Th17/1 and ex-Th17 cells are detected in patients with polyarticular juvenile arthritis and increase following treatment.

BACKGROUND: A better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls. METHODS: Blood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann-Whitney U and Wilcoxon matched-pairs signed rank tests. RESULTS: Treatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p < 0.05), but Tregs (CD3 + CD4 + CD25 + FOXP3 +) from patients did not differ from controls. Changes in STAT3 phosphorylation in CD4 + T cells following ex vivo stimulation were not significantly different in patients compared to controls. We identified dual IL-17 + and interferon (IFN)γ + expressing CD4 + T cells in patients, but not controls. Further, both Th17/1 s (CCR6 + CD161 + IFNγ + IL-17 +) and ex-Th17s (CCR6 + CD161 + IFNγ + IL-17neg) were increased in patients' post-treatment (Th17/1: 0.3% v 0.07%, p < 0.05 and ex-Th17s: 2.3% v 1.4%, p < 0.05). The patients with the highest IL-17 expressing cells post-treatment remained therapy-bound. CONCLUSIONS: Patients with polyJIA have increased baseline Th17 cells, potentially reflecting higher tonic STAT3 activation in vivo. These quantifiable immune markers may identify patients that would benefit upfront from pathway-focused biologic therapies. Our data also suggest that inflammatory CD4 + T cell subsets not detected in controls but increased in post-treatment samples should be further evaluated as a tool to stratify patients in remission on medication. Future work will explore these proposed diagnostic and prognostic biomarkers.

Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS).

Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.

Targeting HIV-1 reservoirs in T cell subsets.

The HIV-1 reservoirs harbor the latent proviruses that are integrated into the host genome. It is a challenging task to eradicate the proviruses in order to achieve an HIV cure. We have described a strategy for the clearance of HIV-1 infection through selective elimination of host cells harboring replication-competent HIV (SECH), by inhibition of autophagy and promotion of apoptosis during viral re-activation. HIV-1 can infect various CD4+ T cell subsets, but it is not known whether the SECH approach is equally effective in targeting HIV-1 reservoirs in these different subsets in vivo. In a humanized mouse model, we found that treatments of HIV-1 infection by suppressive antiretroviral therapy (ART) led to the establishment of latent HIV reservoirs in naïve, central memory and effector memory T cells. Moreover, SECH treatments could clear latent HIV-1 reservoirs in these different T cell subsets of humanized mice. Co-culture studies showed that T cell subsets latently infected by HIV-1, but not uninfected bystander cells, were susceptible to cell death induced by SECH treatments. Our study suggests that the SECH strategy is effective for specific targeting of latent HIV-1 reservoirs in different T cell subsets.

Mitochondrion-Mediated Cell Death through Erk1-Alox5 Independent of Caspase-9 Signaling.

Mitochondrial disruption leads to the release of cytochrome c to activate caspase-9 and the downstream caspase cascade for the execution of apoptosis. However, cell death can proceed efficiently in the absence of caspase-9 following mitochondrial disruption, suggesting the existence of caspase-9-independent cell death mechanisms. Through a genome-wide siRNA library screening, we identified a network of genes that mediate caspase-9-independent cell death, through ROS production and Alox5-dependent membrane lipid peroxidation. Erk1-dependent phosphorylation of Alox5 is critical for targeting Alox5 to the nuclear membrane to mediate lipid peroxidation, resulting in nuclear translocation of cytolytic molecules to induce DNA damage and cell death. Consistently, double knockouts of caspase-9 and Alox5 in mice, but not deletion of either gene alone, led to significant T cell expansion with inhibited cell death, indicating that caspase-9- and Alox5-dependent pathways function in parallel to regulate T cell death in vivo. This unbiased whole-genome screening reveals an Erk1-Alox5-mediated pathway that promotes membrane lipid peroxidation and nuclear translocation of cytolytic molecules, leading to the execution of cell death in parallel to the caspase-9 signaling cascade.

Clearance of HIV-1 or SIV reservoirs by promotion of apoptosis and inhibition of autophagy: Targeting intracellular molecules in cure-directed strategies.

The reservoirs of the HIV display cellular properties resembling long-lived immune memory cells that could be exploited for viral clearance. Our interest in developing a cure for HIV stems from the studies of immunologic memory against infections. We and others have found that long-lived immune memory cells employ prosurvival autophagy and antiapoptotic mechanisms to protect their longevity. Here, we describe the rationale for the development of an approach to clear HIV-1 by selective elimination of host cells harboring replication-competent HIV (SECH). While reactivation of HIV-1 in the host cells with latency reversing agents (LRAs) induces viral gene expression leading to cell death, LRAs also simultaneously up-regulate prosurvival antiapoptotic molecules and autophagy. Mechanistically, transcription factors that promote HIV-1 LTR-directed gene expression, such as NF-κB, AP-1, and Hif-1α, can also enhance the expression of cellular genes essential for cell survival and metabolic regulation, including Bcl-xL, Mcl-1, and autophagy genes. In the SECH approach, we inhibit the prosurvival antiapoptotic molecules and autophagy induced by LRAs, thereby allowing maximum killing of host cells by the induced HIV-1 proteins. SECH treatments cleared HIV-1 infections in humanized mice in vivo and in HIV-1 patient PBMCs ex vivo. SECH also cleared infections by the SIV in rhesus macaque PBMCs ex vivo. Research efforts are underway to improve the efficacy and safety of SECH and to facilitate the development of SECH as a therapeutic approach for treating people with HIV.

Protection of Quiescence and Longevity of IgG Memory B Cells by Mitochondrial Autophagy.

The development of long-lived immune memory cells against pathogens is critical for the success of vaccines to establish protection against future infections. However, the mechanisms governing the long-term survival of immune memory cells remain to be elucidated. In this article, we show that the maintenance mitochondrial homeostasis by autophagy is critical for restricting metabolic functions to protect IgG memory B cell survival. Knockout of mitochondrial autophagy genes, Nix and Bnip3, leads to mitochondrial accumulation and increases in oxidative phosphorylation and fatty acid synthesis, resulting in the loss of IgG+ memory B cells in mice. Inhibiting fatty acid synthesis or silencing necroptosis gene Ripk3 rescued Nix-/-Bnip3-/- IgG memory B cells, indicating that mitochondrial autophagy is important for limiting metabolic functions to prevent cell death. Our results suggest a critical role for mitochondrial autophagy in the maintenance of immunological memory by protecting the metabolic quiescence and longevity of memory B cells.

The Utility of Self-Determination Theory in Predicting Transition Readiness in Adolescents With Special Healthcare Needs.

PURPOSE: Adolescents and young adults with chronic health conditions must learn skills to successfully manage their health as they prepare to transition into adult-based care. Self-determination theory (SDT), an empirically based theory of human motivation, posits that competence (feeling effective), autonomy (volition to perform behaviors), and relatedness (support for autonomy from others) influence behavioral change. This study evaluates the utility of SDT constructs in predicting transition readiness among adolescents and young adults recruited into an intervention to promote successful healthcare transition. METHODS: Baseline assessments were completed by 137 patients aged 17-23 years recruited from pediatric renal, gastroenterology, or rheumatology clinical services. Surveys measured transition readiness (Transition Readiness Assessment Questionnaire) as well as SDT constructs, including competence (Patient Activation Measure); provider relatedness and parent autonomy support (Health Care Climate Questionnaire); and health care-related autonomy (Treatment Self-Regulation Questionnaire). Relationships between SDT constructs and transition readiness were evaluated using linear regression. RESULTS: Between 44 and 48 participants were recruited from each service. Bivariate correlation coefficients between transition readiness and SDT constructs were competence (r = .44), autonomous autonomy (r = .34), controlled autonomy (r = .27), provider relatedness (r = .46), and parental autonomy support (r = .35) (p < .01). Age positively correlated with transition readiness (r = .47, p < .001). After controlling for age, gender, and clinical service, competence (p < .001) and provider relatedness (p = .008) successfully predicted transition readiness (R2 = .423; F change; p < .001). CONCLUSIONS: Findings from this cross-sectional study support the utility of SDT constructs in promoting transition readiness among adolescents and young adults with chronic conditions, underscoring the importance of building competence and provider support for autonomy during this critical period.

Modeling hospital energy and economic costs for COVID-19 infection control interventions.

The study objective assessed the energy demand and economic cost of two hospital-based COVID-19 infection control interventions: negative pressure (NP) treatment rooms and xenon pulsed ultraviolet (XP-UV) equipment. After projecting COVID-19 hospitalizations, a Hospital Energy Model and Infection De-escalation Models quantified increases in energy demand and reductions in infections. The NP intervention was applied to 11, 22, and 44 rooms for small, medium, and large hospitals, while the XP-UV equipment was used eight, nine, and ten hours a day. For small, medium, and large hospitals, the annum kWh for NP rooms were 116,700 kWh, 332,530 kWh, 795,675 kWh, which correspond to annum energy costs of $11,845 ($1,077/room), $33,752 ($1,534/room), and $80,761 ($1,836/room). For XP-UV, the annum-kilowatt-hours (and costs) were 438 ($45), 493 ($50), and 548 ($56) for small, medium, and large hospitals. While energy efficiencies may be expected for the large hospital, the hospital contained more energy-intensive use rooms (ICUs) which resulted in higher operational and energy costs. XP-UV had a greater reduction in secondary COVID-19 infections in large and medium hospitals. NP rooms had a greater reduction in secondary SARS-CoV-2 transmission in small hospitals. Early implementation of interventions can result in realized cost savings through reduced hospital-acquired infections.

The Innate Immune Response to Mycobacterium tuberculosis Infection.

Infection with Mycobacterium tuberculosis causes >1.5 million deaths worldwide annually. Innate immune cells are the first to encounter M. tuberculosis, and their response dictates the course of infection. Dendritic cells (DCs) activate the adaptive response and determine its characteristics. Macrophages are responsible both for exerting cell-intrinsic antimicrobial control and for initiating and maintaining inflammation. The inflammatory response to M. tuberculosis infection is a double-edged sword. While cytokines such as TNF-α and IL-1 are important for protection, either excessive or insufficient cytokine production results in progressive disease. Furthermore, neutrophils-cells normally associated with control of bacterial infection-are emerging as key drivers of a hyperinflammatory response that results in host mortality. The roles of other innate cells, including natural killer cells and innate-like T cells, remain enigmatic. Understanding the nuances of both cell-intrinsic control of infection and regulation of inflammation will be crucial for the successful development of host-targeted therapeutics and vaccines.

Successful treatment of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome with tofacitinib.

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a rare autoinflammatory disorder. Cutaneous manifestations of CANDLE syndrome include characteristic recurring violaceous annular plaques comprised of an immature dermal mononuclear cell infiltrate. In CANDLE syndrome, deleterious genetic mutations inhibit proteasome-immunoproteasome function, resulting in cellular accumulation of ubiquitinated waste proteins that activate type I interferon signaling to drive inflammation. We describe a report of successful treatment of a 12-year-old girl with CANDLE syndrome with tofacitinib.

Optimal Design of Paired Built Environment Interventions for Control of MDROs in Acute Care and Community Hospitals.

OBJECTIVES: Our goal was to optimize infection control of paired environmental control interventions within hospitals to reduce methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Enterobacteriaceae (CRE), and vancomycin-resistant Enterococci (VRE). BACKGROUND: The most widely used infection control interventions are deployment of handwashing (HW) stations, control of relative humidity (RH), and negative pressure (NP) treatment rooms. Direct costs of multidrug-resistant organism (MDRO) infections are typically not included in the design of such interventions. METHODS: We examined the effectiveness of pairing HW with RH and HW with NP. We used the following three data sets: A meta-analysis of progression rates from uncolonized to colonized to infected, 6 years of MDRO treatment costs from 400 hospitals, and 8 years of MDRO incidence rates at nine army hospitals. We used these data as inputs into an Infection De-Escalation Model with varying budgets to obtain optimal intervention designs. We then computed the infection and prevention rates and cost savings resulting from these designs. RESULTS: The average direct cost of an MDRO infection was $3,289, $1,535, and $1,067 for MRSA, CRE, and VRE. The mean annual incidence rates per facility were 0.39%, 0.034%, and 0.011% for MRSA, CRE, and VRE. After applying the cost-minimizing intervention pair to each scenario, the percentage reductions in infections (and annual direct cost savings) in large, community, and small acute care hospitals were 69% ($1.5 million), 73% ($631K), 60% ($118K) for MRSA, 52% ($460.5K), 58% ($203K), 50% ($37K) for CRE, and 0%, 0%, and 50% ($12.8K) for VRE. CONCLUSION: The application of this Infection De-Escalation Model can guide cost-effective decision making in hospital built environment design to improve control of MDRO infections.

Modeling Hospital Energy and Economic Costs for COVID-19 Infection Control Interventions

The objective of this study was to assess the energy demand and economic cost of two hospital-based COVID-19 infection control interventions. The intervention control measures evaluated include use of negative pressure (NP) treatment rooms and xenon pulsed ultraviolet (XP-UV) infection control equipment. After projecting COVID-19 hospitalizations, a Hospital Energy Model and Infection De-escalation Models are applied to quantify increases in energy demand and reductions in secondary infections. The scope of the interventions consisted of implementing NP in 11, 22, and 44 rooms (at small, medium, and large hospitals) while the XP-UV equipment was used eight, nine, and ten hours a day, respectively. The annum kilowatt-hours (kWh) for NP (and costs were at $0.1015 per kWh) were 116,700 ($11,845), 332,530 ($33,752), 795,675 ($80,761) for small, medium, and large hospitals ($1,077, $1,534 $1,836 added annum energy cost per NP room). For XP-UV, the annum kilowatt-hours and costs were 438 ($45), 493 ($50), 548 ($56) for small, medium, and large hospitals. There are other initial costs associated with the purchase and installation of the equipment, with XP-UV having a higher initial cost. XP-UV had a greater reduction in secondary COVID-19 infections in large and medium hospitals. NP rooms had a greater reduction in secondary SARS-CoV-2 transmission in small hospitals. Early implementation of interventions can result in realized cost savings through reduced hospital-acquired infections.

Association between mobility patterns and COVID-19 transmission in the USA: a mathematical modelling study.

BACKGROUND: Within 4 months of COVID-19 first being reported in the USA, it spread to every state and to more than 90% of all counties. During this period, the US COVID-19 response was highly decentralised, with stay-at-home directives issued by state and local officials, subject to varying levels of enforcement. The absence of a centralised policy and timeline combined with the complex dynamics of human mobility and the variable intensity of local outbreaks makes assessing the effect of large-scale social distancing on COVID-19 transmission in the USA a challenge. METHODS: We used daily mobility data derived from aggregated and anonymised cell (mobile) phone data, provided by Teralytics (Zürich, Switzerland) from Jan 1 to April 20, 2020, to capture real-time trends in movement patterns for each US county, and used these data to generate a social distancing metric. We used epidemiological data to compute the COVID-19 growth rate ratio for a given county on a given day. Using these metrics, we evaluated how social distancing, measured by the relative change in mobility, affected the rate of new infections in the 25 counties in the USA with the highest number of confirmed cases on April 16, 2020, by fitting a statistical model for each county. FINDINGS: Our analysis revealed that mobility patterns are strongly correlated with decreased COVID-19 case growth rates for the most affected counties in the USA, with Pearson correlation coefficients above 0·7 for 20 of the 25 counties evaluated. Additionally, the effect of changes in mobility patterns, which dropped by 35-63% relative to the normal conditions, on COVID-19 transmission are not likely to be perceptible for 9-12 days, and potentially up to 3 weeks, which is consistent with the incubation time of severe acute respiratory syndrome coronavirus 2 plus additional time for reporting. We also show evidence that behavioural changes were already underway in many US counties days to weeks before state-level or local-level stay-at-home policies were implemented, implying that individuals anticipated public health directives where social distancing was adopted, despite a mixed political message. INTERPRETATION: This study strongly supports a role of social distancing as an effective way to mitigate COVID-19 transmission in the USA. Until a COVID-19 vaccine is widely available, social distancing will remain one of the primary measures to combat disease spread, and these findings should serve to support more timely policy making around social distancing in the USA in the future. FUNDING: None.

Engineered Cardiac Tissues Generated in the Biowire II: A Platform for Human-Based Drug Discovery.

Recent advances in techniques to differentiate human induced pluripotent stem cells (hiPSCs) hold the promise of an unlimited supply of human derived cardiac cells from both healthy and disease populations. That promise has been tempered by the observation that hiPSC-derived cardiomyocytes (hiPSC-CMs) typically retain a fetal-like phenotype, raising concern about the translatability of the in vitro data obtained to drug safety, discovery, and development studies. The Biowire II platform was used to generate 3D engineered cardiac tissues (ECTs) from hiPSC-CMs and cardiac fibroblasts. Long term electrical stimulation was employed to obtain ECTs that possess a phenotype like that of adult human myocardium including a lack of spontaneous beating, the presence of a positive force-frequency response from 1 to 4 Hz and prominent postrest potentiation. Pharmacology studies were performed in the ECTs to confirm the presence and functionality of pathways that modulate cardiac contractility in humans. Canonical responses were observed for compounds that act via the ß-adrenergic/cAMP-mediated pathway, eg, isoproterenol and milrinone; the L-type calcium channel, eg, FPL64176 and nifedipine; and indirectly effect intracellular Ca2+ concentrations, eg, digoxin. Expected positive inotropic responses were observed for compounds that modulate proteins of the cardiac sarcomere, eg, omecamtiv mecarbil and levosimendan. ECTs generated in the Biowire II platform display adult-like properties and have canonical responses to cardiotherapeutic and cardiotoxic agents that affect contractility in humans via a variety of mechanisms. These data demonstrate that this human-based model can be used to assess the effects of novel compounds on contractility early in the drug discovery and development process.

Cost-Effectiveness of Multifaceted Built Environment Interventions for Reducing Transmission of Pathogenic Bacteria in Healthcare Facilities.

OBJECTIVES: The objective of this study is to determine the optimal allocation of budgets for pairs of alterations that reduce pathogenic bacterial transmission. Three alterations of the built environment are examined: handwashing stations (HW), relative humidity control (RH), and negatively pressured treatment rooms (NP). These interventions were evaluated to minimize total cost of healthcare-associated infections (HAIs), including medical and litigation costs. BACKGROUND: HAIs are largely preventable but are difficult to control because of their multiple mechanisms of transmission. Moreover, the costs of HAIs and resulting mortality are increasing with the latest estimates at US$9.8 billion annually. METHOD: Using 6 years of longitudinal multidrug-resistant infection data, we simulated the transmission of pathogenic bacteria and the infection control efforts of the three alterations using Chamchod and Ruan's model. We determined the optimal budget allocations among the alterations by representing them under Karush-Kuhn-Tucker conditions for this nonlinear optimization problem. RESULTS: We examined 24 scenarios using three virulence levels across three facility sizes with varying budget levels. We found that in general, most of the budget is allocated to the NP or RH alterations in each intervention. At lower budgets, however, it was necessary to use the lower cost alterations, HW or RH. CONCLUSIONS: Mathematical optimization offers healthcare enterprise executives and engineers a tool to assist with the design of safer healthcare facilities within a fiscally constrained environment. Herein, models were developed for the optimal allocation of funds between HW, RH, and negatively pressured treatment rooms (NP) to best reduce HAIs. Specific strategies vary by facility size and virulence.

Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.

The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.

The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages.

The molecular basis of signal-dependent transcriptional activation has been extensively studied in macrophage polarization, but our understanding remains limited regarding the molecular determinants of repression. Here we show that IL-4-activated STAT6 transcription factor is required for the direct transcriptional repression of a large number of genes during in vitro and in vivo alternative macrophage polarization. Repression results in decreased lineage-determining transcription factor, p300, and RNA polymerase II binding followed by reduced enhancer RNA expression, H3K27 acetylation, and chromatin accessibility. The repressor function of STAT6 is HDAC3 dependent on a subset of IL-4-repressed genes. In addition, STAT6-repressed enhancers show extensive overlap with the NF-κB p65 cistrome and exhibit decreased responsiveness to lipopolysaccharide after IL-4 stimulus on a subset of genes. As a consequence, macrophages exhibit diminished inflammasome activation, decreased IL-1ß production, and pyroptosis. Thus, the IL-4-STAT6 signaling pathway establishes an alternative polarization-specific epigenenomic signature resulting in dampened macrophage responsiveness to inflammatory stimuli.

Rapid infusion of rituximab is well tolerated in children with hematologic, oncologic, and rheumatologic disorders.

Traditional administration of rituximab requires careful titration and may involve many hours to minimize the risk of reactions. The objective of this study was to evaluate the safety of rapid infusions of rituximab in a pilot group of children with hematologic, oncologic, and rheumatologic disorders, and to determine the incidence of rate-related infusion reactions. Twenty patients enrolled in the study. All patients tolerated the rapid infusion of rituximab and no patient had an infusion-related reaction. We conclude that rapid infusions of rituximab are well tolerated and safe in our pilot group of patients.

Diagnosis and management of 365 ureteric injuries following obstetric and gynecologic surgery in resource-limited settings.

INTRODUCTION: Ureteric injuries are among the most serious complications of pelvic surgery. The incidence in low-resource settings is not well documented. METHODS: This retrospective review analyzes a cohort of 365 ureteric injuries with ureterovaginal fistulas in 353 women following obstetric and gynecologic operations in 11 countries in Africa and Asia, all low-resource settings. The patients with ureteric injury were stratified into three groups according to the initial surgery: (a) obstetric operations, (b) gynecologic operations, and (c) vesicovaginal fistula (VVF) repairs. RESULTS: The 365 ureteric injuries in this series comprise 246 (67.4%) after obstetric procedures, 65 (17.8%) after gynecologic procedures, and 54 (14.8%) after repair of obstetric fistulas. Demographic characteristics show clear differences between women with iatrogenic injuries and women with obstetric fistulas. The study describes abdominal ureter reimplantation and other treatment procedures. Overall surgical results were good: 92.9% of women were cured (326/351), 5.4% were healed with some residual incontinence (19/351), and six failed (1.7%). CONCLUSIONS: Ureteric injuries after obstetric and gynecologic operations are not uncommon. Unlike in high-resource contexts, in low-resource settings obstetric procedures are most often associated with urogenital fistula. Despite resource limitations, diagnosis and treatment of ureteric injuries is possible, with good success rates. Training must emphasize optimal surgical techniques and different approaches to assisted vaginal delivery.