Calcineurin inhibitor effects on kidney electrolyte handling and blood pressure: tacrolimus versus voclosporin.

BACKGROUND AND HYPOTHESIS: Calcineurin inhibitors affect kidney electrolyte handling and blood pressure through an effect on the distal tubule. The second generation calcineurin inhibitor voclosporin causes hypomagnesemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally. METHODS: Rats were treated with voclosporin, tacrolimus or vehicle for 28 days. Dosing was based on a pilot experiment to achieve clinically therapeutic concentrations. Drug effects were assessed by electrolyte handling at day 18 and 28, thiazide testing at day 20, telemetric blood pressure recordings, and analysis of mRNA and protein levels of distal tubular transporters at day 28. RESULTS: Compared to vehicle, tacrolimus but not voclosporin significantly increased the fractional excretions of calcium (>4-fold), magnesium and chloride (both 1.5-fold) and caused hypomagnesemia. Tacrolimus but not voclosporin significantly reduced distal tubular transporters at mRNA and/or protein level, including the sodium-chloride cotransporter, transient receptor melastatin 6, transient receptor potential vanilloid 5, cyclin M2, sodium-calcium exchanger and calbindin-D28K. Tacrolimus but not voclosporin reduced the mRNA level and urinary excretion of epidermal growth factor. The saluretic response to hydrochlorothiazide at day 20 was similar in the voclosporin and vehicle groups, whereas it was lower in the tacrolimus group. The phosphorylated form of the sodium-chloride cotransporter was significantly higher at day 28 in rats treated with voclosporin than in those treated with tacrolimus. Tacrolimus transiently increased blood pressure, whereas voclosporin caused a gradual but persistent increase in blood pressure which was further characterized by high renin, normal aldosterone, and low endothelin-1. CONCLUSIONS: In contrast to tacrolimus, voclosporin does not cause hypercalciuria and hypomagnesemia, but similarly causes hypertension. Our data reveal differences between the distal tubular effects of tacrolimus and voclosporin and provide a pathophysiological basis for the clinically observed differences between the two calcineurin inhibitors.

The Cyclophilin-Dependent Calcineurin Inhibitor Voclosporin Inhibits SARS-CoV-2 Replication in Cell Culture.

Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcineurin inhibitors (CNIs) are cornerstone immunosuppressants used in KTRs and some have been reported to possess antiviral activity against RNA viruses, including coronaviruses. Here, we evaluated the effect of the CNIs tacrolimus, cyclosporin A, and voclosporin (VCS), as well as other immunosuppressants, on SARS-CoV-2 replication in cell-based assays. Unexpected, loss of compound due to plastic binding and interference of excipients in pharmaceutical formulations (false-positive results) complicated the determination of EC50 values of cyclophilin-dependent CNI's in our antiviral assays. Some issues could be circumvented by using exclusively glass lab ware with pure compounds. In these experiments, VCS reduced viral progeny yields in human Calu-3 cells at low micromolar concentrations and did so more effectively than cyclosporin A, tacrolimus or other immunosuppressants. Although, we cannot recommend a particular immunosuppressive regimen in KTRs with COVID-19, our data suggest a potential benefit of cyclophilin-dependent CNIs, in particular VCS in reducing viral progeny, which warrants further clinical evaluation in SARS-CoV-2-infected KTRs.

Relationships between social climate and indoor environmental quality and frequently reported health symptoms among teachers and staff in a suburban school district.

Public school teachers represent one of the largest occupational groups in the United States and are vulnerable to job stress and burnout. School social and physical environments may be adversely impacting the health of teachers and other staff, though few studies have explored these relationships. We partnered with a suburban school district in Colorado to assess the association between school environmental quality, social climate, and staff member health. We modeled the number of self-reported frequent health symptoms (experienced at least once a week) using generalized linear models. School-level predictors of interest included: overall social climate scores (unitless), building operations report card (ORC) scores (unitless), and indoor air quality (IAQ) scores (unitless). In total, we had data from 134 staff members from 11 schools in the district. A majority (62%) of our participants were teachers, who reported a greater number of frequent (i.e., at least once a week) health symptoms (mean = 3.2 symptoms experienced at least once per week) compared to staff in other roles (mean = 2.3 symptoms per week). We found that a one standard-deviation (10.5) increase in the overall social climate score was associated with a 0.77-fold (95% CI: 0.60-0.99) change in the number of frequent health symptoms reported. However, this association was attenuated among teachers compared to other staff members. Our results suggested effect modification by social climate on the relationship between IAQ and health, albeit with some uncertainty. For participants with a school climate score below the mean, a one standard-deviation (10.5) increase in IAQ score was associated with a 0.49-fold (95% CI: 0.35-0.70) change in the number of frequently reported symptoms. Overall, our study suggests school climate may be associated with self-reported health symptoms, but that the benefits of improved school climates may not be as strong for teachers compared to other staff. Future work should assess perceived climate at the individual level to assess how staff roles impact how school environments are associated with health outcomes.

Implementation of a Digitally Enabled Care Pathway (Part 2): Qualitative Analysis of Experiences of Health Care Professionals.

BACKGROUND: One reason for the introduction of digital technologies into health care has been to try to improve safety and patient outcomes by providing real-time access to patient data and enhancing communication among health care professionals. However, the adoption of such technologies into clinical pathways has been less examined, and the impacts on users and the broader health system are poorly understood. We sought to address this by studying the impacts of introducing a digitally enabled care pathway for patients with acute kidney injury (AKI) at a tertiary referral hospital in the United Kingdom. A dedicated clinical response team-comprising existing nephrology and patient-at-risk and resuscitation teams-received AKI alerts in real time via Streams, a mobile app. Here, we present a qualitative evaluation of the experiences of users and other health care professionals whose work was affected by the implementation of the care pathway. OBJECTIVE: The aim of this study was to qualitatively evaluate the impact of mobile results viewing and automated alerting as part of a digitally enabled care pathway on the working practices of users and their interprofessional relationships. METHODS: A total of 19 semistructured interviews were conducted with members of the AKI response team and clinicians with whom they interacted across the hospital. Interviews were analyzed using inductive and deductive thematic analysis. RESULTS: The digitally enabled care pathway improved access to patient information and expedited early specialist care. Opportunities were identified for more constructive planning of end-of-life care due to the earlier detection and alerting of deterioration. However, the shift toward early detection also highlighted resource constraints and some clinical uncertainty about the value of intervening at this stage. The real-time availability of information altered communication flows within and between clinical teams and across professional groups. CONCLUSIONS: Digital technologies allow early detection of adverse events and of patients at risk of deterioration, with the potential to improve outcomes. They may also increase the efficiency of health care professionals' working practices. However, when planning and implementing digital information innovations in health care, the following factors should also be considered: the provision of clinical training to effectively manage early detection, resources to cope with additional workload, support to manage perceived information overload, and the optimization of algorithms to minimize unnecessary alerts.

Implementation of a Digitally Enabled Care Pathway (Part 1): Impact on Clinical Outcomes and Associated Health Care Costs.

BACKGROUND: The development of acute kidney injury (AKI) in hospitalized patients is associated with adverse outcomes and increased health care costs. Simple automated e-alerts indicating its presence do not appear to improve outcomes, perhaps because of a lack of explicitly defined integration with a clinical response. OBJECTIVE: We sought to test this hypothesis by evaluating the impact of a digitally enabled intervention on clinical outcomes and health care costs associated with AKI in hospitalized patients. METHODS: We developed a care pathway comprising automated AKI detection, mobile clinician notification, in-app triage, and a protocolized specialist clinical response. We evaluated its impact by comparing data from pre- and postimplementation phases (May 2016 to January 2017 and May to September 2017, respectively) at the intervention site and another site not receiving the intervention. Clinical outcomes were analyzed using segmented regression analysis. The primary outcome was recovery of renal function to ≤120% of baseline by hospital discharge. Secondary clinical outcomes were mortality within 30 days of alert, progression of AKI stage, transfer to renal/intensive care units, hospital re-admission within 30 days of discharge, dependence on renal replacement therapy 30 days after discharge, and hospital-wide cardiac arrest rate. Time taken for specialist review of AKI alerts was measured. Impact on health care costs as defined by Patient-Level Information and Costing System data was evaluated using difference-in-differences (DID) analysis. RESULTS: The median time to AKI alert review by a specialist was 14.0 min (interquartile range 1.0-60.0 min). There was no impact on the primary outcome (estimated odds ratio [OR] 1.00, 95% CI 0.58-1.71; P=.99). Although the hospital-wide cardiac arrest rate fell significantly at the intervention site (OR 0.55, 95% CI 0.38-0.76; P<.001), DID analysis with the comparator site was not significant (OR 1.13, 95% CI 0.63-1.99; P=.69). There was no impact on other secondary clinical outcomes. Mean health care costs per patient were reduced by £2123 (95% CI -£4024 to -£222; P=.03), not including costs of providing the technology. CONCLUSIONS: The digitally enabled clinical intervention to detect and treat AKI in hospitalized patients reduced health care costs and possibly reduced cardiac arrest rates. Its impact on other clinical outcomes and identification of the active components of the pathway requires clarification through evaluation across multiple sites.

Fetal membrane imaging and the prediction of preterm birth: a systematic review, current issues, and future directions.

BACKGROUND: Preterm premature rupture of membranes (PPROM) is the largest identifiable cause of preterm birth. There is currently no good screening test for PPROM in low-risk asymptomatic patients. Our goal was to identify how imaging methods can be utilized for examining the risks for PPROM in asymptomatic patients. METHODS: This paper is a systematic review of the literature on fetal membrane thickness and its use for the prediction of PPROM. Four key studies are identified and reviewed; two in vitro studies and two in vivo ultrasound studies each using differing methodologies. Additionally reviewed is a study using Optical Coherence Tomography, an emerging technique using near-infrared technology to produce high-resolution images. RESULTS: There is currently insufficient data to determine the association between fetal membrane thickness and PPROM by ultrasound. CONCLUSIONS: Fetal membrane thickness could have relevant clinical ramifications for the prediction of PPROM. Suggested improvements in study methodology and design will lead to progress in this area of research, as well as the use of newer technologies. Larger sample sizes, histological comparison, uniform methodologies for data collection, longitudinal study design and expanding data analysis beyond fetal membrane thickness to other properties would expand our knowledge in this field. In addition, transvaginal ultrasound should be utilized to improve resolution, as well as emerging methodologies such as MRI fusion imaging using ultrasound and Shear Wave Elastography.

"There Are No Known Benefits . . .": Considering the Risk/Benefit Ratio of Qualitative Research.

Institutional review boards (IRBs) are responsible for weighing the risks and benefits of research participation. Qualitative researchers note numerous instances where IRB ethical frameworks fail to align with the ethics of their research projects and point out that IRB understandings of the benefits and risks of research often differ from those of the participants they seek to protect. This qualitative cross-case research investigates participants' interview experiences in six qualitative studies that differed in their methods, subject of focus, and populations. Our findings indicate that contemporary IRBs' use of population "vulnerability" and topic "sensitivity" to assess project risk does not adequately determine the benefits, risks, or ethicality of research. We recommend that IRBs treat as real the evidence for benefits in qualitative research, recognize that sensitivity and vulnerability do not predict risk, and encourage researchers to attend to relationships in their projects.

The prevalence of occult hepatitis B virus (HBV) infection in a large multi-ethnic haemodialysis cohort.

BACKGROUND: Haemodialysis patients are at increased risk of exposure to blood borne viruses. To reduce transmission in the UK, all haemodialysis patients are regularly screened, and if susceptible to Hepatitis B virus (HBV) infection, vaccinated. METHODS: This retrospective study was undertaken to determine the HBV immune status in a large dialysis cohort and the prevalence of occult HBV infection, defined as the presence of anti-HBcore antibody (anti-HBcAb) and HBV DNA without detectable HB surface antigen (HBsAg). Information on HBV status was retrieved from haemodialysis patients under the care of The Royal Free Hospital, London, UK between 2009-2010. Available sera from 138 of 161 anti-HBcAb positive/HBsAg negative individuals were anonymised and tested for HBV DNA by a real time quantitative PCR. RESULTS: 15 (2%) of 793 patients had chronic HBV infection (HBsAg positive). 161 (20%) were anti-HBcAb positive but HBsAg negative suggesting past infection. 335 (54%) of the remaining 617 patients were considered immune following vaccination (anti-HBsAb > 10 IU/L). Three (2.2%) of the 138 anti-HBcAb positive, HBsAg negative patients had detectable HBV DNA (3, 5 and 9 IU/ml). Standard liver function tests were normal in these patients. CONCLUSIONS: In a large multi-ethnic London haemodialysis cohort, 20% patients had evidence of past HBV infection. Despite this, the prevalence of occult HBV was found to be low and the very low levels of HBV DNA detected are unlikely to pose a nosocomial transmission risk in the presence of robust vaccination and infection control measures.

Changing the paradigm from contraction of peritoneal dialysis programs to increasing prevalent peritoneal dialysis numbers.

Compared with other European and North American countries, the United Kingdom traditionally had proportionally more dialysis patients treated by peritoneal dialysis. However as in many economically developed countries, peritoneal dialysis numbers have fallen in the United Kingdom, particularly since the early 2000s. In an effort to increase home-based dialysis therapies, the U.K. Department of Health introduced a new system of reimbursement tariffs favoring peritoneal dialysis and home hemodialysis compared with standard hospital-based hemodialysis. Here, we report how our own center responded to the impending change in reimbursement rates and turned what had been a declining peritoneal dialysis program into one that almost doubled in size within 3 years.

Complexity leadership in action: a team science case study.

Introduction: This team science case study explores one cross-disciplinary science institute's change process for redesigning a weekly research coordination meeting. The narrative arc follows four stages of the adaptive process in complex adaptive systems: disequilibrium, amplification, emergence, and new order. Methods: This case study takes an interpretative, participatory approach, where the objective is to understand the phenomena within the social context and deepen understanding of how the process unfolds over time and in context. Multiple data sources were collected and analyzed. Results: A new adaptive order for the weekly research coordination meeting was established. The mechanism for the success of the change initiative was best explained by complexity leadership theory. Discussion: Implications for team science practice include generating momentum for change, re-examining power dynamics, defining critical teaming professional roles, building multiple pathways towards team capacity development, and holding adaptive spaces. Promising areas for further exploration are also presented.

Hyaluronan binding identifies the most proliferative activated and memory T cells.

CD44 is expressed on T cells where its ability to bind hyaluronan is tightly regulated. Here, we investigated when T cells bind hyaluronan during an immune response. We found that naïve, murine T cells do not bind fluoresceinated hyaluronan but are induced to bind upon antigen-induced T-cell activation in vitro and in vivo. Hyaluronan binding occurred on proliferating T cells and the percentage of hyaluronan-binding cells correlated with the strength of the activation stimulus. A small percentage of hyaluronan-binding cells persisted after in vitro activation and had a memory phenotype (CD122(+) CD44(hi)). This hyaluronan-binding population increased after culture with IL-7 or IL-15 and proliferated more rapidly than nonbinding cells. In vivo, approximately 20-30% of antigen-specific OT-I CD8(+) memory T cells in the spleen and BM bound hyaluronan. Hyaluronan binding identified memory cells that proliferated faster in IL-7 and IL-15, and enriched for CD62L(+) central memory cells. In vivo homeostatic proliferation induced hyaluronan binding on a small percentage of the most rapidly dividing cells after several cell divisions. This study demonstrates that hyaluronan binding is induced upon antigen-induced T-cell activation and occurs on a percentage of the most proliferative activated and memory T cells.

Fortuitous vasculitis.

A 43-year-old man with a cardiac device for dilated cardiomyopathy presented with fever, night sweats, and weight loss. Investigations revealed pancytopenia, acute renal failure, abnormal lung function, and raised inflammatory markers. A renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis. He was diagnosed with pulmonary-renal antineutrophil cytoplasmic antibody-negative systemic small vessel vasculitis. He commenced immunosuppression with prednisolone and cyclophosphamide with recovery from pancytopenia and improvement in renal function 3 months later. Subsequently, a bone marrow culture grew Mycobacterium fortuitum. Isolation on repeat peripheral mycobacterial blood cultures prompted treatment with ciprofloxacin and clarithromycin. Four months later, he presented with neutropenic sepsis, influenza A/H1N1, and Aspergillus flavus pneumonia. Despite treatment he deteriorated. A transthoracic echocardiogram revealed a vegetation on the right ventricular pacing wire. The device was removed. The vegetation revealed acid and alcohol fast bacilli on Ziehl-Neelsen staining and grew M. fortuitum on culture, sensitive to ciprofloxacin and clarithromycin. Despite device removal and antimicrobial therapy, the patient succumbed to treatment-related complications. The association between glomerulonephritis and endocarditis is well known; however, this is the first case to our knowledge describing pauci-immune necrotizing crescentic glomerulonephritis in the context of M. fortuitum endocarditis. Clinicians should maintain a high index of suspicion for endocarditis in patients with a cardiac device who present with fever and pauci-immune necrotizing crescentic glomerulonephritis. Patients should be investigated with mycobacterial blood cultures, at least three sets of standard blood cultures and transthoracic and transesophageal echocardiography. Clinicians should beware the perils of immunosuppression in the face of an occult sepsis.

Feasibility of an adaptive riding pilot study and acceptability to dementia care partners: "Your spirits are lifted".

OBJECTIVES: We sought to assess the feasibility and acceptability of an adaptive riding program with dyads (persons living with dementia, family care partners) and a gardening comparison condition. DESIGN: This is a two-arm (adaptive riding and adaptive gardening), mixed methods, convergent, feasibility study that occurred February 2019-June 2019. INTERVENTIONS: Upon enrollment, dyads (n=9) self-selected into either community-based adaptive riding (n=5) or adaptive gardening (n=4), two complementary interventions in Northern Colorado. Interventions occurred for hour-long, weekly sessions for eight weeks. OUTCOME MEASURES: Feasibility was measured with recruitment (actual/planned, response rate, participants enrolled/month) retention, adherence to study procedures (attendance, retention, fidelity), and data collection processes (planned versus collected); and analyzed with descriptive statistics. Acceptability of adaptive riding was measured with pre/post care partner interviews and analyzed using thematic analysis. Afterwards, findings were converged. RESULTS: We recruited n=10/24 dyads (6 dyads per month), with the highest response rates for referrals and in-person events, n=9 dyads enrolled. We adhered to study procedures with attendance (6/8 gardening, 8/8 riding), retention (100%), fidelity (100%) and data collected (98%). Care partners (n=5) found the adaptive riding intervention acceptable with two themes Overall hopes: "Joy in the present moment" and "Experience as a Whole: "Your spirits are lifted," affirming quantitative attendance and retention data. CONCLUSION: Findings underscore the feasibility and acceptability of including care partners of persons living with dementia in complementary interventions involving horsemanship activities. Feasibility data can guide study designs and implementation processes for other nature-based complementary interventions for this population.

Associations of parental and peer characteristics with adolescents' social dominance orientation.

Studies with adults of social dominance orientation (SDO), a preference for inequality among social groups, have found correlations with various prejudices and support for discriminatory practices. This study explores the construct among adolescents at an age when they are beginning to recognize the social groups in their environment, particularly adolescent crowds. The relationship of SDO and perceptions of parents' responsiveness and demandingness were also investigated. Subjects were in grades 9-12 (N = 516, 53% female, 96% White). Mother's and father's responsiveness significantly predicted adolescent's SDO scores, with greater perceived responsiveness associated with lower SDO. To analyze the multiple crowd memberships of the 76% belonging to more than one crowd, two-step cluster analysis was used to identify patterns, resulting in 8 clusters of distinct, heterogeneous composition. SDO differed significantly among males in different clusters, but not females. The importance of membership was positively associated with SDO among high-status crowds and negatively associated with SDO among the academic and normal crowds. The findings have implications for prejudices that may be developing in adolescence and indicate a need for further research into the social context of SDO and its development.

Surviving and Thriving: Qualitative Results from a Multi-Year, Multidimensional Intervention to Promote Well-Being among Caregivers of Adults with Dementia.

(1) Introduction: Caring for an adult with dementia is both challenging and rewarding. Research indicates that community-based, social support, and/or arts engagement interventions can play a key role in ameliorating the negative outcomes associated with caregiving while enhancing its more positive attributes. This study explores the psychosocial outcomes experienced by dementia caregivers who participated in a multi-year, multidimensional intervention aimed at promoting caregiver and care recipient well-being. This intervention included bringing caregivers and people with Alzheimer's disease or related dementias (ADRD) to local symphony performances, hosting a social reception prior to the performance, and assessing the outcomes of participation for both caregiver and the care recipient. (2) Materials, Methods, and Analysis: Qualitative data from participant phone interviews (n = 55) as well as focus groups are analyzed using thematic analysis from a phenomenological perspective. (3) Results: Across three years of participation, caregivers reported three main program benefits: relationship building (both with other participants as well as within the broader community); restored humanity (experiencing a greater sense of personal dignity and momentary return to normalcy), and positivity (experiencing positive emotions during the program). (4) Discussion: These findings point to the value of creating caregiver programming that brings together multiple dimensions of successful interventions in order to enhance caregiver experiences and positive intervention outcomes.

A comparison of quality of life indicators during two complementary interventions: adaptive gardening and adaptive riding for people with dementia.

OBJECTIVES: We sought to provide a fine-grain description and comparison of how people living with dementia responded to adaptive gardening and adaptive riding through durations of their observed participation and emotional well-being, two dimensions of quality of life. DESIGN: A descriptive case study design enabled in-depth description and comparison of participation and emotional well-being, two quality of life indicators, observed during four videotaped sessions of adaptive gardening and adaptive riding. INTERVENTIONS: Eight people living with dementia self-selected into one of two complementary interventions, community-based adaptive gardening (n = 4) or adaptive riding (n = 4), in Northern Colorado. Both occurred for hour-long, weekly sessions for eight-weeks. OUTCOME MEASURE: Durations of observed quality of life indicators of participation and apparent affect were documented using a modified version of the Activity-in-Context-in-Time on 31 hours of videotaped data. Durations for each quality of life indicator were averaged per participant and aggregated by group for comparison using a Wilcoxon Mann-Whitney U test RESULTS: Both interventions supported emotional well-being and participation. Longer durations of active participation were observed during adaptive riding with significantly higher durations of complex active participation (U = 16, p= 0.029). CONCLUSION: Both interventions supported quality of life and merit continued development. Adaptive riding appeared to support longer durations of active participation with more complex forms when compared to adaptive gardening. Findings can inform healthcare providers' recommendations for adaptive gardening and adaptive riding for people with dementia. More research is needed with a larger sample size to further examine similarities and differences.

Obesity as a Risk Factor for Radiographic Contrast-Induced Nephropathy.

Contrast-induced nephropathy (CIN) is common. Risk factors include preexisting renal impairment, diabetes, elderly age, and dehydration. In a single-centre prospective study, we investigated which factors are implicated for CIN in patients with peripheral arterial disease due for angiography. Serum creatinine was measured before, 1, 2, and 7 days post-angiography. We also considered the chronic kidney disease stage of the patients at admission and 48 hours post-contrast. All patients received 500 mL normal saline pre- and post-angiography and a low-osmolality contrast medium. 6 of 94 patients developed CIN: 1 required dialysis and 1 died partly due to renal failure. Only 2 factors were associated with CIN: body mass index (BMI; P = .019) and kidney function (P = .001); 4 of 6 patients with CIN were obese (BMI ≥30) and only 2 were nonobese (P = .0092). Diabetes, contrast volume, and age were not significant risk factors. Our results confirm renal impairment raises the risk of CIN. To our knowledge, we report for the first time that obesity may be a risk factor for CIN. Pending confirmatory studies and given the rising prevalence of obesity, this finding could help identify at-risk patients and hence reduce the burden of CIN.

Tiny Bodies, Big Needs: Prospective Biobanking of Neonatal Clinical Remnant Samples.

Repurposing biological samples collected for required diagnostic purposes into suitable biobanking projects is a particularly useful method for enabling research in vulnerable populations. This approach is especially appropriate for the neonate in the neonatal intensive care unit (NICU), where blood volume reductions can quickly increase beyond minimal risk for adverse events, such as iatrogenic anemia, and proxy consent provided by parents or guardians is required. The method described in this study provides a framework to prospectively collect and store blood-derived clinical samples after all clinical and regulatory requirements are fulfilled. The consent approach incorporated a 30-day window to allow parents and guardians ample consideration time with follow-up involvement with NICU embedded study team members. The study enrolled 875 participants over a 3-year period. This established a critically needed biobank to support investigator-initiated research with explicit study aims requiring samples at defined day of life frequencies within the NICU and created a normative control reference bank for case comparisons for premature and full-term neonates with brain injury.

Tyrosine phosphorylation in immune cells: direct and indirect effects on toll-like receptor-induced proinflammatory cytokine production.

Tyrosine phosphorylation is a key means of signal transduction in the immune system, initiating signals from antigen receptors, integrins, and cytokine receptors. Tyrosine phosphorylation is regulated by the balance of tyrosine kinase and tyrosine phosphatase activities. Src family kinases are prevalent in leukocytes and play critical roles in many signaling pathways present in immune cells. For example, they are the key kinases that phosphorylate both immunoreceptor tyrosinebased activation and inhibitory motifs. CD45 is a leukocyte-specific, transmembrane protein tyrosine phosphatase and an important regulator of Src family kinase activity. Here, we briefly review the importance of tyrosine phosphorylation in key signaling pathways in immune cells and then review the accumulating evidence for tyrosine phosphorylation in Toll-like receptor (TLR) signaling leading to proinflammatory cytokine and type I interferon production. We examine how tyrosine phosphorylation directly impacts TLR signaling pathways and review the involvement of specific tyrosine kinases and phosphatases. Finally, we consider how tyrosine phosphorylation signals from other signaling pathways integrate with the TLR signaling pathway to modulate proinflammatory cytokine production.

More than just nickels and dimes: a cross-national analysis of working poverty in affluent democracies.

Despite its centrality to contemporary inequality, working poverty is often popularly discussed but rarely studied by sociologists. Using the Luxembourg Income Study (2009), we analyze whether an individual is working poor across 18 affluent democracies circa 2000. We demonstrate that working poverty does not simply mirror overall poverty and that there is greater cross-national variation in working than overall poverty. We then examine four explanations for working poverty: demographic characteristics, economic performance, unified theory, and welfare generosity. We utilize Heckman probit models to jointly model the likelihood of employment and poverty among the employed. Our analyses provide the least support for the economic performance explanation. There is modest support for unified theory as unionization reduces working poverty in some models. However, most of these effects appear to be mediated by welfare generosity. More substantial evidence exists for the demographic characteristics and welfare generosity explanations. An individual's likelihood of being working poor can be explained by (a) a lack of multiple earners or other adults in one's household, low education, single motherhood, having children and youth; and (b) the generosity of the welfare state in which he or she resides. Also, welfare generosity does not undermine employment and reduces working poverty even among demographically vulnerable groups. Ultimately, we encourage a greater role for the welfare state in debates about working poverty.