UTX condensation underlies its tumour-suppressive activity.

UTX (also known as KDM6A) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers1. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation2-8, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.

Dense sampling of bird diversity increases power of comparative genomics.

Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity1-4. Sparse taxon sampling has previously been proposed to confound phylogenetic inference5, and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species.

Cannabis use in a Canadian long-term care facility: a case study.

BACKGROUND: Following the legalization of cannabis in Canada in 2018, people aged 65 + years reported a significant increase in cannabis consumption. Despite limited research with older adults regarding the therapeutic benefits of cannabis, there is increasing interest and use among this population, particularly for those who have chronic illnesses or are at end of life. Long-term Care (LTC) facilities are required to reflect on their care and policies related to the use of cannabis, and how to address residents' cannabis use within what they consider to be their home. METHODS: Using an exploratory case study design, this study aimed to understand how one LTC facility in western Canada addressed the major policy shift related to medical and non-medical cannabis. The case study, conducted November 2021 to August 2022, included an environmental scan of existing policies and procedures related to cannabis use at the LTC facility, a quantitative survey of Healthcare Providers' (HCP) knowledge, attitudes, and practices related to cannabis, and qualitative interviews with HCPs and administrators. Quantitative survey data were analyzed using descriptive statistics and content analysis was used to analyze the qualitative data. RESULTS: A total of 71 HCPs completed the survey and 12 HCPs, including those who functioned as administrators, participated in the interview. The largest knowledge gaps were related to dosing and creating effective treatment plans for residents using cannabis. About half of HCPs reported providing care in the past month to a resident who was taking medical cannabis (54.9%) and a quarter (25.4%) to a resident that was taking non-medical cannabis. The majority of respondents (81.7%) reported that lack of knowledge, education or information about medical cannabis were barriers to medical cannabis use in LTC. From the qualitative data, we identified four key findings regarding HCPs' attitudes, cannabis access and use, barriers to cannabis use, and non-medical cannabis use. CONCLUSIONS: With the legalization of medical and non-medical cannabis in jurisdictions around the world, LTC facilities will be obligated to develop policies, procedures and healthcare services that are able to accommodate residents' use of cannabis in a respectful and evidence-informed manner.

Findings in percutaneous trans-hepatic cholecysto-cholangiography in neonates and infants presenting with conjugated hyperbilirubinemia: emphasis on differential diagnosis and cholangiographic patterns.

BACKGROUND: Biliary atresia (BA) is one of the causes of conjugated hyperbilirubinemia in infants which if untreated leads to end-stage liver disease and death. Percutaneous Trans-hepatic Cholecysto-Cholangiography (PTCC) is a minimally invasive study which can be utilized in the diagnostic work-up of these patients. This study's purpose is to describe the experience with PTCC in neonates, the imaging findings encountered, and the abnormal patterns which warrant further investigation. METHODS: A 16-year single-center retrospective study of patients with persistent neonatal cholestasis (suspected BA) undergoing PTCC. Patient demographics, laboratory values, PTCC images, pathology and surgical reports were reviewed. RESULTS: 73 patients underwent PTCC (68% male, mean age 8.7 weeks, mean weight 4.0 Kg). The majority of studies were normal (55%). Abnormal patterns were identified in 33 cases, 79% were diagnosed with BA and 12% with Alagille syndrome. Non-opacification of the common hepatic duct with a narrowed common bile duct (42%) and isolated small gallbladder (38%) were the most common patterns in BA. CONCLUSION: PTCC is a minimally invasive study in the diagnostic work-up of infants presenting with conjugated hyperbilirubinemia (suspected BA). Further invasive investigations or surgery can be avoided when results are normal.

Efficacy, pharmacokinetics, and safety of subcutaneous C1-esterase inhibitor as prophylaxis in Japanese patients with hereditary angioedema: Results of a Phase 3 study.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunctional C1-esterase inhibitor (C1-INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1-INH in Japanese patients with HAE. METHODS: The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1-INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1-INH functional activity at Week 16. RESULTS: Nine patients entered the treatment period and completed the study. Treatment with C1-INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1-INH (SC) at Week 16, the mean trough concentration of C1-INH was 59.8%, and the mean area under the plasma concentration-time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h•%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation. CONCLUSIONS: C1-INH (SC) (60 IU/kg twice weekly) was efficacious and well tolerated as a prophylaxis against HAE attacks in Japanese patients with HAE types I or II, which was supported by the increased and maintained C1-INH functional activity. EudraCT Number 2019-003921-99; JapicCTI-205273.

Analysis of relapse by inflammatory Rasch-built overall disability scale status in the PATH study of subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy.

Clinical trials in chronic inflammatory demyelinating polyneuropathy (CIDP) often assess efficacy using the ordinal Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Here, data from the PATH study was reanalyzed using change in Inflammatory Rasch-built Overall Disability Scale (I-RODS) to define CIDP relapse instead of INCAT. The PATH study comprised an intravenous immunoglobulin (IVIG) dependency period and an IVIG (IgPro10 [Privigen]) restabilization period; subjects were then randomized to weekly maintenance subcutaneous immunoglobulin (SCIG; IgPro20 [Hizentra]) 0.2 g/kg or 0.4 g/kg or placebo for 24 weeks. CIDP relapse was defined as ≥1-point deterioration in adjusted INCAT, with a primary endpoint of relapse or withdrawal rates. This retrospective exploratory analysis redefined relapse using I-RODS via three different cut-off methods: an individual variability method, fixed cut-off of ≥8-point deterioration on I-RODS centile score or ≥4-point deterioration on I-RODS raw score. Relapse or withdrawal rates were 47% for placebo, 34% for 0.2 g/kg IgPro20 and 19% for 0.4 g/kg IgPro20 using the raw score; 40%, 28% and 15%, respectively using the centile score, and 49%, 40% and 27%, respectively using the individual variability method. IgPro20 was shown to be efficacious as a maintenance therapy for CIDP when relapse was defined using I-RODS. A stable response pattern was shown for I-RODS across various applied cut-offs, which could be applied in future clinical trials.

Essential Role of Neutrophils in the Protective Immune Response Induced by a Live Attenuated Leishmania Vaccine.

No licensed vaccine exists against visceral leishmaniasis (VL), a disease caused by the Leishmania donovani parasite. We have previously reported both macrophages and dendritic cells play important role in the protection induced by a live attenuated centrin gene-deleted L. donovani (LdCen-/- ) parasite vaccine. The role of neutrophils in orchestrating the initial innate response to pathogens is widely recognized. To investigate the early interaction of LdCen-/- with neutrophils, we immunized mice intradermally in the ear pinna with LdCen-/- Compared with LdWT infection, LdCen-/- parasites induced higher recruitment of neutrophils to the ear dermis and ear draining lymph nodes (dLN) as early as 6-18 h after immunization, which were predominantly proinflammatory in nature. Neutrophils from ear dLN of LdCen-/- -immunized mice exhibited heightened expression of costimulatory molecules and attenuated expression of coinhibitory molecules necessary for higher T cell activation. Further phenotypic characterization revealed heterogeneous neutrophil populations containing Nα and Nß subtypes in the ear dLN. Of the two, the parasitized Nα subset from LdCen-/- -immunized mice exhibited much stronger Ag-specific CD4+ T cell proliferation ex vivo. Adoptive transfer of neutrophils bearing LdCen-/- parasites induced an increased Th1 response in naive mice. Importantly, neutrophil depletion significantly abrogated Ag-specific CD4+ T cell proliferation in LdCen-/- -immunized mice and impaired protection against virulent challenge. Conversely, replenishing of neutrophils significantly restored the LdCen-/- -induced host-protective response. These results suggest that neutrophils are indispensable for protective immunity induced by LdCen-/- parasite vaccine.

The Development of the Love and Respect Marriage Scale.

The constructs of love and respect have been known to be essential ingredients contributing positively to marital satisfaction, but to-date they have mostly been measured using separate scales. However, given the overlap between both constructs this study set out, using self-report methodologies, to develop a comprehensive scale which measures both love and respect known as The Love and Respect Marriage Scale. Using a nonclinical community Singapore sample (n = 400), an initial item pool was developed, and through exploratory factor analysis, a robust factor structure emerged that consisted of eight subscales and 46 items. This factor structure was shown to be a consistent and cross-culturally acceptable model using samples from USA, n = 396, South Africa, n = 390, Nigeria, n = 364, and India, n = 306. Good reliability values were achieved. Construct, convergent, divergent, and incremental validity were also demonstrated as comparisons were made with shorter established marriage scales. Implications and advantages of a longer marital scale were discussed.Supplemental data for this article is available online at https://doi.org/10.1080/0092623X.2021.1963362 .

Multi-stakeholder validation of entrustable professional activities for a family medicine care of the elderly residency program: a focus group study.

Entrustable Professional Activities (EPAs) have become widely used within Competency-Based Medical Education (CBME) for the training and evaluation of residents. Little is known about the effectiveness of incorporating multiple stakeholder groups in the validation of EPAs. Here, we seek to validate an EPA framework developed for the University of Manitoba Care of the Elderly Enhanced Skills program using online focus groups consisting of five stakeholder groups. Participants were recruited to take part in one of five online focus groups, one for each stakeholder group (physician faculty, residents, non-physician healthcare professionals, administrators/managers, and patients). Each group met one time for 90 minutes over ZOOM®. The themes arising from stakeholder feedback suggest that successful EPAs must neither be too specific nor too expansive in scope, clearly delineate appropriate means of evaluation, and indicate specific clinical settings in which each EPA should be evaluated. Cross-cutting themes included requiring trainees to collaborate with other professionals when it would optimize patient care, and preparing trainees to advocate for their patients' health (Advocacy). The present study demonstrates that multi-stakeholder analysis yields diverse feedback that can help make EPAs more clear, easier to use in evaluation, and more socially accountable.

Fetal therapy using rapamycin for a rapidly enlarging, obstructive, cervical lymphatic malformation: a case report.

WHAT'S ALREADY KNOWN ABOUT THIS TOPIC?: Fetal lymphatic malformations (LMs) can be detected on prenatal ultrasound and until recently, therapeutic options were limited. Recently the mammalian target of rapamycin inhibitor rapamycin has emerged as a safe, effective therapy for children with LMs and multiple studies have demonstrated improved efficacy if started early. WHAT DOES THIS STUDY ADD?: We report the first in-utero therapy with rapamycin for a rapidly enlarging, obstructive, fetal cervical LM. Fetal therapy with rapamycin was safe and effective in managing this severe malformation, despite rapamycin being started only in the last 6.5 weeks of pregnancy. We speculate that had rapamycin been commenced earlier, the reduction in mass size might have been even greater.

Multimorbidity in Canadians living in the community: Results from the Canadian Longitudinal Study of Aging.

OBJECTIVE: To determine the mean number of chronic diseases in Canadians aged 45 to 85 years who are living in the community, and to characterize the association of multimorbidity with age, sex, and social position. DESIGN: An analysis of data from the Canadian Longitudinal Study on Aging. The number of self-reported chronic diseases was summed, and then the mean number of chronic health problems was standardized to the 2011 Canadian population. Analyses were conducted stratified on sex, age, individual income, household income, and education level. SETTING: Canada. PARTICIPANTS: A total of 21 241 community-living Canadians aged 45 to 85 years. MAIN OUTCOME MEASURES: Overall, 31 chronic diseases (self-reported from a list) were considered, as were risk factors that were not mental health conditions or acute in nature. Age, sex, education, and household and individual incomes were also self-reported. RESULTS: Multimorbidity was common, and the mean number of chronic illnesses was 3.1. Women had a higher number of chronic illnesses than men. Those with lower income and less education had more chronic conditions. The number of chronic conditions was strongly associated with age. The mean number of conditions was 2.1 in those aged 45 to 54; 2.9 in those 55 to 64; 3.8 in those aged 65 to 74, and 4.8 in those aged 75 and older (P < .05, ANOVA [analysis of variance]). CONCLUSION: Multimorbidity is common in the Canadian population and is strongly related to age.

Use of Tissue Plasminogen Activator in Abdominal Abscesses in Children-A Single-Center Randomized Control Trial.

PURPOSE: To establish the efficacy of once-per-day intracavitary tissue plasminogen activator (tPA) in the treatment of pediatric intra-abdominal abscesses. METHODS: A single-center prospective, double-blinded, randomized controlled trial of the use of intracavitary tPA in abdominal abscesses in children. Patients were randomized to either tPA-treatment or saline-treatment groups. Primary outcome was drainage catheter dwell (hours). Secondary outcomes were length of hospital stay, times to discharge, clinical and sonographic resolution, and adverse events (AEs). RESULTS: Twenty-eight children were randomized to either group (n = 14 each). Demographics between groups were not significantly different (age P = .28; weight P = .40; gender P = .44). There were significantly more abscesses in the tPA-treated group (P = .03). Abscesses were secondary to perforated appendicitis (n = 25) or postappendectomy (n = 3). Thirty-four abscesses were drained, 4 aspirated, 3 neither drained/aspirated. There was no significant difference in number of drains (P = .14), drain size (P = .19), primary outcome (P = .077), or secondary outcomes found. No procedural or intervention drug-related AEs occurred. No patient in the saline-treated group required to be switched/treated with tPA. CONCLUSION: No significant difference in the length of catheter dwell time, procedure time to discharge, or time to resolution was found. Intracavitary tPA was not associated with morbidity or mortality. The results neither support nor negate routine use of tPA in the drainage of intra-abdominal abscess in children. It is possible that a multicentre study with a larger number of patients may answer this question more definitively.

The use of rapamycin to treat vascular tumours and malformations: A single-centre experience.

OBJECTIVES: To assess the safety and efficacy of rapamycin in treating children with vascular tumours and malformations. STUDY DESIGN: We performed a retrospective review at a large tertiary care paediatric centre to assess the efficacy and safety of using rapamycin to treat vascular tumours and malformations. Response to therapy was defined by patient-reported symptom improvement, radiological reduction in size of lesions, and/or improvement of laboratory parameters. RESULTS: Forty-two patients (7 with vascular tumours and 35 with vascular malformations) have been treated with rapamycin. Despite 33 of 42 patients being diagnosed in the first year of life, the median age of initiating rapamycin was 11 years. Of the 38 children treated for a minimum of 4 months, 29 (76%) exhibited a clinical response. Twenty-one patients had follow-up imaging studies and of these, 16 (76%) had radiographic decrease in lesion size. Median time to demonstration of response was 49 days. All five children with vascular tumours and all three children with vascular malformations under the age of 4 years showed a clinical response. Response rate was lower for children ≥ 4 years of age (0/2, 0% for vascular tumours; 21/28, 75% for vascular malformations). No patient experienced an infection directly related to rapamycin or discontinued rapamycin due to toxicity. CONCLUSIONS: Rapamycin is safe and efficacious in most children with select vascular tumours and malformations. Young children appear to respond better, suggesting that early initiation of rapamycin should be considered.

Life satisfaction in adults in rural and urban regions of Canada - the Canadian Longitudinal Study on Aging.

INTRODUCTION: Understanding rural-urban differences, and understanding levels of life satisfaction in rural populations, is important in planning social and healthcare services for rural populations. The objectives of this study were to determine patterns of life satisfaction in Canadian rural populations aged 45-85 years, to determine rural-urban differences in life satisfaction across a rural-urban continuum after accounting for potential confounding factors and to determine if related social and health factors of life satisfaction differ in rural and urban populations. METHODS: A secondary analysis was conducted using data from an ongoing population-based cohort study, the Canadian Longitudinal Study on Aging. A cross-sectional sample from the baseline wave of the tracking cohort was used, which was intended to be as generalizable as possible to the Canadian population. Four geographic areas were compared on a rural-urban continuum: rural, mixed (indicating some rural, but could also include some peri-urban areas), peri-urban, and urban. Life satisfaction was measured using the Satisfaction with Life Scale and dichotomized as satisfied versus dissatisfied. Other factors considered were province of residence, age, sex, education, marital status, living arrangement, household income, and chronic conditions. These factors were self-reported. Bivariate analyses using χ2 tests were conducted for categorical variables. Logistic regression models were constructed with the outcome of life satisfaction, after which a series of models were constructed, adjusting for province of residence, age, and sex, for sociodemographic factors, and for health-related factors. To report on differences in the factors associated with life satisfaction in the different areas, logistic regression models were constructed, including main effects for the variable of interest, for the variable rurality, and for the interaction term between these two variables. RESULTS: Individuals living in rural areas were more satisfied with life than their urban counterparts (odds ratio (OR)=1.23; 95% confidence interval (CI): 1.13-1.35), even after accounting for the effect of confounding sociodemographic and health-related factors (OR=1.32, 95%CI: 1.19-1.45). Those living in mixed (OR=1.30, 95%CI: 1.14-1.49) and peri-urban (OR=1.21, 95%CI: 1.07-1.36) areas also reported being more satisfied than those living in urban areas. In addition, a positive association was found between life satisfaction and age, as well as between life satisfaction and being female. A strong graded association was noted between income and life satisfaction. Most chronic conditions were associated with lower life satisfaction. Finally, no major interaction was noted between rurality and each of the previously mentioned different factors associated with life satisfaction. CONCLUSION: Rural-urban differences in life satisfaction were found, with higher levels of life satisfaction in rural populations compared to urban populations. Preventing and treating common chronic illness, and also reducing inequalities in income, may prove useful to improving life satisfaction in both rural and urban areas. Studies of life satisfaction should consider rurality as a potential confounding factor in analyses of life satisfaction within and across societies.

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

Isoagglutinin reduction in intravenous immunoglobulin (IgPro10, Privigen) by specific immunoaffinity chromatography reduces its reporting rates of hemolytic reactions: an analysis of spontaneous adverse event reports.

BACKGROUND: Hemolysis is an infrequent but recognized and potentially serious adverse effect of intravenous immunoglobulin (IVIG). Relatively elevated hemolysis reporting rates were seen with some IVIG products with high anti-A/B isoagglutinin content, among which IgPro10 (Privigen, CSL Behring). For IgPro10, two isoagglutinin reduction measures were successively implemented: 1) anti-A donor screening and 2) immunoaffinity chromatography (IAC; Ig IsoLo)-based isoagglutinin reduction step included in the production process. The aim of this analysis was to investigate the effects of these isoagglutinin reduction measures on the reporting rates of IgPro10 hemolysis worldwide. STUDY DESIGN AND METHODS: Between February 2008 and December 2018, hemolysis reports from the CSL Behring Global Safety Database were analyzed in relationship to changes in IVIG IgPro10 production methods. Further analysis classified hemolysis reports by indication and blood group. RESULTS: Median (minimum-maximum) anti-A/anti-B titers were 32 (8-64)/16 (8-32) at baseline, 32 (8-64)/16 (8-32) after donor screening, and 8 (8-32)/4 (2-8) after implementation of IAC. The reporting rate of hemolytic reactions per 1000 kg IgPro10 sold was 4.05 cases at baseline, 2.00 after donor screening, and 0.50 after implementation of IAC. In 2018, there were seven reports of hemolytic reactions; representing 0.18 cases per 1000 kg IgPro10 sold, with a reduction of 95.6% versus baseline. CONCLUSION: Following implementation of the IAC isoagglutinin reduction step, spontaneous reports of hemolytic events with IgPro10 were significantly and consistently reduced versus IgPro10 without isoagglutinin reduction, offering patients a more favorable benefit-risk profile.

Is Routine Preprocedural Bloodwork Needed for Elective Central Venous Access Device Removals in Children without Bleeding Dyscrasias?

PURPOSE: To assess the utility of routine preprocedural bloodwork during elective removal of central venous access devices (CVADs) with respect to bleeding complications. MATERIALS AND METHODS: Patients who underwent removal of a CVAD (tunneled central venous catheter [CVC] or port) by the interventional radiology service between January 2009 and December 2013 were retrospectively reviewed. Removals for infection or malfunction, without preprocedural bloodwork, with another concurrent procedure at the time of CVAD removal, or in patients with a bleeding dyscrasia were excluded. Peripherally inserted central catheter removals and temporary CVAD removals were also excluded. Routine preprocedural bloodwork included hemoglobin, platelet count, partial thromboplastin time, and International Normalized Ratio. Postprocedural complications were classified according to the Society of Interventional Radiology clinical practice guidelines. RESULTS: There were 802 CVAD removals in 777 patients (351 female, 426 male). Average patient age was 8.6 years (range, 5 wk to 19 y). In total, 246 permanent CVCs and 556 ports were removed. A total of 802 cases had preprocedural bloodwork. Of the 49 patients who had a bleeding complication after the procedure (6.1%; 49 of 802), 44 had normal findings on preprocedural bloodwork and 5 had abnormal findings. There was no statistically significant difference in bleeding complications between those with normal and abnormal bloodwork results (P = .7740). CONCLUSIONS: Routine bloodwork is not necessary before elective CVAD removal in children without a bleeding dyscrasia. Most children have normal findings on preprocedural bloodwork, and the incidence of postprocedural bleeding is low and not determined by bloodwork results.

Placebo effect in chronic inflammatory demyelinating polyneuropathy: The PATH study and a systematic review.

The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post-hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo-controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non-deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.

Live Attenuated Leishmania donovani Centrin Gene-Deleted Parasites Induce IL-23-Dependent IL-17-Protective Immune Response against Visceral Leishmaniasis in a Murine Model.

No vaccine exists against visceral leishmaniasis. To develop effective vaccines, we have previously reported protective role of live attenuated centrin gene-deleted Leishmania donovani (LdCen-/- ) parasites through induction of Th1 type immune response in mice, hamsters, and dogs. In this study, we specifically explored the role of Th17 cells in LdCen-/- -induced host protection in mice. Our results showed that compared with wild-type L. donovani infection, LdCen-/- parasites induce significantly higher expression of Th17 differentiation cytokines in splenic dendritic cells. There was also induction of IL-17 and its promoting cytokines in total splenocytes and in both CD4 and CD8 T cells following immunization with LdCen-/- Upon challenge with wild-type parasites, IL-17 and its differentiating cytokines were significantly higher in LdCen-/- -immunized mice compared with nonimmunized mice that resulted in parasite control. Alongside IL-17 induction, we observed induction of IFN-γ-producing Th1 cells as reported earlier. However, Th17 cells are generated before Th1 cells. Neutralization of either IL-17 or IFN-γ abrogated LdCen-/- -induced host protection further confirming the essential role of Th17 along with Th1 cytokines in host protection. Treatment with recombinant IL-23, which is required for stabilization and maintenance of IL-17, heightened Th17, and Tc17 responses in immunized mice splenocytes. In contrast, Th17 response was absent in immunized IL-23R-/- mice that failed to induce protection upon virulent Leishmania challenge suggesting that IL-23 plays an essential role in IL-17-mediated protection by LdCen-/- parasites. This study unveiled the role of IL-23-dependent IL-17 induction in LdCen-/- parasite-induced immunity and subsequent protection against visceral leishmaniasis.