17:59543302; c.401 + 3 A > T), also carried by his father who had a typical TBX4-associated skeletal phenotype and mild pulmonary hypertension, and by his deceased sister who died shortly after birth of acinar dysplasia. Analysis of patient-derived cells demonstrated a significant reduction in TBX4 expression resulting from this intronic variant. Our study illustrates the variable expressivity in cardiopulmonary phenotype conferred by TBX4 mutation and the utility of genetic diagnostics in enabling accurate identification and classification of more subtly affected family members.

Reperfusion therapy reduces mortality in patients presenting with ST-segment elevation myocardial infarctions (STEMI). However, some patients may not receive thrombolytic therapy or undergo primary percutaneous coronary intervention. The decision making and clinical outcomes of these patients have not been well described. In this study, 139 patients were identified from a total of 1,126 patients with STEMI who did not undergo reperfusion therapy at a high-volume percutaneous coronary intervention center from October 2006 to March 2011. Clinical data, reasons for no reperfusion, management, and mortality were obtained by chart review. The mean age was 80 ± 13 years (61% women, 31% diabetic, and 37% known coronary artery disease). Of the 139 patients, 72 (52%) presented with primary diagnoses other than STEMI, and 39 (28%) developed STEMI >24 hours after admission. The most common reasons for no reperfusion were advanced age, co-morbid conditions, acute or chronic kidney injury, delayed presentation, advance directives precluding reperfusion, patient preference, and dementia. Eighty-four patients (60%) had ≥3 reasons for no reperfusion. Factors associated with hospital mortality were cardiogenic shock, intubation, and advance directives prohibiting reperfusion after physician consultation. In hospital and 1-year mortality were 53% and 69%, respectively. In conclusion, at a high-volume percutaneous coronary intervention center, most patients presenting with STEMI underwent immediate catheterization. The decision for no reperfusion was multifactorial, with advanced age reported as the most common factor. Outcomes were poor in this population, and fewer than half of these patients survived to hospital discharge.

Mothers of very premature infants often have difficulties expressing breastmilk, which can cause distress and potential negative impact on infant health. Clinical recommendations on breastmilk expression are extrapolated from term infants' breastfeeding patterns. This study's objective was to analyse the association of expressing pattern with lactation outcomes after very premature birth. 132 participants were recruited after birth between 23+0 and 31+6 weeks' gestation. Participants recorded the milk expressed in several 24-hour periods in the three weeks after birth. Expressing frequency was positively associated with 24-hour milk yield, with an adjusted 30.5g increase per expressing session on day four (95% CI 15.7 to 45.3) and 94.4g on day 21 (95% CI 62.7 to 126.2). Expressing ≥8 times per day was associated with higher adjusted milk yield than expressing <6 times (on day four, 146.8g, 95% CI 47.4 to 246.1), but not in comparison to expressing 6-7 times (on day four, 82.1g, 95% CI -25.9 to 190.1). Participants with six months or more prior breastmilk feeding experience had a higher adjusted milk yield than others (on day four, 204.3g, 95% CI 125.2 to 283.3). Night-time (2300-0700 hours) expressing sessions were not associated with increased milk yield after adjustment for time since the prior session. On average, participants who had a longest gap between expressions of less than six hours achieved the UK target of 750g breastmilk, whereas those with a longer gap did not. Expressing frequency was an important determinant of milk yield. Clinical recommendations to express ≥8 times per day were supported but for some, 6-7 times was sufficient. This was particularly likely for those with six months or more of prior breastmilk feeding experience. A need to express during the night-time hours appeared to be related to minimising the gap between expressions rather than an inherent value of night-time expression.

In patients with myocardial infarction and anemia, a liberal transfusion strategy led to fewer deaths and heart attacks than a restricted transfusion strategy, but the difference was of borderline significance.

Background Research on human subjects is a public trust; therefore, there is a need to ensure that research coming out of Africa is conducted to the highest ethical standards. Ethics codes ensure that participants in research projects are treated with dignity and respect while they contribute to the social good. History of past abuse of human participants in research and the need for a body to be responsible for ensuring adherence to the principles of ethics in clinical research has necessitated the formation of ethics committees. This study assessed the knowledge of resident doctors, who are medical specialists in training, on their understanding of ethical issues involved in clinical research and their perception of the working and operations of ethics committees. Methods The study took place at the Lagos State University Teaching Hospital, Ikeja, among resident doctors from all the clinical and laboratory departments of the hospital. The study design was a cross-sectional survey with the use of structured self-administered questionnaires among respondents who volunteered to participate. Qualitative variables were summarised as count and percentages and continuous variables expressed as mean ± standard deviation. Results In total, 102 resident doctors took part in the survey; two-thirds of whom had had previous research experience. Observational studies were the most common type of research activity among the responders, only 7 % had had previous experience with clinical trials. About 50 % believed that statistics and science of study protocol studies should not be reviewed by an ethics committee. Conclusion Many of the residents in the study were involved with clinical research but only a few of them had had previous contact with an ethics committee. There was a gap in the knowledge of the resident doctors about the operations of the ethics committee and some ethical principles that guide clinical research.

Introduction and aim: The purpose of AFFINITY (activating falls and fractures prevention in Ireland together), a national population health improvement project, is to implement a national strategy on the prevention of harmful falls and fractures in older persons. Harmful falls and fractures in older persons are on the whole predictable and preventable and are a significant human, social and economic cost burden. AFFINITY is also a commitment within a pan European programme on active and healthy ageing that aims to increase the average healthy lifespan of citizens by 2 years by 2020.Practice Changes,Timeline and Stakeholders: AFFINITY has adopted a whole system approach (2014-2020), with multi-stakeholders, multi-professional and multi-sectoral collaborative working. Key implementation approaches: empowering citizen self-management, supporting older persons to actively age, robust project governance, integrated service delivery model, work practice changes and system change management supports. AFFINITY is a joint project of the national service provider and the publicly funded health & social care system indemnifier.Highlights and Lessons Learned: AFFINITY is being embedded within new service provider structures and processes, including the national service provider integrated care framework for older persons using enablers such as digital technologies, funding and human resources. Four early adapter sites for falls prevention and bone health are developing bespoke, evidence informed integrated care pathways (ICP) since 2014 to address the needs of their older populations: key indicators include timely access to quality multidisciplinary team interventions with measurable outcomes at an individual and population health level. Learnings from these early adapters is being used to identify and scale up additional sites within all service areas nationally to improve access, quality and outcomes of falls and fracture prevention services in 2017.Outcomes and targeted population: Full implementation of this project will mean that persons 65 years and older:will be proactively co-producing their own health & wellbeing,will have access to quality ICP according to need,will have less harmful falls & fracture sequelaewill enjoy safer age friendly environments and improved quality of life years.Transferability and Sustainability: AFFINITY, enabled by the European programme, will be an exemplar of a coordinated, sustainable and effective model of care for older persons, that is both proactive and reactive. Cooperation between AFFINITY and its European partners will enhance and enrich the underlying information and process models, supporting the embedding of evidence informed practices and upscaling to spread and sustain the gains. Change management success factors and approaches to barriers will be available for similar large scale implementation projects to learn from. The political, funding, legislative and organisational reforms and challenges happening at national level will resonate with other countries in their desire for better quality care, more efficient health and social care delivery systems and new economic opportunities and investments, especially within the digital and silver economy.