Interleukin-23-Induced Transcription Factor Blimp-1 Promotes Pathogenicity of T Helper 17 Cells.

Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome-wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORγt, STAT-3, and p300 at the Il23r, Il17a/f, and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORγt to activate the Th17 inflammatory program.

An Electrochemical Design for Catalytic Dehydration: Direct, Room-Temperature Esterification without Acid or Base Additives.

An electrochemical approach has been leveraged to underpin a new conceptual platform for dehydration reactions, which has been demonstrated in the context of esterification. Esters were prepared from the corresponding acid and alcohol partners at room temperature without acid or base additives and without consuming stoichiometric reagents. This methodology therefore addresses key complications that plague esterification and dehydration reactions more broadly and that represent a leading challenge in synthetic chemistry.

Orphan cytokine reveals IL-17 family secret.

The biology of interleukin-17C (IL-17C) has remained largely a mystery for more than a decade. Chang et al. (2011), in this issue of Immunity, and two other reports (Song et al., 2011; Ramirez-Carrozzi et al., 2011) demonstrate that IL-17C has broad functions in a variety of tissues.

Foxp3(+) regulatory T cells promote T helper 17 cell development in vivo through regulation of interleukin-2.

T helper 17 (Th17) cell development is driven by cytokines including transforming growth factor-ß (TGF-ß), interleukin-6 (IL-6), IL-1, and IL-23. Regulatory T (Treg) cells can provide the TGF-ß in vitro, but their role in vivo remains unclear, particularly because Treg cells inhibit inflammation in many models of Th17 cell-associated autoimmunity. We used mice expressing Diphtheria toxin receptor under control of the Foxp3 promoter to deplete Foxp3(+) Treg cells in adult mice during in vivo Th17 cell priming. Treg cell depletion resulted in a reduced frequency of antigen-specific IL-17 producers in draining lymph nodes and blood, correlating with reduced inflammatory skin responses. In contrast, Treg cells did not promote IL-17 secretion after initial activation stages. Treg cell production of TGF-ß was not required for Th17 cell promotion, and neither was suppression of Th1 cell-associated cytokines. Rather, regulation of IL-2 availability and resultant signaling through CD25 by Treg cells was found to play an important role.

Bilateral Pulmonary Embolism With Right Heart Strain in a Patient With Immune Thrombocytopenia-A Case Report and Review of the Literature.

OBJECTIVES: Patients with immune thrombocytopenia are at risk of both bleeding complications and venous thromboembolism. There is no standard to treating life-threatening pulmonary embolism in this population. This case illustrates the difficulty of treating significant thromboembolism in pediatric patients who have reduced clotting capacity. CASE: This case focuses on a 16-year-old pediatric patient with a history of immune thrombocytopenia presenting with mild chest discomfort and dyspnea on exertion. The d-dimer was mildly elevated, and the subsequent computed tomography angiogram revealed bilateral pulmonary embolisms with right ventricular strain. CONCLUSIONS: The patient underwent thromboembolectomy by interventional radiology with subsequent administration of intravenous immunoglobulin, high-dose steroids, and enoxaparin therapy. There is no standard of care for patients with life-threatening pulmonary embolism in this population. Several authors suggest medical therapy options, but do not include patients with potential hemodynamic instability.

Development of Anti-CD74 Antibody-Drug Conjugates to Target Glucocorticoids to Immune Cells.

Glucocorticoids (GCs) are excellent anti-inflammatory drugs but are dose-limited by on-target toxicity. We sought to solve this problem by delivering GCs to immune cells with antibody-drug conjugates (ADCs) using antibodies containing site-specific incorporation of a non-natural amino acid, novel linker chemistry for in vitro and in vivo stability, and existing and novel glucocorticoid receptor (GR) agonists as payloads. We directed fluticasone propionate to human antigen-presenting immune cells to afford GR activation that was dependent on the targeted antigen. However, mechanism of action studies pointed to accumulation of free payload in the tissue culture supernatant as the dominant driver of activity and indeed administration of the ADC to human CD74 transgenic mice failed to activate GR target genes in splenic B cells. Suspecting dissipation of released payload, we designed an ADC bearing a novel GR agonist payload with reduced permeability which afforded cell-intrinsic activity in human B cells. Our work shows that antibody-targeting offers significant potential for rescuing existing and new dose-limited drugs outside the field of oncology.

A Stroke Mimic: Methotrexate-induced Neurotoxicity in the Emergency Department.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia. The treatment of ALL involves multimodality therapy, and methotrexate (MTX) remains a mainstay of treatment. A complication of MTX therapy includes acute, subacute, and chronic neurotoxocity. Signs and symptoms may range from headaches, dizziness, and mood disorders to seizures and stroke-like symptoms. CASE REPORT: An 18-year-old woman with a history of ALL presented to the emergency department with acute onset of right-sided facial paralysis, right upper extremity flaccid paralysis, and right lower extremity weakness after receiving MTX therapy 3 days earlier. Diagnostic studies were unremarkable and the patient was treated with oral dextromethorphan for presumed MTX-induced neurotoxicity. The patient's symptoms began to improve within hours and she was discharged home within 48 hours with no neurologic deficits. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of this complication of MTX therapy given the sensitivity in regards to time with respect to cerebral vascular accidents. An awareness of this complication in the setting of the appropriate history and physical examination can lead to an accurate diagnosis and intervention and the avoidance of administering thrombolytics.

Th17 cell development: from the cradle to the grave.

T cells surviving the clonal selection process emigrate from the thymus to the periphery as immature naive T cells. In the periphery, upon activation under specific cytokine milieus, naive T cells adopt specific effector phenotypes, e.g. T-helper 1 (Th1), Th2, or Th17, and acquire diverse functions to control a myriad of pathogens, tissue injuries, and other immunological insults. Interleukin-23 (IL-23) is one of the key cytokines that shapes the development and function of Th17 cells with characteristic expression of retinoic acid receptor-related orphan receptor γ-t (RORγt), IL-17, IL-22, and granulocyte macrophage colony-stimulating factor (GM-CSF). More recently, emerging data suggest that IL-23 also promotes development of 'natural Th17' (nTh17) cells that arise from the thymus, analogous to natural regulatory T cells (nTreg). We are just beginning to understand the unique thymic developmental path of nTh17 cells, which are distinct from antigen-experienced memory Th17 cells. In this review, we explore the differentiation and function of inducible, natural, and memory Th17 subsets, which encompass a broad range of immune functions while maintaining tissue hemostasis, and highlight the participation of IL-23 during the life cycle of Th17 cells.

Language Matters: Race, Trust, and Outcomes in the Pediatric Emergency Department.

OBJECTIVE: Trust in physicians and health care system has been positively associated with health care outcomes. The purpose of this study is to explore the relationships among race, ethnicity, language, trust, and health care outcomes. METHODS: This prospective cross-sectional study took place in the pediatric emergency department of an intercity hospital. English- and Spanish-speaking guardians were asked to complete a demographic survey, the Pediatric Trust in Physicians Scale, and the Group-Based Medical Mistrust Scale. RESULTS: Four hundred seventy-five parents were surveyed, of which 21.35% identified as white, 35.05% as African American, and 53.26% as Hispanic; with respect to language: 88% English-speaking and 12% Spanish-speaking. No significant difference was seen in trust scores for sex, ethnicity, or religious affiliation. Non-Hispanics and English speakers demonstrated an overall higher trust in their physician. English-speaking participants were found to have higher percentages in all measured emergency department variables compared to Spanish speakers, including admittance (9.09% and 0.93%, respectively) as well as receiving interventions (42.34% and 5.53%, respectively). CONCLUSIONS: Our study shows that race and ethnicity influence trust and mistrust as well as actual health care outcomes. Interestingly, language barrier proved to be one of the greatest causes of health care disparities. Therefore, more research is needed to find a way to bridge the increasing language barrier between physicians and patients.

c-kit expression profile and regulatory factors during spermatogonial stem cell differentiation.

BACKGROUND: It has been proven that c-kit is crucial for proliferation, migration, survival and maturation of spermatogenic cells. A periodic expression of c-kit is observed from primordial germ cells (PGCs) to spermatogenetic stem cells (SSCs), However, the expression profile of c-kit during the entire spermatogenesis process is still unclear. This study aims to reveal and compare c-kit expression profiles in the SSCs before and after the anticipated differentiation, as well as to examine its relationship with retinoic acid (RA) stimulation. RESULTS: We have found that there are more than 4 transcripts of c-kit expressed in the cell lines and in the testes. The transcripts can be divided into short and long categories. The long transcripts include the full-length canonical c-kit transcript and the 3' end short transcript. Short transcripts include the 3.4 kb short transcript and several truncated transcripts (1.9-3.2 kb). In addition, the 3.4 kb transcript (starting from intron 9 and covering exons 10 ~ 21) is discovered to be specifically expressed in the spermatogonia. The extracellular domain of Kit is obtained in the spermatogonia stage, but the intracellular domain (50 kDa) is constantly expressed in both SSCs and spermatogonia. The c-kit expression profiles in the testis and the spermatogonial stem cell lines vary after RA stimulation. The wave-like changes of the quantitative expression pattern of c-kit (increase initially and decrease afterwards) during the induction process are similar to that of the in vivo male germ cell development process. CONCLUSIONS: There are dynamic transcription and translation changes of c-kit before and after SSCs' anticipated differentiation and most importantly, RA is a significant upstream regulatory factor for c-kit expression.

Sperm cryopreservation for Chinese male cancer patients: a 17-year retrospective analysis in an assisted reproductive unit in Hong Kong.

OBJECTIVE: To review sperm cryopreservation usage rates, corresponding reproductive outcomes, and the current situation in our locality. DESIGN: Retrospective case series. SETTING: Assisted Reproductive Technology Unit of the Department of Obstetrics and Gynaecology, Prince of Wales Hospital and the Chinese University of Hong Kong. PARTICIPANTS: There were 130 Chinese male patients who underwent sperm cryopreservation before proceeding to gonadotoxic treatment from January 1995 to January 2012. MAIN OUTCOME MEASURES: Demographic data, type of cancers and treatments, semen analysis, and reproductive outcomes. RESULTS: The median patient age was 27 (range, 15-43) years. Most (85%) were single at the time of referral. Over half of the patients (51%) had testicular cancer. Five patients declined sperm cryopreservation after counselling. Among the remaining 125 men, 122 men were able to produce sperm by masturbation but 12 were found to have azoospermia, leaving a total of 110 who proceeded to semen cryopreservation. There were no significant differences in semen parameters between different cancer types. After gonadotoxic treatment, in up to 32% (n=11/34) of the patients, semen analysis yielded deterioration; four patients had azoospermia. Four patients (4%, n=4/110) came back to use their thawed semen for in-vitro fertilisation (intracytoplasmic sperm injection), which resulted in three successful singleton pregnancies. CONCLUSION: Sperm cryopreservation is a simple and effective way of preserving the fertility potential of male patients undergoing gonadotoxic treatment. This procedure is underutilised and deserves increased awareness by all possible means.

Long-term reproductive outcome after hysteroscopic proximal tubal cannulation--an outcome analysis.

BACKGROUND: The optimal therapeutic method for proximal tubal obstruction (PTO) has yet to be defined. In addition, the reported successful recanalisation rate and reproductive outcome from hysteroscopic proximal tubal cannulation have been inconsistent. AIMS: To examine the morbidity and efficacy of laparoscopic-hysteroscopic proximal tubal cannulation for treating PTO. MATERIAL AND METHODS: This was a retrospective study evaluating 70 infertile women with PTO who underwent laparoscopic-hysteroscopic proximal tubal cannulation in The Prince of Wales Hospital, a university-affiliated hospital, from January 2005 to December 2010. Demographical data and operative details were reviewed. Women were then contacted by phone and completed a structured questionnaire. Recanalisation rate, intra-operative complication, pregnancy rates and pregnancy outcomes were examined. RESULTS: Fifty women had successful proximal cannulation on at least one side of the tube, providing an overall successful recanalisation rate of 71.4% per woman and 67.0% per tube. The overall pregnancy rate after successful hysteroscopic proximal cannulation of at least one tube is 55%. The overall mean time to become pregnant from natural conception or via clomiphene induction after successful unilateral or bilateral hysteroscopic cannulation was 10.5 ± 8.9 months. The procedure is associated with minimal morbidity. No prognostic factors were significantly associated with recanalisation and pregnancy rate. CONCLUSION: Laparoscopic-hysteroscopic cannulation for proximal obstruction is a procedure with minimal morbidity and a reasonable successful recanalisation rate. It should be considered as an alternative to in vitro fertilisation.

Pediatric emergency department-based rapid HIV testing: adolescent attitudes and preferences.

OBJECTIVE: The objective of this study was to describe adolescent attitudes/preferences toward rapid HIV testing in a pediatric emergency department (PED). METHODS: An anonymous survey was completed by adolescents who presented to an urban PED. The survey was completed while they participated in a rapid HIV prevention/testing program. Survey questions included demographics, HIV risk factors/knowledge, prior testing experience, and attitudes/preferences toward rapid HIV testing. RESULTS: One hundred fourteen adolescents between the ages of 14 and 21 years were surveyed. Most respondents (69%) reported that the emergency department was a very high preference location for testing. Eighty percent of adolescents agreed that they were more likely to get tested for HIV if a rapid test was available. Most participants strongly agreed that it was important to receive pretest and posttest counseling for HIV. In addition, 38% strongly agreed that they preferred a same-sex counselor, whereas 9% strongly agreed that they preferred a same-ethnicity counselor. Eighty-one percent reported that they planned to get retested for HIV in the next 6 to 12 months. CONCLUSIONS: This study offers valuable new insights into adolescent attitudes and preferences for rapid HIV testing in a PED. Adolescents gave high ratings to the location, testing, and counseling process. Our data support the importance of structured counseling, which is contrary to current published perspectives of counseling efficacy. In addition, we found that the PED was a highly preferred location for rapid HIV testing, which supports the need for increased development of prevention and testing programs in this setting.

Intraosseous access.

BACKGROUND: Vascular access is of paramount importance in the care of the critically ill patient. When central or peripheral intravenous access cannot be accomplished in a timely manner, intraosseous access and infusion is a rapid and safe alternative for the delivery of fluids, medications, and blood products. The resurgence of the use of intraosseous access in the 1980s led to the development of new methods and devices that facilitate insertion. OBJECTIVES: This article discusses general indications, contraindications, and complications of intraosseous access and infusion, focusing on new devices and their insertion. DISCUSSION: Current research is focused on product innovation and improving drug delivery using intraosseous autoinjectors, finding new anatomic sites for placement, and expanding the use of different intraosseous devices to the adult population. CONCLUSIONS/SUMMARY: New, improved intraosseous systems provide health care providers with choices beyond traditional manual intraosseous access for administering fluids.

Effects of early luteal-phase vaginal progesterone supplementation on the outcome of in vitro fertilization and embryo transfer.

OBJECTIVE: To determine whether early luteal-phase vaginal progesterone supplementation improves the outcome of in vitro fertilization-embryo transfer (IVF-ET). METHODS: A randomized, controlled trial was conducted on 197 women undergoing IVF-ET cycles with human chorionic gonadotropin (hCG) as the standard luteal-phase support. The participants were randomly assigned to either the study group or the control group. The study group was given 200 mg micronized progesterone vaginally three times per day starting in the afternoon of oocyte retrieval until the morning of embryo transfer, in addition to the standard hCG luteal-phase support. The control group received only the hCG support. The pregnancy rates and the implantation rates were measured. RESULTS: There were no significant differences in pregnancy rates or implantation rates between groups. However, subgroup analysis revealed significantly higher pregnancy and implantation rates in the study group among those women with fibroids or difficult oocyte retrieval involving uterine puncture (38.7% vs. 15.4% and 26.8% vs. 9.4% respectively, both p = 0.04). CONCLUSION: Additional early luteal-phase vaginal progesterone supplementation may improve the outcome of IVF-ET in women with fibroids or difficult oocyte retrieval.

Cost-Effectiveness of Evaluation of Children With Epilepsy in the Emergency Department: Need for Investment in Patient Education.

We aimed to study cost-effectiveness of seizure evaluation of children with epilepsy in the emergency department (ED). We reviewed epilepsy patients seen at our ED for 1 year. Age, laboratory and neuroimaging results, treatment, disposition, and usefulness of the visit (need for hospitalization, clinical improvement) were analyzed. We identified 330 patients, aged 23 days-21 years, 190 (57.5%) had blood tests, 45 (13.6%) urinalysis, 2 (0.6%) cerebrospinal fluid testing, and 44 neuroimaging studies (13.3%). Tests' positive yield were 41%, 11%, 0%, and 4.5%, respectively. One-third of patients (n = 122) were treated with antiepileptic drugs. Other treatments were administered to 44 (13.3%). One hundred eighteen patients (35.7%) were admitted to our hospital, 208 (63%) discharged to home. Two hundred eight visits were useful (63%). One-third of visits did not provide useful patient care. Their visits were expensive and not very cost-effective. Investment in patient education could decrease unnecessary ED visits.

Use of Post-Acute Facility Care in Children Hospitalized With Acute Respiratory Illness.

BACKGROUND: Recovery from respiratory illness (RI), a common reason for hospitalization, can be protracted for some children because of high illness severity or underlying medical complexity. OBJECTIVE: We assessed which children hospitalized with RI are the most likely to use post-acute facility care (PAC) for recovery. METHODS: Retrospective analysis of 609,800 hospitalizations for patients in 43 US children's hospitals between 2010- 2015 for RI, identified with the Agency for Healthcare Research and Quality Clinical Classification System. Discharge to PAC was identified using Centers for Medicare & Medicaid Services Discharge Status Codes. We compared patient characteristics by PAC use with generalized estimating equations. RESULTS: There were 2660 (0.4%) RI hospitalizations resulting in PAC transfer (n = 2660, 0.4%). Discharges to PAC had greater percentages of technology assistance (83.2% vs 15.1%), neuromuscular chronic condition (57.5% vs 8.9%), and mechanical ventilation (52.7% vs 9.1%), 𝑃 < 0.001 for all. The highest likelihood of PAC use occurred with ≥11 vs no chronic conditions (odds ratio [OR] 11.7 [95% CI, 8.0- 17.2]), ≥9 vs no therapeutic medication classes (OR 4.8 [95% CI, 1.8-13.0]), and existing tracheostomy (OR 3.0, 95% confidence interval [CI], 2.6-3.5). Median (interquartile range [IQR]) acute-care length of stay (LOS) for children most likely to use PAC was 19 (8-56) days; LOS remained long (median 13 [6-41] days) for children with the same attributes (n = 9448) not transferred to PAC. CONCLUSIONS: Children with RI who are most likely to use PAC have a high prevalence of multiple chronic conditions, multiple medications, and medical technology. Future investigations should assess the supply of PAC against the demand of hospitalized children with RI who might need it.

Zirconium Carbide Produced by Spark Plasma Sintering and Hot Pressing: Densification Kinetics, Grain Growth, and Thermal Properties.

Spark plasma sintering (SPS) has been employed to consolidate a micron-sized zirconium carbide (ZrC) powder. ZrC pellets with a variety of relative densities are obtained under different processing parameters. The densification kinetics of ZrC powders subjected to conventional hot pressing and SPS are comparatively studied by applying similar heating and loading profiles. Due to the lack of electric current assistance, the conventional hot pressing appears to impose lower strain rate sensitivity and higher activation energy values than those which correspond to the SPS processing. A finite element simulation is used to analyze the temperature evolution within the volume of ZrC specimens subjected to SPS. The control mechanism for grain growth during the final SPS stage is studied via a recently modified model, in which the grain growth rate dependence on porosity is incorporated. The constant pressure specific heat and thermal conductivity of the SPS-processed ZrC are determined to be higher than those reported for the hot-pressed ZrC and the benefits of applying SPS are indicated accordingly.

Pediatric Hospital Discharges to Home Health and Postacute Facility Care: A National Study.

IMPORTANCE: Acute care hospitals are challenged to provide efficient, high-quality care to children who have medically complex conditions and may require weeks or months for recovery. Although the use of home health care (HHC) and facility-based postacute care (PAC) after discharge is well documented for adults, to our knowledge, little is known for children. OBJECTIVE: To assess the national prevalence of, characteristics of children discharged to, and variation in use across states of HHC and PAC for children. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 2,423,031 US acute care hospital discharges in 2012 for patients ages 0 to 21 years from the nationally representative Agency for Healthcare Research and Quality Kids' Inpatient Database. MAIN OUTCOMES AND MEASURES: Discharges to HHC (eg, visiting or private-duty home nursing) and PAC (eg, rehabilitation facility) were identified from Centers for Medicare and Medicaid Services Discharge Status Codes. We compared children's characteristics (eg, race/ethnicity and number of chronic conditions) by discharge type using generalized linear regression. RESULTS: The median age of participants was 3 years (interquartile range, 0-13 years), and 45.6% were female. Of 2,423,031 US acute care hospital discharges in 2012 for patients ages 0 to 21 years, 122,673 discharges (5.1%) were to HHC and 26,282 (1.1%) were to PAC facilities. Neonatal care was the most common reason (44.5%, n = 54,589) for acute care hospitalization with discharge to HHC. Nonneonatal respiratory, musculoskeletal, and trauma-related problems, collectively, were the most common reasons for discharge to PAC (42.9%, n = 11,275). When compared with PAC, more discharges to HHC had no chronic condition (34.4% vs 18.0%, P < .001) and fewer discharges to HHC had 4 or more chronic conditions (22.5% vs 37.7%, P < .001). In multivariable analysis, Hispanic children were less likely to use PAC (0.8% vs 1.1%; odds ratio [OR], 0.9 [95% CI, 0.8-0.9]) or HHC (3.3% vs 5.5%; OR, 0.8 [95% CI, 0.7-0.8]) compared with other children. Children with 4 or more chronic conditions compared with no chronic conditions had a higher likelihood of HHC use (11.0% vs 4.4%; OR, 2.9 [95% CI, 2.8-3.0]) and PAC (3.9% vs 0.8%; OR, 4.5 [95% CI, 4.3-4.9]). After case-mix adjustment, there was significant (P < .001) variation across states in HHC (range, 0.4%-24.5%) and PAC (range, 0.4%-4.9%) use. CONCLUSIONS AND RELEVANCE: Home health care and PAC use after discharge for hospitalized children is infrequent, even for children with multiple chronic conditions. It varies significantly by race/ethnicity and across states. Further investigation is needed to assess reasons for this variation and to determine for which children HHC and PAC are most effective.