X-CHIME enables combinatorial, inducible, lineage-specific and sequential knockout of genes in the immune system.

Annotation of immunologic gene function in vivo typically requires the generation of knockout mice, which is time consuming and low throughput. We previously developed CHimeric IMmune Editing (CHIME), a CRISPR-Cas9 bone marrow delivery system for constitutive, ubiquitous deletion of single genes. Here we describe X-CHIME, four new CHIME-based systems for modular and rapid interrogation of gene function combinatorially (C-CHIME), inducibly (I-CHIME), lineage-specifically (L-CHIME) or sequentially (S-CHIME). We use C-CHIME and S-CHIME to assess the consequences of combined deletion of Ptpn1 and Ptpn2, an embryonic lethal gene pair, in adult mice. We find that constitutive deletion of both PTPN1 and PTPN2 leads to bone marrow hypoplasia and lethality, while inducible deletion after immune development leads to enteritis and lethality. These findings demonstrate that X-CHIME can be used for rapid mechanistic evaluation of genes in distinct in vivo contexts and that PTPN1 and PTPN2 have some functional redundancy important for viability in adult mice.

Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity.

Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that high-fat diet (HFD)-induced obesity impairs CD8+ T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8+ T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8+ T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8+ T cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8+ T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.

LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade.

Chromatin regulators play a broad role in regulating gene expression and, when gone awry, can lead to cancer. Here, we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to double-stranded RNA (dsRNA) stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8+ T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy.

PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity.

CD8+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+ progenitor exhausted and Tim-3+ terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8+ T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3+ cells without altering Slamf6+ numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8+ T cells enhanced Tim-3+ anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3+CD8+ T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.

Immuno-PET identifies the myeloid compartment as a key contributor to the outcome of the antitumor response under PD-1 blockade.

Immunotherapy using checkpoint-blocking antibodies against PD-1 has produced impressive results in a wide range of cancers. However, the response remains heterogeneous among patients. We used noninvasive immuno-positron emission tomography (PET), using 89Zr-labeled PEGylated single-domain antibody fragments (nanobodies or VHHs), to explore the dynamics and distribution of intratumoral CD8+ T cells and CD11b+ myeloid cells in response to anti-PD-1 treatment in the MC38 colorectal mouse adenocarcinoma model. Responding and nonresponding tumors showed consistent differences in the distribution of CD8+ and CD11b+ cells. Anti-PD-1 treatment mobilized CD8+ T cells from the tumor periphery to a more central location. Only those tumors fully infiltrated by CD8+ T cells went on to complete resolution. All tumors contained CD11b+ myeloid cells from the outset of treatment, with later recruitment of additional CD11b+ cells. As tumors grew, the distribution of intratumoral CD11b+ cells became more heterogeneous. Shrinkage of tumors in responders correlated with an increase in the CD11b+ population in the center of the tumors. The changes in distribution of CD8+ and CD11b+ cells, as assessed by PET, served as biomarkers to gauge the efficacy of anti-PD-1 treatment. Single-cell RNA sequencing of RNA from intratumoral CD45+ cells showed that CD11b+ cells in responders and nonresponders were markedly different. The responders exhibited a dominant population of macrophages with an M1-like signature, while the CD45+ population in the nonresponders displayed an M2-like transcriptional signature. Thus, by using immuno-PET and single-cell RNA sequencing, we show that anti-PD-1 treatment not only affects interactions of CD8+ T cells with the tumor but also impacts the intratumoral myeloid compartment.

The relationship between police contacts for drug use-related crime and future arrests, incarceration, and overdoses: a retrospective observational study highlighting the need to break the vicious cycle.

BACKGROUND: Individuals with substance use disorder often encounter law enforcement due to drug use-related criminal activity. Traditional policing approaches may not be effective for reducing recidivism and improving outcomes in this population. Here, we describe the impact of traditional policing approach to drug use-related crime on future recidivism, incarceration, and overdoses. METHODS: Using a local Police Department (PD) database, we identified individuals with a police contact with probable cause to arrest for a drug use-related crime ("index contact"), including for an opioid-related overdose, between September 1, 2015, and August 31, 2016 (Group 1, N = 52). Data on police contacts, arrests, and incarceration 12 months before and after the index contact were extracted and compared using Fisher's exact or Wilcoxon signed-rank tests. County-level data on fatal overdoses and estimates of time spent by PD officers in index contact-related responses were also collected. To determine whether crime-related outcomes changed over time, we identified a second group (Group 2, N = 263) whose index contact occurred between September 1, 2017, and August 31, 2020, and extracted data on police contacts, arrests, and incarceration during the 12 months prior to their index contact. Pre-index contact data between Groups 1 and 2 were compared with Fisher's exact or Mann-Whitney U tests. RESULTS: Comparison of data during 12 months before and 12 months after the index contact showed Group 1 increased their total number of overdose-related police contacts (6 versus 18; p = 0.024), incarceration rate (51.9% versus 84.6%; p = 0.001), and average incarceration duration per person (16.2 [SD = 38.6] to 50 days [SD = 72]; p < 0.001). In the six years following the index contact, 9.6% sustained a fatal opioid-related overdose. For Group 1, an average of 4.7 officers were involved, devoting an average total of 7.2 h per index contact. Comparison of pre-index contact data between Groups 1 and 2 showed similar rates of overdose-related police contacts and arrests. CONCLUSIONS: The results indicated that the traditional policing approach to drug use-related crime did not reduce arrests or incarceration and was associated with a risk of future overdose fatalities. Alternative law enforcement-led strategies, e.g., pre-arrest diversion-to-treatment programs, are urgently needed.

The Vietnamese Version of the Brief Illness Perception Questionnaire and the Beliefs about Medicines Questionnaire: Translation and Cross-cultural Adaptation.

OBJECTIVE: To translate and cross-culturally adapt the Brief Illness Perception Questionnaire (BIPQ) and the Beliefs about Medicines Questionnaire (BMQ) into Vietnamese. METHODS: We followed the guideline by Beaton et al. (2000 & 2007). Stage I: two translators (informed and uninformed) translated the questionnaires. Stage II: the translations were synthesised. Stage III: back translation was performed by two translators fluent in both Vietnamese and English but naïve to the outcome measurement. Stage IV: seven experts reached consensus on the pre-final Vietnamese version (BIPQ-V and BMQ-V). Stage V: field test of the questionnaires on 16 twelve-year-old students and 31 Vietnamese patients. In addition, we determined the internal consistency and test-retest reliability of the questionnaires in 34 Vietnamese patients with acute coronary syndrome. RESULTS: All experts agreed that there was semantic, idiomatic, experiential and conceptual equivalence between the original and pre-final Vietnamese versions of the BIPQ and BMQ. Cronbach's alpha coefficients of the internal consistency were acceptable for the BMQ-V Specific-Necessity (0.64), BMQ-V Specific-Concerns (0.62) and BMQ-V General-Harm (0.60), with the exception of BMQ-V General-Overuse (0.27). Intra-class correlation coefficients of the test-retest reliability were acceptable for the subscales of BMQ-V (range: 0.77-0.86), and BIPQ-V items (range: 0.62-0.85) with the exception of BIPQ-V 1 (0.44, 95% CI -014 to 0.72) and BIPQ-V 4 (0.57, 95% CI 0.22-0.81). CONCLUSIONS: The Vietnamese version of BIPQ and BMQ are reliable tools to assess illness perceptions and beliefs about medicines of patients with acute coronary syndrome. Psychometric properties of these questionnaires should be tested in different patient populations.

OBJECTIF: Traduire en vietnamien et adapter culturellement le Bref Questionnaire sur la Perception de la Maladie (BIPQ) et le Questionnaire sur les Croyances relatives aux Médicaments (BMQ). MÉTHODES: Nous avons suivi les directives de Beaton et al. (2000 et 2007). Etape I: deux traducteurs (informés et non informés) ont traduit les questionnaires. Etape II: les traductions ont été synthétisées. Etape III: une re-traduction a été effectuée par deux traducteurs parlant couramment le vietnamien et l'anglais mais naïfs sur la mesure des résultats. Etape IV: sept experts sont parvenus à un consensus sur la version vietnamienne pré-finale (BIPQ-V et BMQ-V). Etape V: test sur le terrain des questionnaires sur 16 étudiants de 12 ans et 31 patients vietnamiens. En outre, nous avons déterminé la cohérence interne et la fiabilité du test/re-test des questionnaires chez 34 patients vietnamiens atteints de syndrome coronarien aigu. RÉSULTATS: Tous les experts ont convenu qu'il existait une équivalence sémantique, idiomatique, expérientielle et conceptuelle entre les versions originales et pré-finale vietnamiennes du BIPQ et du BMQ. Les coefficients alpha de cohérence interne de Cronbach étaient acceptables pour la nécessité spécifique du BMQ-V (0,64), les préoccupations spécifiques du BMQ-V (0,62) et la nocivité générale du BMQ-V (0,60), à l'exception de la qualité générale du BMQ-V (0,27). Les coefficients de corrélation intra-classe de la fiabilité du test/re-test étaient acceptables pour les sous-échelles de BMQ-V (plage: 0,77-0,86) et les éléments du BIPQ-V (plage: 0,62-0,85) à l'exception du BIPQ-V 1 (0,44; IC95%: −014-0,72) et du BIPQ-V 4 (0,57; IC95%: 0,22-0,81). CONCLUSIONS: Les versions vietnamiennes du BIPQ et du BMQ constituent des outils fiables pour évaluer les perceptions relatives à la maladie et les croyances concernant les médicaments destinés aux patients atteints du syndrome coronarien aigu. Les propriétés psychométriques de ces questionnaires doivent être testées dans différentes populations de patients.

Physicians' adherence to acute coronary syndrome prescribing guidelines in Vietnamese hospital practice: a cross-sectional study.

OBJECTIVES: To determine the extent of physicians' adherence to prescribing guidelines for acute coronary syndrome in Vietnamese hospitals. METHODS: Retrospective cross-sectional study of medical records of all patients with ACS admitted to two public hospitals in Ho Chi Minh City, Vietnam, from January to December 2013. Percentages of eligible patients receiving guideline-recommended medications were determined. Factors associated with non-adherence were identified using multivariate logistic regression. RESULTS: Overall, 711 medical records were reviewed and 284 patients fulfilled inclusion criteria (mean age 64 years; 69.4% male). Of those patients eligible for treatment, aspirin was prescribed for 97.9% at arrival and 96.3% at discharge; dual antiplatelet therapy was prescribed for 92.3% at arrival and 91.7% at discharge; loading doses were prescribed for 79.5% (aspirin) and 55.8% (clopidogrel); beta blockers were prescribed for 58.7% at arrival and 76.7% at discharge; angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) were prescribed for 89.1% at arrival or discharge; and statins were prescribed for 94.1% at arrival and 90.7% at discharge. Patients undergoing an invasive procedure were more likely to receive guideline-recommended medications at discharge: dual antiplatelet therapy (OR 3.77; 95% CI 1.23-11.52), beta blocker (OR 3.95; 95% CI 1.86-8.40) and ACEI/ARB (OR 4.01; 95% CI 1.30-12.41). Ninety of the excluded patients were discharged without completing treatment. CONCLUSIONS: In general, physicians closely adhered to ACS prescribing guidelines in Vietnamese hospital practice. Prescribing of beta blockers and clopidogrel loading doses was probably suboptimal. Why patients do not complete treatment needs to be investigated.

Offering recovery rather than punishment: Implementation of a law enforcement-led pre-arrest diversion-to-treatment program for adults with substance use disorders.

BACKGROUND: The opioid epidemic has strained the US criminal justice system. Law enforcement frequently encounters persons with substance use disorder (SUD). Law enforcement-led, pre-arrest diversion programs linking individuals with SUD to addiction treatment instead of arrest and prosecution has the potential to reduce crime, overdoses, and other community harms. We implemented a pre-arrest diversion-to-treatment program-the Madison Addiction Recovery Initiative (MARI)-from September 2017 to August 2020, and describe the key components of MARI's effective implementation. METHODS: Adults who committed an eligible, drug use-related crime were offered a 6-month MARI participation with referral to treatment in lieu of arrest; criminal charges for that crime were "voided" upon the successful MARI completion. Formative evaluation, with stakeholder feedback and team meeting minutes, assessed key factors influencing implementation. Process evaluation consisted of tracking participant referrals, enrollment, and engagement. Police officers, MARI participants, and treatment center staff members were surveyed about program experiences and attitudes. The study used descriptive statistics to describe quantitative survey responses; thematic qualitative analysis identified major themes in qualitative responses. RESULTS: Of 263 participants, 160 initiated program engagement, with 100 successfully completing MARI. Interim evaluations and community partner feedback informed program protocol adjustments to increase participant enrollment, retention and diversity, streamline the referral processes, and transition to telehealth during the COVID-19 pandemic. CONCLUSION: Rigorous evaluation and community partner feedback are essential components of effective implementation and sustainability of a law enforcement-led pre-arrest diversion-to-treatment program, which has the potential to both reduce crime and overdose, and change the lives of people with SUD.

Law enforcement-led, pre-arrest diversion-to-treatment may reduce crime recidivism, incarceration, and overdose deaths: Program evaluation outcomes.

INTRODUCTION: Substance use disorder (SUD), overdose, and drug use-related crime continue to increase in the U.S. Pre-arrest diversion-to-treatment programs may decrease crime recidivism and overdose deaths. We assessed the impact of a community-wide diversion-to-treatment initiative on crime, incarceration, and overdose. METHODS: This article reports on the prospective evaluation of a law enforcement-led, pre-arrest diversion-to-treatment program on crime, incarceration, and overdose deaths compared between participants who did not engage (non-engaged; n = 103), engaged but did not complete (non-completers; n = 60) and completed (completers; n = 100) the program. Participants included 263 adults apprehended by police officers for low-level, drug use-related crimes between September 1, 2017 and August 31, 2020. The program offered eligible persons participation in a six-month program consisting of a clinical assessment, referral to addiction treatment services based on each individual's needs, connection to recovery peer support, and treatment engagement monitoring. Completers had their initial criminal charges 'voided,' while non-engaged and non-Completer participants had their original charges filed with local prosecutors. The project collected participant-level data on arrests and incarceration within 12 months before and 12 months after program enrollment and data on fatal overdose within 12 months after program enrollment. Logistic regression predicted outcomes using baseline demographics (sex, age, race, housing status) and pre-index crime arrest and incarceration indices as covariates. RESULTS: After accounting for baseline demographics and pre-enrollment arrest/incarceration history, logistic regression models found that the non-engaged and the non-Completer groups were more likely than completers to be arrested (odds ratios [ORs]: 3.9 [95 % CI, 2.0-7.7] and 3.6 [95 % CI, 1.7-7.5], respectively) and incarcerated (ORs: 10.3 [95 % CI, 5.0-20.8] and 21.0 [95 % CI, 7.9-55.7], respectively) during the 12-month follow-up. Rates of overdose deaths during the 12-month follow-up were greatest in non-engaged (6/103, 5.8 %) and non-Completer (2/60, 3.3 %) groups; completers had the lowest rate (2/100, 2.0 %), with all deaths occurring after completion of the six-month treatment/monitoring program. CONCLUSIONS: Collaboration between law enforcement, clinicians, researchers, and the broader community to divert adults who commit a low-level, drug use-related crime from criminal prosecution to addiction treatment may effectively reduce crime recidivism, incarceration, and overdose deaths.

Framework for in vivo T cell screens.

In vivo T cell screens are a powerful tool for elucidating complex mechanisms of immunity, yet there is a lack of consensus on the screen design parameters required for robust in vivo screens: gene library size, cell transfer quantity, and number of mice. Here, we describe the Framework for In vivo T cell Screens (FITS) to provide experimental and analytical guidelines to determine optimal parameters for diverse in vivo contexts. As a proof-of-concept, we used FITS to optimize the parameters for a CD8+ T cell screen in the B16-OVA tumor model. We also included unique molecular identifiers (UMIs) in our screens to (1) improve statistical power and (2) track T cell clonal dynamics for distinct gene knockouts (KOs) across multiple tissues. These findings provide an experimental and analytical framework for performing in vivo screens in immune cells and illustrate a case study for in vivo T cell screens with UMIs.

High-sensitivity cardiac troponin T is associated with disease activity in patients with inflammatory arthritis.

OBJECTIVE: To investigate whether high-sensitivity cardiac troponin T (hsTnT) correlates to markers of disease activity in inflammatory arthritis (IA), and whether antirheumatic treatment influences hsTnT levels. METHODS: We assessed 115 patients with active IA (64 rheumatoid arthritis (RA), 31 psoriatic arthritis and 20 ankylosing spondylitis) before and after using methotrexate (MTX) alone or tumor necrosis factor inhibitor (TNFi) with or without MTX co-medication (TNFi±MTX). All patients starting with TNFi had been previously unsuccessfully treated with MTX monotherapy. HsTnT (measured in serum by electro-chemiluminescence immunoassay (Roche Elecsys® Troponin T- high-sensitivity)), and other clinical and laboratory parameters were evaluated at baseline, and after 6 weeks and 6 months of treatment. RESULTS: Of markers of disease activity, baseline levels of hsTnT positively correlated with Physicians' Global Assessment Score of disease activity in the total patient cohort (p = 0.039). In RA group, hsTnT positively correlated with swollen joints, Disease Activity Score for 28 joints with ESR and serum tumor necrosis factor levels (p = 0.025, p = 0.008, p = 0.01, respectively). Median hsTnT at baseline was 5.0 ng/L, and did not change significantly at 6-week visit (6.0 ng/L, p = 0.37) and 6-month visit (6.0 ng/L, p = 0.18) with either antirheumatic therapy. CONCLUSIONS: HsTnT levels were associated with inflammatory markers for IA disease activity. However, while inflammatory markers significantly improved after antirheumatic treatment, hsTnT did not change during the 6-month follow-up period.

Natural killer cells suppress cancer metastasis by eliminating circulating cancer cells.

Despite significant advances in cancer treatment, the metastatic spread of malignant cells to distant organs remains a major cause of cancer-related deaths. Natural killer (NK) cells play a crucial role in controlling tumor metastasis; however, the dynamics of NK cell-mediated clearance of metastatic tumors are not entirely understood. Herein, we demonstrate the cooperative role of NK and T cells in the surveillance of melanoma metastasis. We found that NK cells effectively limited the pulmonary seeding of B16 melanoma cells, while T cells played a primary role in restricting metastatic foci growth in the lungs. Although the metastatic foci in the lungs at the endpoint were largely devoid of NK cells, they played a prominent role in promoting T cell recruitment into the metastatic foci. Our data suggested that the most productive interaction between NK cells and metastatic cancer cells occurred when cancer cells were in circulation. Modifying the route of administration so that intravenously injected melanoma cells bypass the first liver passage resulted in significantly more melanoma metastasis to the lung. This finding indicated the liver as a prominent site where NK cells cleared melanoma cells to regulate their seeding in the lungs. Consistent with this notion, the liver and the lungs of the tumor-bearing mice showed dominance of NK and T cell activation, respectively. Thus, NK cells and T cells control pulmonary metastasis of melanoma cells by distinct mechanisms where NK cells play a critical function in shaping T cell-mediated in situ control of lung-seeded cancer cells. A precise understanding of the cooperative role of NK and T cells in controlling tumor metastasis will enable the development of the next generation of cancer immunotherapies.

Titanium hydride nanoparticles and nanoinks for aerosol jet printed electronics.

Conductive inks commonly rely on oxidation-resistant metallic nanoparticles such as gold, silver, copper, and nickel. The criterion of air stability limits the scope of material properties attainable in printed electronic devices. Here we present an alternative approach based on air-stable nanoscale metal hydrides. Conductive patterns based on titanium hydride (TiH2) nanoinks were successfully printed on polyimide under ambient atmosphere and cured using intense pulsed light processing. Nanoparticles of TiH2 were generated by heating TiH2 powder in octylamine followed by wet ball milling, yielding <100 nm platelets. The addition of a suitable polymer dispersant during ball milling yielded stable colloidal dispersions suitable for liquid-phase processing. Aerosol jet printing of the resultant TiH2 nanoinks was demonstrated on glass and polyimide substrates, with a resolution as fine as 20 µm. Following intense pulsed light curing, samples on polyimide were found to exhibit a sintered, porous morphology with an electrical sheet resistance of ∼150 Ω â–¡-1.

A randomized controlled trial of a pharmacist-led intervention to enhance knowledge of Vietnamese patients with type 2 diabetes mellitus.

OBJECTIVES: We aimed to assess whether a pharmacist-led intervention enhances knowledge, medication adherence and glycemic control in patients with type 2 diabetes mellitus (T2DM). METHODS: We conducted a single-blinded randomized controlled trial in Vietnam. Individuals with T2DM were recruited from a general hospital and randomly allocated to intervention and routine care. The intervention group received routine care plus counselling intervention by a pharmacist, including providing drug information and answering individual patients' queries relating to T2DM and medications, which had not been done in routine care. We assessed the outcomes: knowledge score as measured by the Diabetes Knowledge Questionnaire, self-reported adherence and fasting blood glucose (FBG) at the 1-month follow-up. KEY FINDINGS: A total of 165 patients (83 intervention, 82 control) completed the study; their mean age was 63.33 years, and 49.1% were males. The baseline characteristics of the patients were similar between the groups. At 1-month follow-up, the pharmacist's intervention resulted in an improvement in all three outcomes: knowledge score [B = 5.527; 95% confidence intervals (CI): 3.982 to 7.072; P < 0.001], adherence [odds ratio (OR) = 9.813; 95% CI: 2.456 to 39.205; P = 0.001] and attainment of target FBG (OR = 1.979; 95% CI: 1.029 to 3.806; P = 0.041). CONCLUSIONS: The pharmacist-led intervention enhanced disease knowledge, medication adherence and glycemic control in patients with T2DM. This study provides evidence of the benefits of pharmacist counselling in addition to routine care for T2DM outpatients in a Vietnam population.

Antirheumatic therapy is associated with reduced complement activation in rheumatoid arthritis.

BACKGROUND: The complement system plays an important role in pathophysiology of cardiovascular disease (CVD), and might be involved in accelerated atherogenesis in rheumatoid arthritis (RA). The role of complement activation in response to treatment, and in development of premature CVD in RA, is limited. Therefore, we examined the effects of methotrexate (MTX) and tumor necrosis factor inhibitors (TNFi) on complement activation using soluble terminal complement complex (TCC) levels in RA; and assessed associations between TCC and inflammatory and cardiovascular biomarkers. METHODS: We assessed 64 RA patients starting with MTX monotherapy (n = 34) or TNFi with or without MTX co-medication (TNFi±MTX, n = 30). ELISA was used to measure TCC in EDTA plasma. The patients were examined at baseline, after 6 weeks and 6 months of treatment. RESULTS: Median TCC was 1.10 CAU/mL, and 57 (89%) patients had TCC above the estimated upper reference limit (<0.70). Compared to baseline, TCC levels were significantly lower at 6-week visit (0.85 CAU/mL, p<0.0001), without significant differences between the two treatment regimens. Notably, sustained reduction in TCC was only achieved after 6 months on TNFi±MTX (0.80 CAU/mL, p = 0.006). Reductions in TCC after treatment were related to decreased C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and interleukin 6, and increased levels of total, high and low-density lipoprotein cholesterol. Similarly, baseline TCC was significantly related to baseline CRP, ESR and interleukin 6. Patients with endothelial dysfunction had higher baseline TCC than those without (median 1.4 versus 1.0 CAU/mL, p = 0.023). CONCLUSIONS: Patients with active RA had elevated TCC, indicating increased complement activation. TCC decreased with antirheumatic treatment already after 6 weeks. However, only treatment with TNFi±MTX led to sustained reduction in TCC during the 6-month follow-up period. RA patients with endothelial dysfunction had higher baseline TCC compared to those without, possibly reflecting involvement of complement in the atherosclerotic process in RA.

Left renal vein as a graft for aortic reconstruction in a patient with primary aortoenteric fistula secondary to a mycotic aneurysm.

Description of the use of the left renal vein for aortic reconstruction in primary aortoenteric fistula secondary to a mycotic aneurysm has not been found in the literature. We report here a case of primary aortoenteric fistula secondary to a mycotic aneurysm with gross retroperitoneal contamination that was successfully treated by using a left renal vein graft for aortic reconstruction.

Pre-arrest diversion to addiction treatment by law enforcement: protocol for the community-level policing initiative to reduce addiction-related harm, including crime.

BACKGROUND: Despite evidence that treatment reduces addiction-related harms, including crime and overdose, only a minority of addiction-affected individuals receive it. Linking individuals who committed an addiction-related crime to addiction treatment could improve outcomes. METHODS: The aim of this city-wide, pre-arrest diversion program, Madison Addiction Recovery Initiative (MARI) is to reduce crime and improve health (i.e., reduce the overdose deaths) among adults who committed a minor, non-violent, drug use-related offense by offering them a referral to treatment in lieu of arrest and prosecution of criminal charges. This manuscript outlines the protocol and methods for the MARI program development and implementation. MARI requires its participants to engage in the recommended treatment, without reoffending, during the six-month program, after which the initial criminal charges are "voided" by the law enforcement agency. The project, implemented in a mid-size U.S. city, has involved numerous partners, including law enforcement, criminal justice, public health, and academia. It includes training of the police officer workforce and collaboration with clinical partners for treatment need assessment, treatment placement, and peer support. Program evaluation includes formative, process, outcome (participant-level) and exploratory impact (community-level) assessments. For outcome evaluation, we will compare crime (primary outcome), overdose-related offenses, and incarceration-related data 12 months before and 12 months after the index crime between participants who completed (Group 1), started but not completed (Group 2), and were offered but did not start (Group 3) the program, and adults who would have been eligible should MARI existed (Historical Comparison, Group 4). Clinical characteristics will be compared at baseline between Groups 1-2, and pre-post the program within Group 1. Participant baseline data will be assessed as potential covariates. Surveys of police officers and program completers, and community-level indicators of crime and overdose pre- versus post-program will provide additional data on the program impact. DISCUSSION: By offering addiction treatment in lieu of arrest and prosecution of criminal charges, this pre-arrest diversion program has the potential to disrupt the cycle of crime, reduce the likelihood of future offenses, and promote public health and safety.

Antirheumatic therapy is not associated with changes in circulating N-terminal pro-brain natriuretic peptide levels in patients with autoimmune arthritis.

BACKGROUND: Patients with autoimmune arthritis (AA) are at increased risk for impaired cardiac function and heart failure. This may be partly due to the effect of inflammation in heart function. The impact of antirheumatic drugs on cardiac dysfunction in AA remains controversial. Therefore, we aimed to examine effects of antirheumatic treatment on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in AA patients and its relationship to inflammatory markers. METHODS: We examined 115 patients with AA (64 rheumatoid arthritis (RA), 31 psoriatic arthritis and 20 ankylosis spondylitis) starting with methotrexate (MTX) monotherapy or tumor necrosis factor inhibitors (TNFi) with or without MTX co-medication. NT-proBNP (measured in serum by ECLIA from Roche Diagnostics), and other clinical and laboratory parameters were evaluated at baseline, after 6 weeks and 6 months of treatment. RESULTS: NT-proBNP levels did not change significantly after 6 weeks and 6 months of antirheumatic therapy (pbaseline-6weeks = 0.939; pbaseline-6months = 0.485), although there was a modest improvement from 6 weeks to 6 months in the MTX only treatment group (median difference = -18.2 [95% CI = -32.3 to -4.06], p = 0.013). There was no difference in the effects of MTX monotherapy and TNFi regimen on NT-proBNP levels. The changes in NT-proBNP after antirheumatic treatment positively correlated with changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Baseline NT-proBNP levels were related to baseline CRP and ESR levels, and some other established markers of disease activities in crude analyses. CONCLUSION: Circulating levels of NT-proBNP were related to established inflammatory markers at baseline, and the changes in NT-proBNP after antirheumatic treatment were positively related to these markers. Nevertheless, antirheumatic therapy did not seem to affect NT-proBNP levels compared to baseline, even though inflammatory markers significantly improved.