Boosting Apoptotic Cell Clearance by Colonic Epithelial Cells Attenuates Inflammation In Vivo.

Few apoptotic corpses are seen even in tissues with high cellular turnover, leading to the notion that the capacity for engulfment in vivo is vast. Whether corpse clearance can be enhanced in vivo for potential benefit is not known. In a colonic inflammation model, we noted that the expression of the phagocytic receptor Bai1 was progressively downmodulated. Consistent with this, BAI1-deficient mice had more pronounced colitis and lower survival, with many uncleared apoptotic corpses and inflammatory cytokines within the colonic epithelium. When we engineered and tested transgenic mice overexpressing BAI1, these had fewer apoptotic cells, reduced inflammation, and attenuated disease. Boosting BAI1-mediated uptake by intestinal epithelial cells (rather than myeloid cells) was important in attenuating inflammation. A signaling-deficient BAI1 transgene could not provide a similar benefit. Collectively, these complementary genetic approaches showed that cell clearance could be boosted in vivo, with potential to regulate tissue inflammation in specific contexts.

Development and implementation of competency-based assessment for urological ultrasound training using SonoSim: A preliminary evaluation.

INTRODUCTION: Urology residents are encouraged to learn ultrasound (U/S) imaging, yet there are few tools available for teaching and assessing a resident`s competence. The aim of this study was to test the new SonoSim LiveScan® and to propose a competency-based assessment model for the urology graduate medical education. MATERIALS AND METHODS: Urology residents attended an interactive training session covering the urological U/S techniques guided by the assessment model developed by the authors. Faculty members evaluated the residents using defined objectives, and the residents were surveyed on their comfort level for performing each of the model tasks. A subset of the residents then underwent a structured testing using the SonoSim LiveScan device 6 months following the training. The model developed assessed: general U/S setup, structure identification, and pathologic clinical scenarios. RESULTS: The residents felt most comfortable in identifying the bladder (4.73/5) and the kidneys (4.53/5) during the training sessions. They felt least comfortable while testing for total ureteric obstruction (3.13/5). All the residents were confident that additional U/S training sessions would improve their comfort level in performing the assessed objectives. Resident`s assessment performed at 6 months had a median test score of 15.5/20 and the assessment scores increased with resident seniority. Self-reported comfort, however, did not seem to correlate with seniority. In general, the residents felt that the SonoSim device was highly functional (4.4/5) and the pathologic assessments in particular were very helpful (4.4/5). CONCLUSIONS: Through pilot testing, we propose that a competency-based assessment used with the SonoSim LiveScan could guide the resident`s education through the acquisition of U/S skills and warrants testing in a larger cohort.

Bacillus Calmette-Guérin treatment of bladder cancer: a systematic review and commentary on recent publications.

PURPOSE OF REVIEW: Bacillus Calmette-Guérin (BCG) is the standard immune therapy for nonmuscle invasive bladder cancer. A systematic review of published articles regarding BCG treatment of bladder cancer was conducted and a commentary of these is provided to gain a perspective of the current major developments in the field. RECENT FINDINGS: Several BCG strains are utilized worldwide. As the understanding of genetic and phenotypic differences in these strains is elucidated, inquiries into the potential clinical effects of these various strains have been studied. Data suggest that some strains could be more effective than others but further study is needed. Although response to BCG is heterogenous, current clinical practice does not incorporate use of biomarkers to delegate treatment selection. Thus, biomarker prediction is an important area of research in this area. Novel urine and tissue markers show promise in this endeavor. Notable publications also include mechanistic studies showing a role for T cells, natural killer cells, mast cells, and granulocytes in BCG's antitumor efficacy. SUMMARY: Significant developments have occurred in understanding BCG's response and mechanism of action, which remains incompletely understood. Future work includes efforts to create recombinant BCG strains to decrease side effects, repeated instillations, and increase overall efficacy.

The Microbiome and Prostate Cancer Risk.

PURPOSE OF THE REVIEW: There is an abundance of evidence that the human microbiome plays an important and nuanced role in controlling human metabolism, immunity, and cancer. Herein we aim to review the most current research looking at prostate cancer and its link with the gut and genitourinary microbiome. There is now a host of evidence for a unique genitourinary (GU) microbiome. The prostate microbiota, to include viral, bacterial, fungal, and parasitic contributions, as assessed from formalin-fixed tissue is described nicely in the study by Banerjee et al. Further hierarchical analysis by this group found a unique microbiome signature for higher Gleason score cancers and validation PCR studies noted a marked number of viral genomic insertions into host DNA. Shretha et al. also recently established unique GU microbiomes in patients with prostate cancer or benign prostate pathology based on urine samples. The gut microbiome likely also has an indirect but significant role in prostate cancer development and treatment. Liss et al. and Golombos et al. found significant associations between specific gut microbiota and prostate cancer. Interestingly, the balance of inflammatory and anti-inflammatory bacterial lipopolysaccharides, production of bile salts, and metabolism of dietary fiber to short chain fatty acids all likely play important roles in creating systemic pro- or anti-carcinogenic states. In terms of prostate cancer treatment effects, Sfanos et al. noted a unique microbial signature in patients undergoing oral androgen deprivation therapy (ADT) as compared with prostate cancer patients not on ADT. Patients undergoing ADT also had enrichment of bacterial metabolic pathways promoting androgen synthesis. Together, these studies have identified a unique GU microbiome and linked both the GU microbiome and unique gut microbial signatures with prostate cancer and prostate cancer treatments. Whether this information can be used in cancer prevention, treatment, or diagnosis are areas of ongoing and active research.

Improvements in semen parameters in men treated with clomiphene citrate-A retrospective analysis.

Clomiphene citrate (CC) is commonly used off-label for the treatment of male infertility, yet there is limited data to guide patient selection. To identify a subset of patients more likely to benefit from CC, we aimed to define predictors of improvement in semen parameters among men receiving CC. We retrospectively analysed 151 men treated with at least 25 mg CC daily for male infertility and/or hypogonadism at two institutions between 2004 and 2014. Men previously on testosterone were excluded. The primary outcome was change in semen parameters. Variables included baseline patient characteristics, pre-treatment hormone profiles and pre-treatment semen analyses. A total of 77 men met inclusion criteria. Median length of therapy was 2.8 months. There was significant improvement in sperm concentration (14-21 million/ml; p = 0.002) and total motile count (TMC; 13-28 million; p = 0.04). One third of patients who began with fewer than 5 million motile spermatozoon improved to a TMC > 5 million, increasing reproductive options to include intrauterine insemination. Patient characteristics, pre-treatment hormone profile and degree of oligozoospermia did not predict treatment response. While no predictors of improvement were identified, clinically useful response rates are described for use in shared decision-making.

Quantitative Ultrasound and Tibial Dysplasia in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with unilateral anterolateral bowing with subsequent fracture and nonunion. In infancy, physiologic bowing of the lower leg can be confused with pathologic tibial dysplasia in NF1. Little is known about the bone physiology of the tibiae prior to fracture or predictors of fracture. The aim of this study was to characterize bone quality of bowed tibiae prior to fracture in NF1 using quantitative ultrasound (QUS). Bone quality was assessed on both tibiae (the non-bowed and bowed tibiae) using QUS to measure speed of sound (SOS) at the mid-shaft in 23 individuals with NF1. SOS (m/s) was determined and Z-scores generated using cross-sectional reference data of the same sex and age. The mean difference in SOS Z-scores when comparing the bowed tibia vs the individual's contralateral unaffected tibia was statistically significant with lower mean Z-scores in the bowed tibia (p = 0.001). Radiographs of all individuals with a clinical diagnosis of anterolateral bowing were reviewed, and in 2 individuals the radiographs showed minimal bowing with absence of characteristic cortical thickening and medullary canal narrowing in NF1-related tibial dysplasia, suggesting physiologic bowing. In both individuals, the Z-scores of the bowed leg were not lower than the unaffected leg supporting the suggestion of physiologic bowing rather than pathologic tibial dysplasia. These data show that dysplastic tibiae in NF1 prior to fracture and nonunion have abnormal bone quality with significant decreases in SOS even though radiographically the tibiae show a thickened cortex. These data also suggest that QUS can help distinguish dysplastic bowing vs physiologic bowing in infancy in NF1. QUS is an effective quantitative outcome measure for trials aimed at improving tibial bowing to prevent fracture, and it is a potential aid in diagnosis and clinical management in NF1.

The value of delaying hCG administration to enable maturation of medium-sized follicles in patients undergoing superovulation for IVF/ICSI.

PURPOSE: The purpose of the study is to determine whether continued stimulation of mature follicles to allow "catch up" growth of medium-sized follicles in assisted reproductive technology compromises the clinical pregnancy (CPR) and live birth (LBR) rates in IVF/ICSI cycles. METHODS: This retrospective cohort study reviewed 200 first IVF ± ICSI cycles out of a total of 340 cycles with complete data. Women underwent stimulation protocols with gonadotropins (Gn) and GnRH antagonist. Treatment cycles were divided into two groups (Gp): hCG administration delayed despite the presence of two mature follicles, defined as ≥ 18 mm [Gp1, n = 79] and hCG administration given when there were two mature follicles [Gp2, n = 121]. RESULTS: The patients in Gp1 were significantly younger than those in Gp2 [32.9 (4.5) vs. 34.3 (4.8), p = 0.04] and needed a median of one more day of superovulation before ovulation was triggered with hCG. The extra days was associated with the use of 450 [75-2025] more Gn, such that at the time the hCG was administered, patient's in group 1 had developed significantly greater number of follicles ≥ 18 mm [mean (SD), 4.9 (1.8) vs. 3.4 (1.7), p < 0.0001]. The clinical pregnancy (48.1 vs. 38.0%, [OR (95% CI)] [1.6 (1.0-2.5), p = 0.09]) and live birth (43.0 vs. 35.5%, [1.4 (0.9-2.3), p = 0.21]) rates per cycle started were not significantly different between the two groups. Forward stepwise logistic regression showed that only maternal age (p = 0.04) influenced clinical pregnancy rates (OR = 0.88, CI 0.78-0.99) and only the number of days for superovulation influenced live birth rates (OR = 0.65, CI 0.486-0.869). CONCLUSION: This study demonstrated that delaying hCG administration to allow further growth of the medium-sized follicles added further days of superovulation and cost without improvement in CPR and LBR.

A Comparison of Secondary Polycythemia in Hypogonadal Men Treated with Clomiphene Citrate versus Testosterone Replacement: A Multi-Institutional Study.

PURPOSE: We evaluated the relative prevalence of secondary polycythemia in hypogonadal men treated with clomiphene citrate or testosterone replacement therapy. MATERIALS AND METHODS: In this retrospective, multi-institutional study, we included 188 men who received clomiphene citrate and 175 who received testosterone replacement therapy with symptomatic hypogonadism. The overall prevalence and ORs of secondary polycythemia for clomiphene citrate treatment vs testosterone replacement were primarily measured, as were baseline characteristics. Subset analysis included polycythemia rates for different types of testosterone replacement therapy. RESULTS: Overall, men on testosterone replacement therapy were older than clomiphene citrate treated men (age 51.5 vs 38 years). Men on testosterone replacement had longer treatment duration than clomiphene citrate treated men (19.6 vs 9.2 months). For testosterone replacement therapy and clomiphene citrate the mean change in hematocrit was 3.0% and 0.6%, and the mean change in serum testosterone was 333.1 and 367.6 ng/dl, respectively. The prevalence of polycythemia in men on testosterone replacement was 11.2% vs 1.7% in men on clomiphene citrate (p = 0.0003). This significance remained on logistic regression after correcting for age, site, smoking history and pretreatment hematocrit. CONCLUSIONS: The prevalence of polycythemia in men treated with clomiphene citrate was markedly lower than that in men on testosterone replacement therapy. The improvement in absolute serum testosterone levels was similar to that in men on testosterone replacement. There is no significant risk of polycythemia in men treated with clomiphene citrate for hypogonadism.

Transvaginal Ultrasound for the Diagnosis of Abnormal Uterine Bleeding.

Transvaginal ultrasound is the first-line imaging test for the evaluation of abnormal uterine bleeding in both premenopausal and postmenopausal women. Transvaginal ultrasound can be used to diagnose structural causes of abnormal bleeding such as polyps, adenomyosis, leiomyomas, hyperplasia, and malignancy, and can also be beneficial in making the diagnosis of ovulatory dysfunction. Traditional 2-dimensional imaging is often enhanced by the addition of 3-dimension imaging with coronal reconstruction and saline infusion sonohysterography. In this article we discuss specific ultrasound findings and technical considerations useful in the diagnosis of abnormal uterine bleeding.

Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy.

Vasectomy is a well accepted global contraceptive approach frequently associated with epididymal granuloma and sperm autoantibody formation. To understand the long-term sequelae of vasectomy, we investigated the early immune response in vasectomized mice. Vasectomy leads to rapid epithelial cell apoptosis and necrosis, persistent inflammation, and sperm granuloma formation in the epididymis. Vasectomized B6AF1 mice did not mount autoimmune response but instead developed sperm antigen-specific tolerance, documented as resistance to immunization-induced experimental autoimmune orchitis (EAO) but not experimental autoimmune encephalomyelitis. Strikingly, tolerance switches over to pathologic autoimmune state following concomitant CD4(+)CD25(+)Foxp3(+) regulatory T cell (Treg) depletion: unilaterally vasectomized mice produce dominant autoantibodies to an orchitogenic antigen (zonadhesin), and develop CD4 T-cell- and antibody-dependent bilateral autoimmune orchitis. Therefore, (i) Treg normally prevents spontaneous organ-specific autoimmunity induction by persistent endogenous danger signal, and (ii) autoantigenic stimulation with sterile autoinflammation can lead to tolerance. Finally, postvasectomy tolerance occurs in B6AF1, C57BL/6, and A/J strains. However, C57BL/6 mice resisted EAO after 60% Treg depletion, but developed EAO after 97% Treg reduction. Therefore, variance in intrinsic Treg function--a possible genetic trait--can influence the divergent tolerogenic versus autoimmune response to vasectomy.

Perioperative Immune Checkpoint Blockade for Muscle-Invasive and Metastatic Bladder Cancer.

Checkpoint inhibitors offer promise in treating muscle-invasive and metastatic bladder cancer, but the optimal timing of their administration-neoadjuvant or adjuvant-remains unclear. To determine the efficacy of combining checkpoint inhibition with standard cisplatin-based chemotherapy, we conducted a phase II trial of neoadjuvant anti-PD-1 (αPD-1) and anti-CTLA-4 (αCTLA-4), in combination with cisplatin-gemcitabine, for patients with muscle-invasive bladder cancer prior to radical cystectomy. In addition, a novel murine model of spontaneous metastatic bladder cancer was used to compare the efficacy of neoadjuvant versus adjuvant anti-PD-L1 (αPD-L1) treatment. The clinical trial was closed prematurely due to the industry's withdrawal of drug provision. Adverse events were observed in all patients; however, serious adverse events were not observed in any patient. A complete pathologic response was observed in 50% of the 4 patients enrolled. Response to treatment was significantly associated with elevated urinary T cells including CD8+ and IFNγ+ CD4+ T cells, suggesting potential reinforcement of immune responses by neoadjuvant αPD-1 and αCTLA-4 against bladder tumor cells. These findings suggest that combining chemotherapy and immunotherapy in the neoadjuvant setting could be safe. However, the complete response rate of this four-drug regimen was modest and emphasizes the need for randomized controlled trials to properly assess immunotherapy efficacy in the neoadjuvant setting. In corresponding murine studies, the MB49-met model consistently displayed widespread metastasis, including tumor growth in the lungs, liver, and bowel mesentery, within 20 days of subcutaneous transplantation. Mice receiving surgery plus neoadjuvant αPD-L1 or adjuvant αPD-L1 exhibited improved survival compared to those receiving only αPD-L1. However, no significant difference in survival was observed between the neoadjuvant and adjuvant αPD-L1 cohorts. Furthermore, the timing of neoadjuvant therapy administration (early vs. late) did not significantly impact survival. This study highlights the potential of perioperative immunotherapy in the treatment of locally advanced and metastatic bladder cancer.

Advancing integrated paediatric care in Australian general practices: Qualitative insights from the SC4C GP-paediatrician model of care.

The Strengthening Care for Children (SC4C) is a general practitioner (GP)-paediatrician integrated model of care that consists of co-consulting sessions and case discussions in the general practice setting, with email and telephone support provided by paediatricians to GPs during weekdays. This model was implemented in 21 general practices in Australia (11 Victoria and 10 New South Wales). Our study aimed to identify the factors moderating the implementation of SC4C from the perspectives of GPs, general practice personnel, paediatricians and families. We conducted a qualitative study as part of the mixed-methods implementation evaluation of the SC4C trial. We collected data through virtual and in-person focus groups at the general practices and phone, virtual and in-person interviews. Data was analysed using an iterative hybrid inductive-deductive thematic analysis. Twenty-one focus groups and thirty-seven interviews were conducted. Overall, participants found SC4C acceptable and suitable for general practices, with GPs willing to learn and expand their paediatric care role. GPs cited improved confidence and knowledge due to the model. Paediatricians reported an enhanced understanding of the general practice context and the strain under which GPs work. GPs and paediatricians reported that this model allowed them to build trust-based relationships with a common goal of improving care for children. Additionally, they felt some aspects, including the lack of remuneration and the work and effort required to deliver the model, need to be considered for the long-term success of the model. Families expressed their satisfaction with the shared knowledge and quality of care jointly delivered by GPs and paediatricians and highlighted that this model of care provides easy access to specialty services without out-of-pocket costs. Future research should focus on finding strategies to ensure the long-term Implementation of this model of care with a particular focus on the individual stressors in general practices.

Impact of Finasteride on Survival in Bladder Cancer: A Retrospective Multi-institutional Database Analysis.

INTRODUCTION: Androgen suppression therapy has been associated with a lower incidence of bladder cancer (BCa) or improved overall/cancer-specific survival. Results are ofent conflicting; therefore, we aim to assess the impact of use of finasteride on overall survival (OS) for BCa using multi-institutional database. METHODS: The South Texas Veterans Healthcare System from 5 medical centers was queried for patients with BCa with or without use of finasteride after diagnosis of BCa. The primary outcome was the impact of finasteride use after diagnosis on the OS in BCa and in the high-risk Non-muscle invasive BCa (NMIBC) cohort. RESULTS: A total of 1890 patients were included, amongst which 619 (32.8%) men were classified as finasteride users and 1271 (67.2%) men as controls. At a median (IQR) follow up of 53.8 (27.4, 90.9) months, death due to any cause was noted in 272 (43.9%) finasteride-treated, and 672 (49.3%) control groups (P = .028). The patients in the finasteride group had significantly better OS in overall cohort (112.1 months vs. 84.8 months, P < .001) as well as in the NMIBC cohort (129.3months vs. 103.2 months, P = .0046). The use of finasteride was independently associated with improved OS in both, overall cohort (HR 0.74, 95% CI 0.63-0.86; P < .001) and in the NMIBC cohort (HR = 0.71, 95% CI 0.55-0.93; P = .011). CONCLUSION: Finasteride use is associated with the improved overall survival in patients with BCa, specifically in patients with NMIBC. We, further, propose a randomized clinical trial to investigate the use of finasteride in BCa patients.

Exposed and Sequestered Antigens in Testes and Their Protection by Regulatory T Cell-Dependent Systemic Tolerance.

Continuous exposure of tissue antigen (Ag) to the autoantigen-specific regulatory T cells (Treg) is required to maintain Treg-dependent systemic tolerance. Thus, testis autoantigens, previously considered as sequestered, may not be protected by systemic tolerance. We now document that the complete testis antigen sequestration is not valid. The haploid sperm Ag lactate dehydrogenase 3 (LDH3) is continuously exposed and not sequestered. It enters the residual body (RB) to egress from the seminiferous tubules and interact with circulating antibody (Ab). Some LDH3 also remains inside the sperm cytoplasmic droplets (CD). Treg-depletion in the DEREG mice that express diphtheria toxin receptor on the Foxp3 promoter results in spontaneous experimental autoimmune orchitis (EAO) and Ab to LDH3. Unlike the wild-type male mice, mice deficient in LDH3 (wild-type female or LDH3 NULL males) respond vigorously to LDH3 immunization. However, partial Treg depletion elevated the wild-type male LDH3 responses to the level of normal females. In contrast to LDH3, zonadhesin (ZAN) in the sperm acrosome displays properties of a sequestered Ag. However, when ZAN and other sperm Ag are exposed by vasectomy, they rapidly induce testis Ag-specific tolerance, which is terminated by partial Treg-depletion, leading to bilateral EAO and ZAN Ab response. We conclude that some testis/sperm Ag are normally exposed because of the unique testicular anatomy and physiology. The exposed Ag: 1) maintain normal Treg-dependent systemic tolerance, and 2) are pathogenic and serve as target Ag to initiate EAO. Unexpectedly, the sequestered Ags, normally non-tolerogenic, can orchestrate de novo Treg-dependent, systemic tolerance when exposed in vasectomy.

Protocol for the implementation evaluation of an integrated paediatric and primary care model: Strengthening Care for Children (SC4C).

INTRODUCTION: Implementation evaluations provide insight into how interventions are delivered across varying contexts and why interventions work in some contexts and not in others. This manuscript outlines a detailed protocol of an implementation evaluation embedded in a stepped-wedge cluster randomised controlled trial of a model of care, Strengthening Care for Children (SC4C), that integrates paediatric care in general practice. The purpose of this manuscript is to describe the pragmatic methods that will be used to capture implementation evaluation process and outcome data within this trial. METHODS AND ANALYSIS: Our implementation evaluation will use a mixed methods design, with data collected in the intervention arm of the SC4C trial guided by a logic model developed using the Consolidated Framework for Implementation Research (CFIR) and Proctor and colleague's taxonomy of implementation outcomes. Data collection will be via questionnaires and semistructured interviews with general practitioners, paediatricians, general practice administrative staff and children and families. Each of the 21 general practices recruited into the study will be described in terms of staffing, patient throughput and location, in addition to the nuanced inner and outer contexts, use of the intervention and its acceptability. We will quantify implementation effectiveness in each general practice clinic using the CFIR validated scoring system. Importantly, we have embedded data collection post intervention to enable assessment of the sustainable adoption of the intervention. An inductive approach to the analysis of qualitative data will identify additional emerging themes that may not be covered by the formal frameworks underpinning our analysis. ETHICS AND DISSEMINATION: Ethical approval was granted by the Royal Children's Hospital Ethics Committee in August 2020 (HREC: 65955). Results will be submitted for publication in peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry 12620001299998 on 1 December 2020.

Strengthening Care for Children (SC4C): protocol for a stepped wedge cluster randomised controlled trial of an integrated general practitioner-paediatrician model of primary care.

INTRODUCTION: Australia's current healthcare system for children is neither sustainable nor equitable. As children (0-4 years) comprise the largest proportion of all primary care-type emergency department presentations, general practitioners (GPs) report feeling undervalued as an integral member of a child's care, and lacking in opportunities for support and training in paediatric conditions. This Strengthening Care for Children (SC4C) randomised trial aims to evaluate a novel, integrated GP-paediatrician model of care, that, if effective, will improve GP quality of care, reduce burden to hospital services and ensure children receive the right care, at the right time, closer to home. METHODS AND ANALYSIS: SC4C is a stepped wedge cluster randomised controlled trial (RCT) of 22 general practice clinics in Victoria and New South Wales, Australia. General practice clinics will provide control period data before being exposed to the 12-month intervention which will be rolled out sequentially each month (one clinic per state) until all 22 clinics receive the intervention. The intervention comprises weekly GP-paediatrician co-consultation sessions; monthly case discussions; and phone and email paediatrician support, focusing on common paediatric conditions. The primary outcome of the trial is to assess the impact of the intervention as measured by the proportion of children's (0-<18 years) GP appointments that result in a hospital referral, compared with the control period. Secondary outcomes include GP quality of care; GP experience and confidence in providing paediatric care; family trust in and preference for GP care; and the sustainability of the intervention. An implementation evaluation will assess the model to inform acceptability, adaptability, scalability and sustainability, while a health economic evaluation will measure the cost-effectiveness of the intervention. ETHICS AND DISSEMINATION: Human research ethics committee (HREC) approval was granted by The Royal Children's Hospital Ethics Committee in August 2020 (Project ID: 65955) and site-specific HRECs. The investigators (including Primary Health Network partners) will communicate trial results to stakeholders and participating GPs and general practice clinics via presentations and publications. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry 12620001299998.

Impact of integrated care coordination on pediatric asthma hospital presentations.

Introduction: Frequent asthma attacks in children result in unscheduled hospital presentations. Patient centered care coordination can reduce asthma hospital presentations. In 2016, The Sydney Children's Hospitals Network launched the Asthma Follow up Integrated Care Initiative with the aim to reduce pediatric asthma emergency department (ED) presentations by 50% through developing and testing an integrated model of care led by care coordinators (CCs). Methods: The integrated model of care was developed by a multidisciplinary team at Sydney Children's Hospital Randwick (SCH,R) and implemented in two phases: Phase I and Phase II. Children aged 2-16 years who presented ≥4 times to the ED of the SCH,R in the preceding 12 months were enrolled in Phase I and those who had ≥4 ED presentations and ≥1 hospital admissions with asthma attack were enrolled in Phase II. Phase I included a suite of interventions delivered by CCs including encouraging parents/carers to schedule follow-up visits with GP post-discharge, ensuring parents/carers are provided with standard asthma resource pack, offering referrals to asthma education sessions, sending a letter to the child's GP advising of the child's recent hospital presentation and coordinating asthma education webinar for GPs. In addition, in Phase II CCs sent text messages to parents/carers reminding them to follow-up with the child's GP. We compared the change in ED visits and hospital admissions at baseline (6 months pre-enrolment) and at 6-and 12-months post-enrolment in the program. Results: During December 2016-January 2021, 160 children (99 in Phase I and 61 in Phase II) were enrolled. Compared to baseline at 6- and 12-months post-enrolment, the proportion of children requiring ≥1 asthma ED presentations reduced by 43 and 61% in Phase I and 41 and 66% in Phase II. Similarly, the proportion of children requiring ≥1 asthma hospital admissions at 6- and 12-months post-enrolment reduced by 40 and 47% in Phase I and 62 and 69% in Phase II. Conclusion: Our results support that care coordinator led integrated model of asthma care which enables integration of acute and primary care services and provides families with asthma resources and education can reduce asthma hospital presentations in children.

Cutting edge: normal regional lymph node enrichment of antigen-specific regulatory T cells with autoimmune disease-suppressive capacity.

Natural CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) effectively prevent autoimmune disease development, but their role in maintaining physiological tolerance against self-Ag of internal organs is not yet defined. In this study, we quantified disease-specific Treg (DS-Treg) as Treg that preferentially suppress one autoimmune disease over another in day 3 thymectomized recipients. A striking difference was found among individual lymph nodes (LN) of normal mice; Treg from draining LN were 15-50 times more efficient than those of nondraining LN at suppressing autoimmune diseases of ovary, prostate, and lacrimal glands. The difference disappeared upon auto-Ag ablation and returned upon auto-Ag re-expression. In contrast, the CD4(+)CD25(-) effector T cells from different individual LN induced multiorgan inflammation with comparable organ distribution. We propose that peripheral tolerance for internal organs relies on the control of autoreactive effector T cells by strategic enrichment of Ag-specific Treg in the regional LN.

Correlates of refusal of radical cystectomy in patients with muscle-invasive bladder cancer.

PURPOSE: To evaluate factors associated with radical cystectomy (RC) refusal, subsequent treatment decisions, and their influence on overall survival (OS). MATERIALS AND METHODS: We queried the National Cancer Database for patients with non-metastatic muscle-invasive bladder cancer (MIBC), cT2-T4M0. Patients who refused recommended RC were further stratified by treatment into chemotherapy, radiation therapy, chemoradiotherapy, and no treatment groups. Patients were excluded from the analysis if surgery was not planned, not recommended; or if survival data were unknown. Multivariate logistic regression modeling was utilized to identify independent predictors of refusing RC. Cox proportional hazards model with propensity score overlap weighting was utilized to identify survival predictors. Kaplan-Meier analysis was utilized to evaluate survival according to treatment. RESULTS: A total of 74,159 MIBC patients were identified. Among patients with documented reasons for no surgery, 5.4% refused RC despite physician recommendation. Predictors of refusal on multivariate analysis included female gender (P = 0.016), advancing age ≥80 (vs. <60, P < 0.001), African American race (vs. white, P < 0.001) Medicaid (vs. private insurance, P < 0.001) and advancing T stage (T4 vs. T2, P < 0.001). Patients treated at academic centers were less likely to decline RC (vs. community centers, P < 0.001). Median survival after RC was 40.44 months vs. 12.52 months in refusal group. Undergoing chemoradiation had significantly improved survival in those patients compared to monotherapy or no treatment (hazard ratio 0.25, P < 0.001). Overlap weighted model Identified RC refusal as an independent predictor of poor OS (P < 0.001). CONCLUSIONS: Several sociodemographic and clinical factors are associated with refusing radical cystectomy. Such refusal is associated with poor survival outcomes.