Monday-Enhanced CEASE Program for Underserved Ethnic Minorities: a Mixed-Methods Study.

BACKGROUND: Due to the persistence of tobacco-related health disparities in the U.S., there is a need for innovative strategies to reach the underserved ethnic minority populations who are most at risk. As contemplations for health behavior modification tend to surge on Mondays, we explored the feasibility and effect of a Monday-enhanced smoking cessation program on quitting outcomes in a low-income ethnic minority community. AIMS: To compare a Monday-enhanced with a standard Communities Engaged and Advocating for a Smoke-free Environment (CEASE) program and understand the overall experiences of participants in the program. METHODS: In this mixed-methods study, affordable housing complexes (n = 4) and a church were randomly assigned either a Monday-enhanced (n = 3) or standard (n = 2) CEASE smoking cessation program. CEASE comprised twelve weekly group counseling sessions facilitated by trained peer motivators plus nicotine replacement products. Participants in the Monday-enhanced arm were encouraged to pick Mondays as a quitting day. Quantitative and qualitative data were collected during the program and at 3-month post-graduation. RESULTS: Seventy-seven participants were enrolled in the study arms. In both groups combined, tobacco consumption reduced from 7.7 to 5.6 cig/day (mean reduction, 2.1; 95% CI: 0.9 to 5.1, p = 0.08). Although no significant difference in quit rate was observed between the two arms, more participants completed the follow-up survey in the Monday-enhanced than standard CEASE program [82.4% vs. 36.0%, p < 0.05]. While qualitative data suggested an overall satisfaction of participants with the program, motivation for quitting was higher in the Monday-enhanced CEASE program compared to the standard CEASE program. CONCLUSION: The Monday-enhanced program is promising and may enhance participants' engagement and willingness to quit smoking, particularly in low-income ethnic minority communities. Further research should include larger sample sizes to better assess the efficacy of a Monday-enhanced program across diverse populations.

Apmerrke Areye-kenhe Utnenge Rlterrke-irrirtne-tyenhenge.

Arrurle-nge-ntyele researchers lhentere areye-le intelhe-ilepe-ileme apmerrke areye-akerte. Itne akaltye-arle-irreke apmerrke areye akwele urreme-urreme-irreme, utnenge alhwarrpe awelhemele. Kenhe alhentere nhenhe areye akaltye-irretyakenhe iwenhenge-arle apmerrke areye alakenhe anerlte-aneme. Itne itelaretyakenhe nthakenhe-arle arne ingkirreke urrperle-areye-kenhe-le apmerrke areye atnerre ilirtnemere. Researchers itne akaltye-irreke artwe apmerrke Central Australia-arenye-arle akwele health akurne anthurre-ulkere, Australia arenye-arrpenhe areye-nge. Arrpenheme apeke clinic-werne alheme, kenhe itne akenhe itelaretyakenhe iwenhe-arle alhentere ngangkere-le itneke ileme, health itnekenhe-akerte, medications-akerte-arlke. Artwe atningke apeke itelaretyakenhe iwenhenge-arle itne ilkelhetyakenhe uthene akangketyakenhe uthene. The kwenhe PhD project mpwarerle-aneme apmerrke anwerneke-akerte. Anwerne ahentye aneme apmerrke areye atyenpe-irrirtnetyeke, atnerre anemele. Project nhenhe arne atyeperre anwerne-kenhe areye-akerte, angkentye, anpernirrentye, nthakenhe angkentye anwernekenhe intelhetyeke, anyenhenge, apmere-kenhe arritnye ingkirreke, thipe-kenhe arritnye, arne-kenhe arritnye, atnunthe apmere-altye-arlke. Apmerrke areye kwenhe akaltye-irretyeke nthakenhe English angketyeke, read-eme-iletyeke, intelhetyeke-arlke. Apmerrke areye apeke akaltye-irretyeke Akngerrepate arrwekelenye areye-ke, arne mwerre areye itne-arle mpware-warretyarte, kele itne anteme itnenhe ingkentetyeke. Artwe akaperte altywere-areye role models anwernekenhe aneme. 1930's-nge-ntyele governments-le laws mpwareke arritnye Assimilation Policy. Yanhe-iperre, atningke areye uye-akaltye-irreke urrperle-kenhe arne areye-kenhe-ke. Alhentere areye-le anamelhe-ileke arrpenheme apmere itnekenhe-nge-ntyele bungalow-atheke, ayerrere-werne atheke, antekerre-arlke. Assimilation Policys-nge ularre, tyerrtye atningke angkentye-ke uye akaltye-irreke, apmere-akerte, apmere-ke-artweye-ke, kwertengwerle-ke, laws anwernekenhe-arlke. Lhentere arrpenheme ahentye-aneke akaltye-irretyeke Tywerrenge-ke. Arne arrpenheme-ke itne-arle akaltye-irreke artwe-kenhe-ante, kenhe arrpenhe akenhe ingkirreke-ke. Arne nhenhe areye museums-uthene-le organisations arrpenhe areye uthene-le akwete atnyeneme. Alhentere areye-le itnenhe akeme "archives." Itnekenge-ntyele anwerne apmerrke areye akaltye-le-anthetyeke, nthakenhe arrwekelenye anwernekenhe anirntyeke-arteke. Kele, the pipe nhenhe intelhe-ileke apmerrke itnenhe alpeme-iletyeke rlterrke-irrirtnetyeke.

Increasing angiotensin-converting enzyme concentrations and absent angiotensin-converting enzyme activity are associated with adverse kidney outcomes in pediatric septic shock.

BACKGROUND: Sepsis-induced endothelial dysfunction is proposed to cause angiotensin-converting enzyme (ACE) dysfunction and renin-angiotensin-aldosterone system (RAAS) derangement, exacerbating vasodilatory shock and acute kidney injury (AKI). Few studies test this hypothesis directly, including none in children. We measured serum ACE concentrations and activity, and assessed their association with adverse kidney outcomes in pediatric septic shock. METHODS: A pilot study of 72 subjects aged 1 week-18 years from an existing multicenter, observational study. Serum ACE concentrations and activity were measured on Day 1; renin + prorenin concentrations were available from a previous study. The associations between individual RAAS components and a composite outcome (Day 1-7 severe persistent AKI, kidney replacement therapy use, or mortality) were assessed. RESULTS: 50/72 subjects (69%) had undetectable ACE activity (< 2.41 U/L) on Day 1 and 27/72 (38%) developed the composite outcome. Subjects with undetectable ACE activity had higher Day 1 renin + prorenin compared to those with activity (4533 vs. 2227 pg/ml, p = 0.017); ACE concentrations were no different between groups. Children with the composite outcome more commonly had undetectable ACE activity (85% vs. 65%, p = 0.025), and had higher Day 1 renin + prorenin (16,774 pg/ml vs. 3037 pg/ml, p < 0.001) and ACE concentrations (149 vs. 96 pg/ml, p = 0.019). On multivariable regression, increasing ACE concentrations (aOR 1.01, 95%CI 1.002-1.03, p = 0.015) and undetectable ACE activity (aOR 6.6, 95%CI 1.2-36.1, p = 0.031) retained associations with the composite outcome. CONCLUSIONS: ACE activity is diminished in pediatric septic shock, appears uncoupled from ACE concentrations, and is associated with adverse kidney outcomes. Further study is needed to validate these findings in larger cohorts.

Exogenous nitric oxide delivery protects against cardiopulmonary bypass-associated acute kidney injury: Histologic and serologic evidence from an ovine model.

OBJECTIVE: Several human studies have associated nitric oxide administration via the cardiopulmonary bypass circuit with decreased incidence of cardiopulmonary bypass-associated acute kidney injury, but histopathologic and serologic evidence of nitric oxide efficacy for acute kidney injury attenuation are lacking. METHODS: By using a survival ovine model (72 hours), acute kidney injury was induced by implementing low-flow cardiopulmonary bypass for 2 hours, followed by full-flow cardiopulmonary bypass for 2 hours. The nitric oxide cohort (n = 6) received exogenous nitric oxide through the cardiopulmonary bypass circuit via the oxygenator, and the control group (n = 5) received no nitric oxide. Serial serologic biomarkers and renal histopathology were obtained. RESULTS: Baseline characteristics (age, weight) and intraoperative parameters (cardiopulmonary bypass time, urine output, heart rate, arterial pH, and lactate) were equivalent (P > .10) between groups. Postoperatively, urine output, heart rate, respiratory rate, and peripheral arterial saturation were equivalent (P > .10) between groups. Post-cardiopulmonary bypass creatinine elevations from baseline were significantly greater in the control group versus the nitric oxide group at 16, 24, and 48 hours (all P < .05). Histopathologic evidence of moderate/severe acute kidney injury (epithelial necrosis, tubular slough, cast formation, glomerular edema) occurred in 60% (3/5) of the control group versus 0% (0/6) of the nitric oxide group. Cortical tubular epithelial cilia lengthening (a sensitive sign of cellular injury) was significantly greater in the control group than in the nitric oxide group (P = .012). CONCLUSIONS: In a survival ovine cardiopulmonary bypass model, nitric oxide administered with cardiopulmonary bypass demonstrated serologic and histologic evidence of renal protection from acute kidney injury. These results provide insight into 1 potential mechanism for cardiopulmonary bypass-associated acute kidney injury and supports continued study of nitric oxide via cardiopulmonary bypass circuit for prevention of acute kidney injury.

Manual single lumen alternating micro-batch dialysis achieves reliable clearance via diffusion.

BACKGROUND: Acute kidney injury is a cause of preventable deaths in low resource settings due to lack of dialysis access and cost. A manual single lumen alternating micro-batch (mSLAMB) dialysis technique performs kidney replacement therapy using single lumen access, low-cost bags/tubing, intravenous fluids, and a filter without electricity, a battery, or a pump. We propose a protocol whereby mSLAMB can perform diffusive clearance simply and efficiently to bring dialysis to underserved populations. METHODS: Expired packed red blood cells mixed with crystalloid solution were spiked with urea and anticoagulated with heparin. A Static diffusion Technique (with short flushes of fluid before each filter pass) was compared to a Dynamic diffusion Technique (with fluid running through the filter during the forward pass) to assess urea and potassium clearance. Passive ultrafiltration was the difference between the 200 mL batch volume and volume returned to the blood bag per cycle. RESULTS: Five cycles achieved urea reduction ratios (URR) between 17-67% and potassium clearance of 18-60%, with higher percentages achieved from higher proportions of batch volume dialyzed to patient volume. Dynamic Technique increased clearance over the Static Technique. Passive ultrafiltration volumes were 2.5-10% of batch volume. CONCLUSION: mSLAMB dialysis performs diffusive clearance and passive ultrafiltration efficiently, while preserving resources and available manpower. IMPACT: mSLAMB is a dialysis technique that can perform efficient diffusive clearance and passive ultrafiltration without electricity, batteries, or a pump. With basic medical supplies and limited manpower, mSLAMB is a cost-effective means of providing emergency dialysis in low resource areas. We propose a basic algorithm for safe and cost-effective dialysis for people of different ages and sizes.

Acute kidney injury biomarker olfactomedin 4 predicts furosemide responsiveness.

BACKGROUND: Acute kidney injury (AKI) is associated with increased morbidity and mortality in critically ill patients. Olfactomedin 4 (OLFM4), a secreted glycoprotein expressed in neutrophils and stressed epithelial cells, is upregulated in loop of Henle (LOH) cells following AKI. We hypothesized that urine OLFM4 (uOLFM4) will increase in patients with AKI and may predict furosemide responsiveness. METHODS: Urine from critically ill children was collected prospectively and tested for uOLFM4 concentrations with a Luminex immunoassay. Severe AKI was defined by KDIGO (stage 2/3) serum creatinine criteria. Furosemide responsiveness was defined as > 3 mL/kg/h of urine output in the 4 h after a 1 mg/kg IV furosemide dose administered as part of standard of care. RESULTS: Fifty-seven patients contributed 178 urine samples. Irrespective of sepsis status or AKI cause, uOLFM4 concentrations were higher in patients with AKI (221 ng/mL [IQR 93-425] vs. 36 ng/mL [IQR 15-115], p = 0.007). uOLFM4 concentrations were higher in patients unresponsive to furosemide (230 ng/mL [IQR 102-534] vs. 42 ng/mL [IQR 21-161], p = 0.04). Area under the receiver operating curve for association with furosemide responsiveness was 0.75 (95% CI, 0.60-0.90). CONCLUSIONS: AKI is associated with increased uOLFM4. Higher uOLFM4 is associated with a lack of response to furosemide. Further testing is warranted to determine whether uOLFM4 could identify patients most likely to benefit from earlier escalation from diuretics to kidney replacement therapy to maintain fluid balance. A higher resolution version of the Graphical abstract is available as Supplementary information.

Distinct transcriptomic and epigenomic modalities underpin human memory T cell subsets and their activation potential.

Human memory T cells (MTC) are poised to rapidly respond to antigen re-exposure. Here, we derived the transcriptional and epigenetic programs of resting and ex vivo activated, circulating CD4+ and CD8+ MTC subsets. A progressive gradient of gene expression from naïve to TCM to TEM is observed, which is accompanied by corresponding changes in chromatin accessibility. Transcriptional changes suggest adaptations of metabolism that are reflected in altered metabolic capacity. Other differences involve regulatory modalities comprised of discrete accessible chromatin patterns, transcription factor binding motif enrichment, and evidence of epigenetic priming. Basic-helix-loop-helix factor motifs for AHR and HIF1A distinguish subsets and predict transcription networks to sense environmental changes. Following stimulation, primed accessible chromatin correlate with an augmentation of MTC gene expression as well as effector transcription factor gene expression. These results identify coordinated epigenetic remodeling, metabolic, and transcriptional changes that enable MTC subsets to ultimately respond to antigen re-encounters more efficiently.

Manual Single-Lumen Alternating Micro-Batch Device as Renal Replacement Therapy in Austere Environments.

INTRODUCTION: Electrolyte derangements, acidosis, and volume overload remain life-threatening emergencies in people with acute kidney injury in austere environments. A single-lumen alternating micro-batch (SLAMB) dialysis technique was designed to perform renal replacement therapy using a single-lumen access, low-cost disposable bags and tubing, widely available premade fluids, and a dialysis filter. A manual variation (mSLAMB) works without electricity, battery, or a pump. We modeled mSLAMB dialysis and predicted it could achieve adequate small solute clearance, blood flow rates, and ultrafiltration accuracy. METHODS: A 25- to 30-kg pediatric patient's blood volume was simulated by a 2-L bag of expired blood and spiked with 5 g of urea initially, then with 1-2 g between experiments. Experiments had 8 cycles totaling prescription volumes of 800-2,400 mL and were conducted with different ratios of hemofiltration fluid to blood volume. Concentrations of urea and potassium, final effluent volumes, and cycle duration were measured at the end of each cycle to determine clearance, ultrafiltration accuracy, and blood flow rates. RESULTS: Each cycle lasted 70-145 s. Experiments achieved a mean urea reduction ratio of 27.4 ± 7.1% and a mean potassium reduction of 23.4 ± 9.3%. The largest urea and potassium reduction percentage occurred with the first cycle. Increased hemofiltration fluid to blood volume ratio did not increase clearance. Mean (+/- standard deviation) blood flow ranged from 79.7 +/- 4.4 mL/min to 90.8 +/- 6.5 mL/min and increased with larger batch volume and height difference between reservoirs. Ultrafiltration accuracy ranged from 0 to 2.4% per cycle. DISCUSSION: mSLAMB dialysis is a simple, manual, cost-effective mode of dialysis capable of providing clearance and accurate ultrafiltration. With further refinement of technique, we believe this can be a potentially lifesaving treatment in austere conditions and low-resource settings.

Stability of novel urinary biomarkers used for lupus nephritis.

Background: The Renal Activity Index for Lupus (RAIL) is a composite score of six urinary biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1), kidney injury molecule-1 (KIM-1), ceruloplasmin, adiponectin, and hemopexin) used to monitor lupus nephritis activity in children. We tested stability of RAIL biomarkers prior to meaningful clinical use. Methods: Urine samples were tested by ELISA under shipping conditions, freeze/thaw, ambient and longer-term storage. Statistical analysis was performed via Deming Regression, Bland-Altman and Spearman Correlation Coefficient. Results: Biomarker concentration were comparable to freshly collected urine following storage at -80 °C for up to 3 months, and at 4 or 25 °C up to 48 h followed by -80 °C. Neither shipping on dry or wet ice exposure nor addition of two freeze-thaw cycles led to loss of signal, with excellent Spearman Correlation coefficients under all conditions. Conclusions: RAIL biomarkers are stable following short-term storage at clinically relevant conditions.

Clinical measurement of lupus nephritis activity is inferior to biomarker-based activity assessment using the renal activity index for lupus nephritis in childhood-onset systemic lupus erythematosus.

OBJECTIVES: The renal activity index for lupus (RAIL) measures lupus nephritis (LN) activity considering urine levels of 6 biomarkers (neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, kidney injury molecule-1, adiponectin, haemopexin, ceruloplasmin). We aimed to compare the accuracy of the RAIL and the renal domain-score of the SLE disease activity index (rSLEDAI) in detecting LN activity. METHODS: Random urine samples of patients with childhood-onset SLE with and without LN were assayed and scores of the RAIL, and RAIL standardised for urine creatinine (RAIL-Cr) were calculated. Clinical LN activity was measured by the rSLEDAI, and histological activity of LN was categorised as inactive/low-moderate/high for National Institute of Health-activity index scores of <2/2-10/>10, respectively. RESULTS: 115 patients were included in the analysis (47 patients without and 68 with LN). RAIL, RAIL-Cr and rSLEDAI scores at the time (±3 months) of kidney biopsy were available for 32 patients. Median rSLEDAI, RAIL and RAIL-Cr values were 4, -0.04, 0.02 for inactive LN, 12, 0.7 and 0.9 for low-moderate LN activity and 12, 2 and 1.8 for high LN activity, respectively. The area under the receiver operating characteristic curve (AUC) to capture high LN activity was the lowest for the rSLEDAI (AUC=0.62), followed by the RAIL-Cr (AUC=0.73) and RAIL (AUC=0.79). Notably, when testing urine samples collected during routine clinic visits remote (>3 months) from a kidney biopsy, 50% patients with rSLEDAI scores of 0 had RAIL scores reflecting low-moderate LN activity. CONCLUSION: Monitoring of renal inflammation in children and adolescents with SLE can be improved by the measurement of urine biomarkers. The RAIL may constitute important auxiliary tool for the surveillance of LN in a clinical setting and assist with the decision to obtain a kidney biopsy.

Cell-Free DNA, Neutrophil extracellular traps (NETs), and Endothelial Injury in Coronavirus Disease 2019- (COVID-19-) Associated Acute Kidney Injury.

Introduction: Neutrophil extracellular traps (NETs) release (i.e., NETosis) has been recently implicated in the pathomechanism underlying severe end-organ damage in Coronavirus Disease 2019 (COVID-19) and could present a novel therapeutic target. We aimed to determine whether circulating levels of cell-free DNA (cfDNA), a surrogate for NETosis, may be associated with the development of acute kidney injury (AKI), a major contributor to poor outcomes and mortality in COVID-19. Methods: Blood samples were collected prospectively from adult patients infected with SARS-CoV-2 presenting to the emergency department (ED). Circulating levels of cfDNA were quantified from patients' serum. Further assessment of correlations between cfDNA levels and markers of AKI (i.e., serum creatinine (SCr), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL)), biomarkers of thrombotic microangiopathy and of inflammation in patients' serum was performed. Results: Fifty-one COVID-19 patients were enrolled. cfDNA levels were found to be significantly higher in those who developed severe AKI (p < 0.001) and those needing renal replacement therapy (p = 0.020). cfDNA positively correlated with ED SCr, NGAL, cystatin C, neutrophil count, neutrophil-to-lymphocyte ratio, C3a, C5a, Scb5-9, IL-6, IL-8, IL-10, TNF-α, LDH, CRP, ferritin, and fibrinogen and negatively correlated with ADAMTS13/von-Willebrand factor ratio and lymphocyte count. In a multivariate logistic regression, a one-unit increase in cfDNA value was associated with 4.6% increased odds of severe AKI (OR = 1.046; p = 0.040). Finally, cfDNA significantly correlated with established NETs components, myeloperoxidase, and neutrophil elastase. Conclusion: Intravascular NETosis could be an important contributing factor in the development of microthrombosis and COVID-19-associated AKI. Further research is urgently needed to understand the role of NETosis in COVID-19 and evaluate therapeutic avenues for targeting this process.

Neurological manifestations of Kyasanur Forest disease: a retrospective cohort study from South India.

BACKGROUND: Kyasanur Forest disease (KFD) is a viral zoonotic disease where patients present with febrile illness and haemorrhagic manifestations in the first phase. In a small fraction of patients, the fever may be biphasic. This study aimed to describe the neurological manifestations of patients with KFD in the first and second phases of the illness. METHODS: This is a retrospective cohort study of 297 patients admitted with a molecular diagnosis of KFD from December 2018 to December 2020. The case records of these patients were reviewed for evidence of neurological involvement. RESULTS: A total of 34 (11.5%) patients in the first phase and 16 (36.4%) patients in the second phase had neurological involvement. Altered sensorium, seizures and focal infarcts were common in the first phase, while cerebellar signs and leptomeningeal enhancement were common in the second phase. CONCLUSIONS: Neurological involvement is seen in both phases of KFD. While in the first phase it is a result of possible encephalitis/encephalopathy, the second phase involvement is possibly due to postinfectious cerebellitis or meningitis.

New thinking about old ways: Cultural continuity for improved mental health of young Central Australian Aboriginal men.

Decades of reports and policy have drawn attention to the significant social and occupational impairment of many young Aboriginal men in Central Australia. However, the role of mental ill-health as a contributing factor to this impairment, and culturally appropriate intervention targets have received insufficient attention in the psychiatry literature. Despite having the worst health outcomes of any population in Australia, Aboriginal men chronically underuse primary health care services. It's proposed that interventions ensuring cultural continuity through Identity-strengthening with a particular focus on positive Aboriginal masculinities will address a critical mental health gap for young men. In Central Australian and broader Indigenous populations, tangible and measurable kinship, language, religious and economic (KLRE) activities are catalytic vehicles for restoring traditional knowledge that suffer ongoing pressures as a result of colonization and assimilationist Government policy. By transforming KLRE knowledge content from ethnographic archives, these culturally rich repositories may be utilized to create education and engagement materials that will support young Aboriginal men's efforts to obtain and maintain positive mental health. This proposal focuses on building resilience through the acquisition of KLRE knowledge which young Aboriginal men can utilize as resources for enhancing positive identity and mental health outcomes.

Digital cognitive behavioural therapy for insomnia and primary care costs in England: an interrupted time series analysis.

BACKGROUND: Sleepio is an automated digital program that delivers digital cognitive behavioural therapy for insomnia (dCBT-I). Sleepio has been proven effective in improving sleep difficulties; however, evidence for the possible impact of Sleepio use on healthcare costs in the UK has not, to the authors' knowledge, previously been developed. AIM: To identify the effect of a population-wide rollout of Sleepio in terms of primary care costs in the NHS in England. DESIGN & SETTING: The study was conducted in the Thames Valley region of England, where access to Sleepio was made freely available to all residents between October 2018 and January 2020. The study relies on a quasi-experimental design, using an interrupted time series (ITS) to compare the trend in primary care costs before and after the rollout of Sleepio. METHOD: Primary care data for people with relevant characteristics from nine general practices in Buckinghamshire was used. Primary care costs include general practice contacts and prescriptions. Segmented regression analysis was used to estimate primary and secondary outcomes. RESULTS: For the 10 705 patients included in the sample, the total saving over the 65-week follow-up period was £71 027. This corresponds to £6.64 per person in the sample or around £70.44 per Sleepio user. Secondary analyses suggest that savings may be driven primarily by reductions in prescribing. CONCLUSION: Sleepio rollout reduced primary care costs. National adoption of Sleepio may reduce primary care costs by £20 million in the first year. The expected impact on primary care costs in any particular setting will depend on the uptake of Sleepio.

An IRF4-MYC-mTORC1 Integrated Pathway Controls Cell Growth and the Proliferative Capacity of Activated B Cells during B Cell Differentiation In Vivo.

Cell division is an essential component of B cell differentiation to Ab-secreting plasma cells, with critical reprogramming occurring during the initial stages of B cell activation. However, a complete understanding of the factors that coordinate early reprogramming events in vivo remain to be determined. In this study, we examined the initial reprogramming by IRF4 in activated B cells using an adoptive transfer system and mice with a B cell-specific deletion of IRF4. IRF4-deficient B cells responding to influenza, 4-hydroxy-3-nitrophenylacetyl-Ficoll, and LPS divided but stalled during the proliferative response. Gene expression profiling of IRF4-deficient B cells at discrete divisions revealed IRF4 was critical for inducing MYC target genes, oxidative phosphorylation, and glycolysis. Moreover, IRF4-deficient B cells maintained an inflammatory gene expression signature. Complementary chromatin accessibility analyses established a hierarchy of IRF4 activity and identified networks of dysregulated transcription factor families in IRF4-deficient B cells, including E-box binding bHLH family members. Indeed, B cells lacking IRF4 failed to fully induce Myc after stimulation and displayed aberrant cell cycle distribution. Furthermore, IRF4-deficient B cells showed reduced mTORC1 activity and failed to initiate the B cell activation unfolded protein response and grow in cell size. Myc overexpression in IRF4-deficient cells was sufficient to overcome the cell growth defect. Together, these data reveal an IRF4-MYC-mTORC1 relationship critical for controlling cell growth and the proliferative response during B cell differentiation.

Serum ACE activity and plasma ACE concentration in patients with SARS-CoV-2 infection.

Significant controversy has arisen over the role of the renin-angiotensin-aldosterone system (RAAS) in COVID-19 pathophysiology. In this prospective, observational study, we evaluated plasma angiotensin converting enzyme (ACE) concentration and serum ACE activity in 52 adults with laboratory-confirmed SARS-CoV-2 infection and 27 non-COVID-19 sick controls. No significant differences were observed in ACE activity in COVID-19 patients versus non-COVID-19 sick controls (41.1 [interquartile range (IQR): 23.0-55.2] vs. 42.9 [IQR 13.6-74.2] U/L, p = .649, respectively). Similarly, no differences were observed in ACE concentration in COVID-19 patients versus non-COVID-19 sick controls (108.4 [IQR: 95.8-142.2] vs. 133.8 [IQR: 100.2-173.7] µg/L, p = .059, respectively). Neither ACE activity (p = .751), nor ACE concentration (p = .283) was associated with COVID-19 severity. Moreover, neither ACE activity, nor ACE concentration was correlated with any inflammatory biomarkers.

The anti-inflammatory cytokine response characterized by elevated interleukin-10 is a stronger predictor of severe disease and poor outcomes than the pro-inflammatory cytokine response in coronavirus disease 2019 (COVID-19).

OBJECTIVES: Severe coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune state. While research has focused on the hyperinflammation, little research has been performed on the compensatory anti-inflammatory response. The aim of this study was to evaluate the anti-inflammatory cytokine response to COVID-19, by assessing interleukin-10 (IL-10) and IL-10/lymphocyte count ratio and their association with outcomes. METHODS: Adult patients presenting to the emergency department (ED) with laboratory-confirmed COVID-19 were recruited. The primary endpoint was maximum COVID-19 severity within 30 days of index ED visit. RESULTS: A total of 52 COVID-19 patients were enrolled. IL-10 and IL-10/lymphocyte count were significantly higher in patients with severe disease (p<0.05), as well as in those who developed severe acute kidney injury (AKI) and new positive bacterial cultures (all p≤0.01). In multivariable analysis, a one-unit increase in IL-10 and IL-10/lymphocyte count were associated with 42% (p=0.031) and 32% (p=0.013) increased odds, respectively, of severe COVID-19. When standardized to a one-unit standard deviations scale, an increase in the IL-10 was a stronger predictor of maximum 30-day severity and severe AKI than increases in IL-6 or IL-8. CONCLUSIONS: The hyperinflammatory response to COVID-19 is accompanied by a simultaneous anti-inflammatory response, which is associated with poor outcomes and may increase the risk of new positive bacterial cultures. IL-10 and IL-10/lymphocyte count at ED presentation were independent predictors of COVID-19 severity. Moreover, elevated IL-10 was more strongly associated with outcomes than pro-inflammatory IL-6 or IL-8. The anti-inflammatory response in COVID-19 requires further investigation to enable more precise immunomodulatory therapy against SARS-CoV-2.

HPV-Related Neovaginal Squamous Cell Carcinoma Presenting as Lung Metastasis after Male-to-Female Gender Confirmation Surgery.

There have been 4 reported cases of squamous cell carcinoma (SCC) of the neovagina in transgender women. In this report, we present another case of neovaginal SCC in a transgender woman, which was HPV-related, with lung metastasis as the initial presentation, and which was also complicated by her previous history of metastatic renal cell carcinoma. This unique case highlights the diagnostic challenges in these unusual scenarios. Through this report, we hope to address the benefits of multidisciplinary tumor board rounds, provision of detailed clinical information, and familiarization of the transgender anatomy within the pelvis in this group of patients. We also propose that transgender women undergo a continuous annual follow-up after postoperative follow-up is completed.

Hydrogen-bonded frameworks for molecular structure determination.

Single crystal X-ray diffraction is arguably the most definitive method for molecular structure determination, but the inability to grow suitable single crystals can frustrate conventional X-ray diffraction analysis. We report herein an approach to molecular structure determination that relies on a versatile toolkit of guanidinium organosulfonate hydrogen-bonded host frameworks that form crystalline inclusion compounds with target molecules in a single-step crystallization, complementing the crystalline sponge method that relies on diffusion of the target into the cages of a metal-organic framework. The peculiar properties of the host frameworks enable rapid stoichiometric inclusion of a wide range of target molecules with full occupancy, typically without disorder and accompanying solvent, affording well-refined structures. Moreover, anomalous scattering by the framework sulfur atoms enables reliable assignment of absolute configuration of stereogenic centers. An ever-expanding library of organosulfonates provides a toolkit of frameworks for capturing specific target molecules for their structure determination.

Optimization of microorganism preservation conditions for the development of an acute toxicity bioassay for biocides.

Biocides, also referred to as 'microbicides' or 'inhibitors', are widely used in industrial processes (e.g. utility water in cooling towers) to control and/or eliminate the growth of microorganisms. Because of their inherent toxicity, their presence in various sources (e.g. river sediments, potable water) can negatively affect ecosystems. Currently available biocide detection techniques are not suitable for 'point-of-use' applications since they are tedious, complicated, and often require experienced personnel to operate. To address this concern, we sought to develop a simple-to-use toxicity bioassay based on a model microorganism (E. coli) after short (<30 min) exposure to known biocides that can be stored at room temperature (preferably) or in the fridge. Based on recent work and our expertise in polymer-based preservation of biomolecules, we leveraged this knowledge to improve E. coli preservation for biocide detection purposes. A design-of-experiments strategy was used to evaluate 16 different preservation conditions from 5 process parameters (i.e. 25-1 fractional factorial). It was found that pullulan, a sugar-based polymer, improved E. coli culturability by an order of magnitude after three months of storage. Also, it was found that storing E. coli in the fridge in Milli-Q water was favorable for maintaining a high level of culturability. Finally, the toxicity of three common biocides (Cetyltrimethylammonium bromide (CTAB), ProClin™ 300, and Grotan® BK) was evaluated using a fluorescence-based assay across all 16 preservation conditions. The response of the preserved E. coli was biocide specific and at certain conditions did not vary during the entire three-month storage period.