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The Centers for AIDS Research (CFAR) program was established by the National Institutes of Health in 1988 to catalyze and support high-impact HIV research and to develop the next generation of HIV investigators at academic institutions throughout the United States. In 2014, the Penn CFAR, the Johns Hopkins University CFAR and the District of Columbia CFAR developed a partnership—the Mid-Atlantic CFAR Consortium (MACC)—to promote cross-CFAR scientific collaboration, mentoring, and communication and to address the regional HIV epidemic. Over the past 6 years, the creation of the MACC has resulted in a rich web of interconnectivity, which has fostered scientific collaboration through working groups on the black men who have sex with men (MSM) and Latinx regional HIV epidemics, joint peer-reviewed publications, and successful collaborative grant applications on topics ranging from HIV prevention in young MSM, transgender women, implementation science, and clinical epidemiology; supported developmental activities through the MACC Scholars program, cross-CFAR mentoring, joint symposia, cross-CFAR seminar participation, and keynote speakers; and promoted strategic communication through advisory committees, best practices consultations, and the social and behavioral science research network. The MACC has been highly impactful by promoting HIV science through regional collaboration, supporting a diverse network of scholars across three cities and focusing on the epidemic in underrepresented and marginalized communities. Lessons learned from this consortium may have implications for scientific research centers beyond the field of HIV.

Southern giant pouched rats (Cricetomys ansorgei) are muroid rodents native to subSaharan Africa. They are increasingly used as service animals because of their keen sense of smell and are primarily known for clearing minefields in Africa. The objectives of this study were to determine hematologic and biochemical reference intervals from clinically healthy wild-caught captive adult rats, to describe the cytochemical staining reactions of peripheral blood leukocytes, and to document urinalysis findings. Blood samples were collected from the coccygeal artery of 60 isoflurane-anesthetized rats (36 males and 24 females) and analyzed with automated hematologic and biochemical analyzers; manual differential cell counts were performed on modified Wright–stained blood smears. Urine was collected by cystocentesis, and dipsticks were analyzed on a urine analyzer, with visual examination of unstained sediments. Samples from a male rat with chronic renal disease were excluded from analysis. Reference intervals were determined according to guidelines established by the American Society of Veterinary Clinical Pathology. Lymphocytes were the dominant leukocyte in peripheral blood and granular lymphocytes were identified in most animals. Male rats had significantly higher RBC, absolute reticulocyte counts, and MCV than did female rats. Minor sex-associated differences in urea nitrogen concentration and GGT activity were noted. Leukocytes showed unique cytochemical staining characteristics. Small amounts of protein and bilirubin were found in the urine of rats of both sexes and of female rats, respectively, particularly in concentrated urine. These results will provide benchmarks for determining health status and identifying disease in this species of rat.

Blood is one of the most subtle and sensitive indicators that indicate the functional state of the body, reflecting the picture of its struggle with intruded harm and its reactivity. A detailed study of the pictures of red and white blood opens before us the possibility of not only a diagnostic assessment of the state of hematopoietic tissue, its reaction to a harmful principle, but also the possibility of a prognostic assessment of the state and development of the body's defenses in liberating the body from disease-causing influences.

Summary Background Patients with systemic lupus erythematosus (SLE) are at risk of developing COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. We aimed to evaluate the presence of SARS-CoV-2 IgG antibodies in patients with SLE with or without previous COVID-19-related symptoms or RT-PCR-confirmed SARS-CoV-2 infection. Methods For this analysis, we included patients with SLE from two cohorts based in New York City: the Web-based Assessment of Autoimmune, Immune-Mediated and Rheumatic Patients during the COVID-19 pandemic (WARCOV) study; and the NYU Lupus Cohort (a prospective registry of patients at NYU Langone Health and NYC Health + Hospitals/Bellevue). Patients in both cohorts were tested for SARS-CoV-2 IgG antibodies via commercially available immunoassays, processed through hospital or outpatient laboratories. Patients recruited from the NYU Lupus Cohort, referred from affiliated providers, or admitted to hospital with COVID-19 were tested for SARS-CoV-2 IgG antibodies as part of routine surveillance during follow-up clinical visits. Findings 329 patients with SLE were included in this analysis, 146 from the WARCOV study and 183 from the NYU Lupus Cohort, and were tested for SARS-CoV-2 antibodies between April 29, 2020, and Feb 9, 2021. 309 (94%) were women and 91 (28%) were of Hispanic ethnicity. 51 (16%) of 329 patients had a positive SARS-CoV-2 IgG antibody test. Seropositive patients were more likely than seronegative patients to be Hispanic (24 [47%] of 51 vsz 67 [24%] of 278). Other demographic variables, SLE-specific factors, and immunosuppressant use were not associated with SARS-CoV-2 positivity. Of the 29 patients with COVID-19 previously confirmed by RT-PCR, 18 (62%) were on immunosuppressants; 24 (83%) of 29 patients tested positive for SARS-CoV-2 IgG antibodies. Of 17 patients who had symptoms of COVID-19 but negative concurrent RT-PCR testing, one (6%) developed an antibody response. Of 26 patients who had COVID-19-related symptoms but did not undergo RT-PCR testing, six (23%) developed an antibody response. Of 83 patients who had no symptoms of COVID-19 and no RT-PCR testing, four (5%) developed an antibody response. Among 36 patients who were initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially (88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks). Seven (70%) of ten patients with confirmed COVID-19 had antibody positivity beyond 30 weeks from disease onset. Interpretation Most patients with SLE and confirmed COVID-19 were able to produce and maintain a serological response despite the use of a variety of immunosuppressants, providing reassurance about the efficacy and durability of humoral immunity and possible protection against re-infection with SARS-CoV-2. Funding National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Bloomberg Philanthropies COVID-19 Response Initiative Grant.

Objectives. To explore whether beneficial health care policies, when implemented in the context of gender inequality, yield unintended structural consequences that stigmatize and ostracize women with HIV from “what matters most” in local culture. Methods. We conducted 46 in-depth interviews and 5 focus groups (38 individuals) with men and women living with and without HIV in Gaborone, Botswana, in 2017. Results. Cultural imperatives to bear children bring pregnant women into contact with free antenatal services including routine HIV testing, where their HIV status is discovered before their male partners’. National HIV policies have therefore unintentionally reinforced disadvantage among women with HIV, whereby men delay or avoid testing by using their partner’s status as a proxy for their own, thus facilitating blame toward women diagnosed with HIV. Gossip then defines these women as “promiscuous” and as violating the essence of womanhood. We identified cultural and structural ways to resist stigma for these women. Conclusions. Necessary HIV testing during antenatal care has inadvertently perpetuated a structural vulnerability that propagates stigma toward women. Individual- and structural-level interventions can address stigma unintentionally reinforced by health care policies.

Introduction Activation of the complement pathway by immune complexes is a key feature of systemic lupus erythematosus (SLE) and SLE glomerulonephritis, which translates into low levels of C3 and C4 during active disease. C3 glomerulonephritis (C3GN) is part of a broader group of rare renal diseases, the C3 glomerulopathies, characterized by prominent C3 accumulation in the glomeruli with minimal to no immunoglobulin (Ig) deposition secondary to dysregulation of the alternative pathway of the complement system. Distinguishing lupus nephritis from other complement-mediated kidney disorders, including C3GN, represents a diagnostic challenge with potential therapeutic implications. Methods We report an unusual case of a 55-year-old woman with SLE and previous biopsy-proven class IV lupus nephritis, subsequently diagnosed with C3GN. Furthermore, we review the available literature published from January 2010—March 2021 on the clinical features and management of C3GN in the setting of SLE. Results In addition to our case, very few reports exist in the literature regarding C3GN in association with SLE. The underlying pathogenic mechanism of C3GN consists of dysregulation of the alternative pathway of the complement system, either due to genetic variation in complement-related genes or to acquired autoantibodies targeting C3 or C5 convertases; the latter mechanism could explain the occurrence of C3GN in the setting of autoimmune diseases, although it was not definitively identified in our patient or others with SLE. Similar to some of the previous reports, after suboptimal renal response on mycophenolate mofetil and rituximab, our patient has been successfully treated with eculizumab, thus far with >50% improvement in proteinuria. Conclusions C3GN represents an additional mechanism of renal injury in SLE mediated by alternative complement pathway dysregulation. Although rare, patients with SLE and persistent proteinuria with very low C3 would benefit from expedited renal biopsy to evaluate for C3GN as well as genetic testing, since this entity could require a different therapeutic approach.

Despite a comprehensive national program of free HIV services, men living with HIV in Botswana participate at lower rates and have worse outcomes than women. Directed content analysis of five focus groups ( n = 38) and 50 in-depth interviews with men and women with known and unknown HIV status in Gaborone, Botswana in 2017 used the “what matters most” (WMM) and “structural vulnerability” frameworks to examine how the most valued cultural aspects of manhood interact with HIV-related stigma. WMM for manhood in Botswana included fulfilling male responsibilities by being a capable provider and maintaining social status. Being identified with HIV threatened WMM, which fear of employment discrimination could further exacerbate. Our findings indicate how cultural and structural forces interact to worsen or mitigate HIV-related stigma for urban men in Botswana. These threats to manhood deter HIV testing and treatment, but interventions could capitalize on cultural capabilities for manhood to promote stigma resistance.

For the rational treatment of diabetes, a daily quantitative study of the diabetic's urine for sugar content is necessary in order to be able to judge the effect of one or another diet and develop a treatment plan accordingly.

Summary Despite undeniable improvement in the management of rheumatoid arthritis (RA), the discovery of more effective, less toxic and, ideally, less immune suppressive drugs are much needed. In the current study, we set to explore the potential anti-rheumatic activity of the non-toxic, tellurium-based immunomodulator, AS101 in an experimental animal model of RA. The effect of AS101 was assessed on adjuvant-induced arthritis (AIA) rats. Clinical signs of arthritis were assessed. Histopathological examination was used to assess inflammation, synovial changes and tissue lesions. Very late antigen-4 (VLA-4)+ cellular infiltration was detected using immunohistochemical staining. Enzyme-linked immunosorbent assay (ELISA) was used to measure circulating anti-cyclic citrullinated-peptide autoantibody (ACPA) and real-time polymerase chain reaction (PCR) was used to measure the in-vitro effect of AS101 on interleukin (IL)-6 and IL-1β expression in activated primary human fibroblasts. Prophylactic treatment with intraperitoneal AS101 reduced clinical arthritis scores in AIA rats (P

Summary Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that leads to joint destruction and disability. Despite a significant progress in administration of biological agents for RA patients, there is still a need for improved therapy. Intravenous immunoglobulins (IVIG), a pooled polyspecific immunoglobulin (Ig)G extracted from 5000 to 20 000 healthy subjects, showed beneficial therapeutic effect in patients with immune deficiency, sepsis and autoimmune diseases. The current study aimed to investigate the beneficial effect of treatment with IVIG in established collagen-induced arthritis in DBA/1j mice. Murine arthritis was induced in DBA/1j mice. Treatment with IVIG began when the disease was established. The clinical score was followed twice a week until day 48. The mice were bled for plasma and the paws were hematoxylin and eosin (H&E)-stained. Cytokine profile in the plasma was analyzed by Luminex technology and titers of circulating anti-collagen antibodies in the plasma was tested by enzyme-linked immunosorbent assay. Our results show that treatment with IVIG in murine significantly reduced the clinical arthritis score (P

OBJECTIVE: To characterize the hospitalization and death rates among patients with inflammatory arthritis (IA) affected by coronavirus disease 2019 (COVID-19) and to analyze the associations of comorbidities and immunomodulatory medications with infection outcomes. METHODS: Data on clinical and demographic features, maintenance treatment, disease course, and outcomes in individuals with IA (rheumatoid arthritis and spondyloarthritis) with symptomatic COVID-19 infection were prospectively assessed via web-based questionnaire followed by individual phone calls and electronic medical record review. Baseline characteristics and medication use were summarized for hospitalized and ambulatory patients, and outcomes with the different medication classes were compared using multivariable logistic regression. RESULTS: A total of 103 patients with IA were included in the study (80 with confirmed COVID-19 and 23 with high suspicion of COVID-19). Hospitalization was required in 26% of the participants, and 4% died. Patients who were hospitalized were significantly more likely to be older (P < 0.001) and have comorbid hypertension (P = 0.001) and chronic obstructive pulmonary disease (P = 0.02). IA patients taking oral glucocorticoids had an increased likelihood of being admitted for COVID-19 (P < 0.001), while those receiving maintenance anticytokine biologic therapies did not. CONCLUSION: Among patients with underlying IA, COVID-19 outcomes were worse in those receiving glucocorticoids but not in patients receiving maintenance anticytokine therapy. Further work is needed to understand whether immunomodulatory therapies affect COVID-19 incidence.

From birth, humans coexist and coevolve with trillions of micro-organisms inhabiting most body surfaces and cavities, referred to as the human microbiome. Advances in sequencing technologies and computational methods have propelled the exploration of the microbiome’s contribution to human health and disease, spearheaded by massive efforts such as the Human Microbiome Project and the Europe-based MetaHit Consortium. Yet, despite the accumulated body of literature and a growing awareness among patients, microbiome research in rheumatology has not had a key impact on clinical practice. Herein, we describe some of the landmark microbiome studies in autoimmunity and rheumatology, the challenges and opportunities of microbiome research and how to navigate them, advances in related fields that have overcome these pitfalls, and future directions of harnessing the microbiome for diagnostic and therapeutic purposes.

To evaluate seroreactivity and disease flares after COVID-19 vaccination in a multiethnic/multiracial cohort of patients with systemic lupus erythematosus (SLE).Ninety SLE patients and 20 healthy controls receiving a complete COVID-19 vaccine regimen were included. IgG seroreactivity to the SARS-CoV-2 spike receptor-binding domain (RBD) and SARS-CoV-2 microneutralization were used to evaluate B cell responses; interferon-γ (IFNγ) production was measured by enzyme-linked immunospot (ELISpot) assay in order to assess T cell responses. Disease activity was measured by the hybrid SLE Disease Activity Index (SLEDAI), and flares were identified according to the Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI flare index.Overall, fully vaccinated SLE patients produced significantly lower IgG antibodies against SARS-CoV-2 spike RBD compared to fully vaccinated controls. Twenty-six SLE patients (28.8%) generated an IgG response below that of the lowest control (100 units/ml). In logistic regression analyses, the use of any immunosuppressant or prednisone and a normal anti-double-stranded DNA antibody level prior to vaccination were associated with decreased vaccine responses. IgG seroreactivity to the SARS-CoV-2 spike RBD strongly correlated with the SARS-CoV-2 microneutralization titers and correlated with antigen-specific IFNγ production determined by ELISpot. In a subset of patients with poor antibody responses, IFNγ production was similarly diminished. Pre- and postvaccination SLEDAI scores were similar in both groups. Postvaccination flares occurred in 11.4% of patients; 1.3% of these were severe.In a multiethnic/multiracial study of SLE patients, 29% had a low response to the COVID-19 vaccine which was associated with receiving immunosuppressive therapy. Reassuringly, severe disease flares were rare. While minimal protective levels remain unknown, these data suggest that protocol development is needed to assess the efficacy of booster vaccination.

Significance The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated in cancer cells, and a GLS-selective inhibitor is being evaluated in clinical trials. Previous screens identified succinylated lysine residues on GLS, but the functional consequences of these posttranslational modifications have remained unclear. Here, we report that the mitochondrial desuccinylase SIRT5 stabilizes GLS. Both GLS and SIRT5 are upregulated during cellular transformation, and high expression of SIRT5 in human breast tumors correlates with poor patient prognosis. Mechanistically, SIRT5-mediated desuccinylation of residue K164 protects GLS from ubiquitination at K158 and from subsequent degradation. These findings reveal an important role for SIRT5 in mammary tumorigenesis and establish a posttranslational mechanism regulating GLS levels. Collectively, they support further investigation of SIRT5 as a potential therapeutic target.

Background There is an urgent need to intentionally develop and expand mentoring for junior faculty from underrepresented communities in the area of HIV research. Such a goal is increasingly recognized as essential across all scientific fields because profound disparities exist regarding which doctorally prepared individuals ultimately end up entering research fields in academic settings. The purpose of this article is to describe a novel inter-Center for AIDS Research (CFAR) program designed to support underrepresented scientists in research to address the HIV epidemic in the Mid-Atlantic region. Methods Three CFARs in the Mid-Atlantic region (the District of Columbia, Johns Hopkins University CFAR, and University of Pennsylvania CFARs) developed a Scholars program designed for underrepresented minority scholars interested in studying the HIV epidemic in the region. The program provided resources for scholarship as well as cross-institutional mentoring and training. Results Scholars in the first cohort have been successful in implementing novel research that informs our understanding of the HIV epidemic in the region as well as increasing skills, publications, and grant submissions and funded applications. Lessons learned from the first cohort will inform future years of the MACC Scholars Program. Conclusions The MACC Scholars Program offers a model for other inter-CFAR collaborations wishing to find novel ways to support the next generation of scientists.

The purpose of this study was to identify causal pathways between HIV infection and severe mental illness. Data were collected through open-ended, semi-structured interviews. An integrated approach to the analysis, using inductive and deductive coding, was used to identify patterns among respondents. Standardized instruments were used to characterize the sample in terms of risk behaviors, physical and mental functioning and depression. Twenty-six men and women with a diagnosis of HIV and unipolar depression (n = 11) or schizophrenia/schizoaffective versus bipolar disorder (n = 15) participated. For persons with unipolar depression, the HIV diagnosis often preceded depressive symptoms. For persons with schizophrenia/schizoaffective versus bipolar disorder, mania and psychosis symptoms often preceded HIV. Substance use, incarceration and adverse childhood experiences were common across diagnoses. Attention to the directionality of effects between mental illness and HIV has important implications for anticipatory guidance for infectious disease specialists, primary care providers and public health practitioners as well as policymakers.

Mental illness is a common comorbidity of HIV and complicates treatment. In Botswana, stigma impedes treatment of mental illness. We examined explanatory beliefs about mental illness, stigma, and interactions between HIV and mental illness among 42 adults, from HIV clinic and community settings, via thematic analysis of interviews. Respondents endorse witchcraft as a predominant causal belief, in addition to drug abuse and effects of HIV. Respondents describe mental illness as occurring “when the trees blossom,” underscoring a conceptualization of it as seasonal, chronic, and often incurable and as worse than HIV. Consequently, people experiencing mental illness (PEMI) are stereotyped as dangerous, untrustworthy, and cognitively impaired and discriminated against in the workplace, relationships, and sexually, increasing vulnerability to HIV. Clinical services that address local beliefs and unique vulnerabilities of PEMI to HIV, integration with peer support and traditional healers, and rehabilitation may best address the syndemic by facilitating culturally consistent recovery-oriented care.

Background Opioid use disorders are associated with increased risk of suicide thoughts, attempts, and death. We explored key variables from two theories of the development of suicidal thoughts and attempts (the interpersonal and three-step theories of suicide) to understand possible mechanisms underlying the association between opioid use and suicide risk. We hypothesized that interpersonal connections, variables reflecting psychological and physical pain, and variables that reduce fear of death (prior overdoses and risk-taking behaviors) would be associated with increased risk of thoughts of suicide. Methods Participants (N = 141) were opioid users recruited from an epicenter of the opioid crisis in Philadelphia using a mobile research center and completed an interview to assess substance use, depression, medical comorbidities, and suicidal thoughts among other variables. Results Univariate analyses showed that prior history of overdose, diagnosis of depression, older age, homelessness, and interpersonal connection were each associated with increased likelihood of endorsing thoughts of death/suicide. Multivariable analyses revealed prior history of overdose and depression were the variables most strongly associated with risk for thoughts of suicide. Conclusions Consistent with two theories of the development of suicidal thoughts and attempts, exposure to variables that reduce fear of death (e.g., overdoses) were associated with suicidal thoughts. In contrast, other risk-taking behaviors, medical comorbidities, and substance use were not key predictors of suicidal thoughts in this sample. Implications for targeted risk assessment among clinicians are discussed.

ObjectiveTo investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.MethodsEstablished patients at NYU Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunization. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analyzed for humoral response. Cellular immune response to SARS-CoV-2 was further analyzed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany were also analyzed for humoral immune response.ResultsAlthough healthy subjects (n=208) and IMID patients on biologic treatments (mostly on TNF blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, IMID patients do not demonstrate an increase in CD8+ T cell activation after vaccination.ConclusionsIn two independent cohorts of IMID patients, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunization efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines.KEY MESSAGESWhat is already known about this subject?The impact of COVID-19 has been felt across the globe and new hope has arisen with the approval of mRNA vaccines against the SARS-CoV-2. Studies have shown immunogenicity and efficacy rates of over 90% in the immunocompetent adult population. However, there is a lack of knowledge surrounding the response of patients with immune-mediated inflammatory diseases (IMIDs) who may also be on immunomodulatory medications.Patients with IMID have been shown to have attenuated immune responses to seasonal influenza vaccination.What does this study add?This study looks at the humoral and cellular immune response to two doses of BNT162b2 mRNA COVID-19 Vaccine in participants with IMID (on immunomodulators) compared with healthy controls.Individuals with IMID on methotrexate demonstrate up to a 62% reduced rate of adequate immunogenicity to the BNT162b2 mRNA vaccination. Those on anti-cytokine or non-methotrexate oral medications demonstrate similar levels of immunogenicity as healthy controls (greater than 90%).Similarly, vaccination did not induce an activated CD8+ T cell response in participants on background methotrexate, unlike healthy controls and patients with IMID not receiving methotrexate.How might this impact of clinical practice or future developments?These results suggest that patients on methotrexate may need alternate vaccination strategies such as additional doses of vaccine, dose modification of methotrexate, or even a temporary discontinuation of this drug. Further studies will be required to explore the effect of these approaches on mRNA vaccine immunogenicity.

Using a mobile research facility, we enrolled 141 opioid users from a neighborhood of Philadelphia, an urban epicenter of the opioid epidemic. Nearly all (95.6%) met DSM-5 criteria for severe opioid use disorder. The prevalence of HIV infection (8.5%) was more than seven times that found in the general population of the city. Eight of the HIV-positive participants (67.0%) reported receiving antiretroviral treatment but almost all of them had unsuppressed virus (87.5%). The majority of participants (57.4%) reported symptoms consistent with major depressive disorder. Severe economic distress (60.3%) and homelessness were common (57%). Polysubstance use was nearly universal, 72.1% had experienced multiple overdoses and prior medication for opioid use disorder (MOUD) treatment episodes (79.9%), but few currently engaged in addiction care. The prevalence, multiplicity and severity of chronic health and socioeconomic problems highlight consequences of the current opioid epidemic and underscore the urgent need to develop integrated models of treatment.Utilizando un Centro de Investigación Móvil, inscribimos a 141 usuarios de opioides del vecindario de Filadelfia, un epicentro urbano de la epidemia de opioides. Casi todos (95,6%) cumplieron con los criterios del DSM-5 para el trastorno del uso severo del consumo de opioides. La prevalencia de la infección de VIH (8,5%) fue másﹶ de 7 veces superior a las encontrada en la población general de la ciudad. Ocho de los participantes con VIH positivo (67,0%) reportaron haber recibido tratamiento antirretroviral pero casi todos tuvieron virus no suprimido (87,5%). La mayoría de los participantes (57,4%) informaron síntomas compatibles con el Desorden Depresivo Mayor. La angustia severa por lo económico (60,3%) y las personas sin hogar fueron comunes (57%). El uso de múltiples sustancias fue casi universal, el 721% había experimentado múltiples sobredosis y previos medicamentos para el tratamiento del trastorno por consumo de opioides (MOUD) (79,9%), pero muy pocos estaban comprometidos con la atención a las adicciones. La prevalencia, la multiplicidad y la seriedad de los problemas de salud crónica y los problemas socioeconómicos destacan las consecuencias de la actual epidemia de opioides y subrayan la urgente necesidad de desarrollar nuevos modelos de tratamiento integrados.

Perceived stigma deters engagement in HIV care and is powerfully shaped by culture. Yet few stigma measures consider how cultural capabilities that signify "full personhood" could be engaged to resist stigma. By applying a theory conceptualizing how culturally-salient mechanisms can worsen or mitigate HIV stigma in relation to "what matters most" (WMM), we developed the WMM Cultural Stigma Scale for Women Living with HIV in Botswana (WMM-WLHIV-BW) and psychometrically evaluated it among 201 respondents with known and unknown HIV status. The two subscales, Cultural Factors Shape Stigma (CFSS) and Cultural Capabilities Protect against Stigma (CCPS) were reliable (both [Formula: see text]). Among WLHIV, the CFSS Subscale showed initial construct validity with depressive symptoms (r = .39, p = .005), similar to an established HIV stigma scale, whereas the CCPS Subscale showed initial construct validity with self-esteem (r = .32, p = .026) and social support number (r = .29, p = .047), suggesting that achieving local cultural capabilities mitigates stigma and is linked with positive psychosocial outcomes. This culturally-derived scale could help WLHIV in Botswana experience improved stigma-related outcomes.El estigma percibido detetiza la participación en la atención de VIH y está fuertemente moldeado por la cultura. Sin embargo, pocas medidas de estigma consideran cómo las capacidades culturales que significan “personalidad plena” podrían ser utilizadas para resistir el estigma. Mediante la aplicación de una teoría que conceptualiza cómo los mecanismos culturalmente destacados pueden empeorar o mitigar el estigma del VIH en relación con “lo que más importa" (WMM), desarrollamos la Escala de Estigma Cultural WMM para mujeres que viven con VIH en Botswana (WMM-WLHIV-BW) y lo evaluamos psicométricamente entre 201 encuestados con estatus de VIH conocido y desconocido. Las dos subescalas, Factores Culturales dan Forma al Estigma (CFSS) y la protección de las Capacidades Culturales contra el Estigma (CCPS) eran fiables (ambos α = 0.90). Entre WLHIV, la subescala CFSS mostró la validez inicial de la construcción con síntomas depresivos (r = .39, p =.005), similar a una escala establecida de estigma del VIH, mientras que la subescala CCPS mostró la validez de la construcción inicial con autoestima (r = .32, p = .026) y el numero de apoyo social (r = .29, p = .047), lo que sugiere que lograr capacidades culturales locales mitiga el estigma y esta asociado con resultados psicosociales positivos. Esta escala culturalmente derivada podría ayudar a WLHIV en Bostwana a mejorar los resultados relacionados con el estigma.

Background With high rates of HIV and multiple vulnerable subgroups across diverse settings, there is a need for culturally based, HIV stigma reduction interventions. Pregnant women who are living with HIV are especially in need of services to protect not only their own but also their children’s lives. Uptake of HIV services worldwide is hindered by stigma towards persons living with HIV/AIDS. While cultural context plays a key role in shaping HIV stigma, these insights have not yet been fully integrated into stigma reduction strategies. By utilizing the “What Matters Most” stigma framework, we propose that an intervention to counter culturally salient aspects of HIV stigma will improve treatment adherence and other relevant outcomes. A pragmatic clinical trial in Botswana will evaluate the “Mothers Moving towards Empowerment” (MME) intervention, which seeks to address HIV stigma in Botswana and to specifically engage pregnant mothers so as to promote antiretroviral therapy (ART) adherence in the postpartum period. Methods This study will test MME against treatment as usual (TAU) among pregnant mothers diagnosed with HIV and their infants. Outcomes will be assessed during pregnancy and 16 weeks postpartum. Women who meet eligibility criteria are assigned to MME or TAU. Women assigned to MME are grouped with others with similar estimated delivery dates, completing up to eight intervention group sessions scheduled before week 36 of their pregnancies. Primary outcomes among mothers include (i) reducing self-stigma, which is hypothesized to mediate improvements in (ii) psychological outcomes (quality of life, depression and social functioning), and (iii) adherence to antenatal care and ART. We will also examine a set of follow-up infant birth outcomes (APGAR score, preterm delivery, mortality (at Discussion Our trial will evaluate MME, a culturally based HIV stigma reduction intervention using the “What Matters Most” framework, to reduce stigma and improve treatment adherence among pregnant women and their infants. This study will help inform further refinement of MME and preparation for a future large-scale, multisite, randomized controlled trial (RCT) in Botswana. Trial registration ClinicalTrials.gov NCT03698981. Registered on October 8, 2018

Nuclear lamins (NLs) are essential components of the animal cell nucleus involved in the regulation of a plethora of molecular and cellular processes. These include the nuclear envelope assembly and stability, mechanotransduction and chromatin organization, transcription, DNA replication, damage repair, and genomic integrity maintenance. Mutations in NLs can lead to the development of a wide range of distinct disease phenotypes, laminopathies, consisting of cardiac, neuromuscular, metabolic and premature aging syndromes. In addition, alterations in the expression of nuclear lamins were associated with different types of neoplastic diseases. Despite the importance and critical roles that NLs play in the diverse cellular activities, we only recently started to uncover the complexity of regulatory mechanisms governing their expression, localization and functions. This integrative review summarizes and discusses the recent findings on the emerging roles of ubiquitin and ubiquitin-like modifiers (ULMs) in the regulation of NLs, highlighting the intriguing molecular associations and cross-talks occurring between NLs and these regulatory molecules under physiological conditions and in the disease states.

While psychiatric disorder prevalence is higher among patients living with HIV (PLWH), there are no prior studies on rates of psychiatric diagnosis documentation in electronic medical records (EMRs) of PLWH, which was the goal of this study. Participants (n = 2,336) were enrolled in the Center for AIDS Research (CFAR) Longitudinal Database study. Diagnostic codes were extracted to assess the prevalence rates of depressive, alcohol/substance use, PTSD, sleep, and adjustment disorders. Prevalence rates for psychiatric disorders were extracted from national epidemiological studies for comparison. Rates of Major Depressive Disorder in the EMR were comparable to prior epidemiological reports in PLWH. In contrast, rates of PTSD, substance use, alcohol use, adjustment, and insomnia disorders were all markedly lower compared to epidemiological studies. While clinicians appropriately documented depression, other psychiatric comorbidities were largely overlooked. This indicates a potential bias in the detection or documentation of psychiatric disorders in PLWH.

14-3-3η may represent a useful diagnostic biomarker for rheumatoid arthritis (RA). We assessed the prevalence and serum levels of 14-3-3η in patients with RA and in patients with other rheumatic diseases. Serum levels of 14-3-3η were measured in 96 patients with RA, in 101 patients with other rheumatic diseases, and in 66 healthy subjects. All of the sera samples were evaluated by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). Median (IQR) 14-3-3η levels were significantly higher in the early RA group [0.25 ng/ml (0.075-3.11)] and in patients with established RA [0.15 ng/ml (0.08-1.26)] than in healthy subjects [0 ng/ml (0-0)] and disease controls: SLE [0.01 ng/ml (0-0.055)], AS [0.05 ng/ml (0-0.255)], and PsA [0.01 ng/ml (0-0.065)]. The prevalence of 14-3-3η positivity in patients with early RA was 58%, significantly higher than that in disease controls and healthy subjects (p 0.001). In patients with established RA, this prevalence was 43%, and it was significantly higher than that in patients with other rheumatic diseases and healthy subjects (p 0.05), excluding the AS group (p = 0.054). In the early RA cohort, the positivity for 14-3-3η, RF, and anti-CCP was 58%, 67%, and 71%, respectively. Eighty-two percent of the patients in this cohort were positive for at least one of these biomarkers. The concentration of 14-3-3η protein may be used to distinguish between patients with early RA and patients with other rheumatic diseases.

BACKGROUND Place of residence has been associated with HIV transmission risks. Social capital, defined as features of social organization that improve efficiency of society by facilitating coordinated actions, often varies by neighborhood, and hypothesized to have protective effects on HIV care continuum outcomes. We examined whether the association between social capital and 2 HIV care continuum outcomes clustered geographically and whether sociocontextual mechanisms predict differences across clusters. METHODS Bivariate Local Moran's I evaluated geographical clustering in the association between social capital (participation in civic and social organizations, 2006, 2008, 2010) and [5-year (2007-2011) prevalence of late HIV diagnosis and linkage to HIV care] across Philadelphia, PA, census tracts (N = 378). Maps documented the clusters and multinomial regression assessed which sociocontextual mechanisms (eg, racial composition) predict differences across clusters. RESULTS We identified 4 significant clusters (high social capital-high HIV/AIDS, low social capital-low HIV/AIDS, low social capital-high HIV/AIDS, and high social capital-low HIV/AIDS). Moran's I between social capital and late HIV diagnosis was (I = 0.19, z = 9.54, P < 0.001) and linkage to HIV care (I = 0.06, z = 3.274, P = 0.002). In multivariable analysis, median household income predicted differences across clusters, particularly where social capital was lowest and HIV burden the highest, compared with clusters with high social capital and lowest HIV burden. DISCUSSION The association between social participation and HIV care continuum outcomes cluster geographically in Philadelphia, PA. HIV prevention interventions should account for this phenomenon. Reducing geographic disparities will require interventions tailored to each continuum step and that address socioeconomic factors such as neighborhood median income.

We examined HIV prevalence among patients 18–49 year olds admitted to a psychiatric hospital in Botswana in 2011 and 2012. The retrospective study analyzed females (F) and males (M) separately, comparing proportions with Chi square test and continuous variables with Wilcoxon rank-sum test, assessing significance at the 5% level. HIV seroprevalence among hospitalized psychiatric patients was much more common among females (53%) compared with males (19%) (p

The HECT domain E3 ubiquitin ligase SMURF2 regulates stability of several key protein targets involved in tumorigenesis, cell proliferation, migration, differentiation, and senescence. While altered levels and aberrant cellular distribution of SMURF2 were reported in different types of cancer, its role in tumorigenesis is far from understood. To elucidate the role of SMURF2 in cancer, appropriate human cancer cell models are needed. Here, we describe approaches that can be used to generate human normal and cancer cell strains knocked-out for SMURF2 using the clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene-editing technology.

E3 ubiquitin ligases (E3s) play essential roles in the maintenance of tissue homeostasis under normal and stress conditions, as well as in disease states, particularly in cancer. However, the role of E3s in the initiation of human tumors is poorly understood. Previously, we reported that genetic ablation of the HECT-type E3 ubiquitin ligase Smurf2 induces carcinogenesis in mice; but whether and how these findings are pertinent to the inception of human cancer remain unknown. Here we show that SMURF2 is essential to protect human dermal fibroblasts (HDFs) from malignant transformation, and its depletion converts HDFs into tumorigenic entity. This phenomenon was associated with the radical changes in chromatin structural and epigenetic landscape, dysregulated gene expression and cell-cycle control, mesenchymal-to-epithelial transition and impaired DNA damage response. Furthermore, we show that SMURF2-mediated tumor suppression is interlinked with SMURF2’s ability to regulate the expression of two central chromatin modifiers—an E3 ubiquitin ligase RNF20 and histone methyltransferase EZH2. Silencing these factors significantly reduced the growth and transformation capabilities of SMURF2-depleted cells. Finally, we demonstrate that SMURF2-compromised HDFs are highly tumorigenic in nude mice. These findings suggest the critical role that SMURF2 plays in preventing malignant alterations, chromosomal instability and cancer.

SMURF2, an E3 ubiquitin ligase and suggested tumor suppressor, operates in normal cells to prevent genomic instability and carcinogenesis. However, the mechanisms underlying SMURF2 inactivation in human malignancies remain elusive, as SMURF2 is rarely found mutated or deleted in cancers. We hypothesized that SMURF2 might have a distinct molecular biodistribution in cancer versus normal cells and tissues. The expression and localization of SMURF2 were analyzed in 666 human normal and cancer tissues, with primary focus on prostate and breast tumors. These investigations were accompanied by SMURF2 gene expression analyses, subcellular fractionation and biochemical studies, including SMURF2&rsquo, s interactome analysis. We found that while in normal cells and tissues SMURF2 has a predominantly nuclear localization, in prostate and aggressive breast carcinomas SMURF2 shows a significantly increased cytoplasmic sequestration, associated with the disease progression. Mechanistic studies showed that the nuclear export machinery was not involved in cytoplasmic accumulation of SMURF2, while uncovered that its stability is markedly increased in the cytoplasmic compartment. Subsequent interactome analyses pointed to 14-3-3s as SMURF2 interactors, which could potentially affect its localization. These findings link the distorted expression of SMURF2 to human carcinogenesis and suggest the alterations in SMURF2 localization as a potential mechanism obliterating its tumor suppressor activities.

One representative case of burns caused by the negligent use of bioethanol, which was treated at our burns centre is used to illustrate the severity and depth of the burn injuries as well as the complexity of the further long-term course of treatment including complex secondary-reconstructive techniques.

Anti-HMGCR antibodies represent a characteristic serological feature of statin-exposed and statin-unexposed patients with immune-mediated necrotizing myopathy (IMNM). We assessed anti-HMGCR antibodies in patients with suspected IMNM following statin exposure and patients with other autoimmune rheumatic diseases. We evaluated the presence of anti-HMGCR autoantibodies in sera samples from 13 statin-exposed patients who were suspected of having IMNM, 38 patients with different inflammatory and autoimmune rheumatic diseases and 29 healthy subjects. The autoantibodies were evaluated by two assays: a new chemiluminescence QUANTA Flash HMGCR kit utilizing BIO-FLASH system and QUANTA Lite® HMGCR ELISA kit. Twelve samples from patients with suspicion for IMNM were found positive for anti-HMGCR antibodies by both assays. Only one of the 13 samples that were found positive by ELISA was negative by CIA. A very good qualitative correlation (κ = 0.95; 95 % CI 0.85–1.0) and quantitative agreement (Spearman’s rho 0.87; P value

We would like to thank van der Meulen et al for their interest in our review and their comments regarding the role of the microbiome in Sjogren’s syndrome (SS).1 2 As they correctly point out, SS was not mentioned in our review primarily because we, along with the editors, have decided to include the most studied rheumatic and autoimmune conditions as they pertain to microbiome research. We agree that SS is a common disorder with an intriguing and yet to be fully elucidated etiopathogenesis, and that the characterisation of the microbiome in this context is indeed worth pursuing. We also note that the disease …

International audience; The beta decay of the Tz=-2 nucleus 64Se has been studied in a fragmentation reaction at RIKEN-Nishina Center. 64Se is the heavies Tz=-2 nucleus that decays to bound states in the daughter nucleus and the heaviest case where the mirror reaction 64Zn(3He,t)64Ga on the Tz=+2 64Zn stable target exists and can be compared. Beta-delayed gamma and proton radiation is reported for the 64Se and 64As cases. New levels have been observed in 64As, 64Ge (N=Z), 63Ge and 63Ga. The associated T1/2 values have been obtained.

14-3-3η protein is a proinflammatory mediator that may represent a novel diagnostic and prognostic biomarker for rheumatoid arthritis (RA). We assessed the correlation between changes in serum 14-3-3η levels and changes in clinical disease activity measures in RA patients treated with Tofacitinib (TOF). Paired serum samples from 35 patients with RA were obtained at baseline and 5 months after the initiation of treatment with TOF. The levels of 14-3-3η were measured by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. 14-3-3η positivity was found in 57% of the patients at baseline and in 37% of the patients after 5 months of treatment. Mean ± SD baseline 14-3-3η levels [4.92 ± 8.86 ng/ml] were significantly higher (p 0.005) than 14-3-3η levels following treatment [1.97 ± 4.59 ng/ml]. A statistically significant improvement (p 0.001) of CDAI, SDAI, DAS4ESR and DAS4CRP was achieved after 5 month of treatment. Decrease in 14-3-3η protein levels was highly correlated with improvement in DAS4ESR (r = 0.50, p 0.01), DAS4CRP (r = 0.46, p 0.01) and ESR (r = 0.36, p = 0.03) and moderately correlated with improvement in CDAI (r = 0.32, p = 0.065) and SDAI (r = 0.33, p = 0.051). The correlation between decrease in 14-3-3η levels and improvement in DAS4ESR remained significant in a partial correlation analysis controlling for ESR (r = 0.39, p = 0.02). This study demonstrates that in RA patients who were treated with TOF, decrease in 14-3-3η levels is correlated with improvement in clinical disease activity parameters. The 14-3-3η protein may serve as an objective biomarker for monitoring of TOF therapy response.

Excited states in the $T_z=-1$ nucleus $^{70}$Kr have been populated using inelastic scattering of a radioactive $^{70}$Kr beam as well as one- and two-neutron removal reactions from $^{71,72}$Kr at intermediate beam energies. The level scheme of $^{70}$Kr was constructed from the observed $\gamma$-ray transitions and coincidences. Tentative spin and parity assignments were made based on comparison with the mirror nucleus $^{70}$Se. A second $2^+$ state and a candidate for the corresponding $4^+_2$ state suggest shape coexistence in $^{70}$Kr., Comment: accepted Phys. Lett. B

Background 14–3–3η is a protein that is overexpressed in serum and joint fluid of patients with rheumatoid arthritis (RA) and may represent a diagnostic biomarker for RA. Objectives We assessed the prevalence and serum levels of 14–3–3η in patients with RA and with other rheumatic diseases. Methods Serum levels of 14–3–3η were measured in 96 patients with RA, in 101 patients with other rheumatic diseases and in 66 healthy subjects. The RA group consisted of 51 patients with well-established RA who were treated with different DMARDs, and 45 patients with early untreated disease (onset of less than 1 year). The disease control group included 33 patients with systemic lupus erythematosus (SLE), 44 patients with ankylosing spondylitis (AS) and 24 psoriatic arthritis (PsA) patients. All of the sera samples were evaluated by JOINT stat 14–3–3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. Results Median (IQR) 14–3–3η levels were significantly higher in the early RA group [0.25 ng/ml (0.075–3.11)] and in established RA patients [0.15 ng/ml (0.08–1.26)] in comparison with healthy subjects [0 ng/ml (0–0)] and disease controls: SLE [0.01 ng/ml (0–0.055)], AS [0.05 ng/ml (0–0.255)] and PsA [0.01 ng/ml (0–0.065)]. The prevalence of 14–3–3η positivity in early RA patients was 58%, significantly higher than in the disease control group (SLE: 9%, p Conclusions The concentration of 14–3–3η protein may be used to distinguish between patients with early RA and patients with other rheumatic diseases and serve as an additional biomarker in the diagnosis of RA. Disclosure of Interest O. Shovman: None declared, B. Gilburd: None declared, A. Watad: None declared, H. Amital: None declared, P. Langevitz: None declared, N. L. Bragazzi: None declared, M. Adawi: None declared, D. Perez: None declared, G. Bornstein : None declared, M. Lidar : None declared, M. Blank: None declared, Y. Azuri: None declared, N. K. Biln Employee of: Augurex Life Sciences Corp, A. Marotta Employee of: Augurex Life Sciences Corp, Y. Shoenfeld: None declared

Background 14–3–3η protein is a proinflammatory mediator that may represent a novel diagnostic and prognostic biomarker for rheumatoid arthritis (RA). Objectives To assess the disease activity parameters and 14–3–3η protein concentrations in serum of early RA patients treated with Tofacitinib. Methods Paired serum samples from 35 previously non-treated early RA patients (disease onset less than 1 year) receiving Tofacitinib were obtained at baseline and 5 months after the initiation of treatment. Levels of 14–3–3η were measured by JOINT stat 14–3–3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. We investigated the correlation between changes in serum 14–3–3η concentrations and changes in clinical disease activity index (CDAI), simplified disease activity index (SDAI), Disease Activity Score (DAS) 4CRP and DAS4ESR. Results Increased concentrations of 14–3–3η were found in 57% of the patients at baseline and in 37% of the patients after 5 months of treatment. Mean ±SD baseline 14–3–3η concentrations [4.92±8.86 ng/ml] were significantly higher (p=0.005) than those found following treatment [1.97±4.59 ng/ml]. Statistically significant improvement (p Conclusions The study demonstrates that decrease in 14–3–3η protein concentrations in RA patients treated with Tofacitinib is correlated with improvement of clinical disease activity parameters. 14–3–3η protein is a useful biomarker for monitoring Tofacitinib therapy. Disclosure of Interest O. Shovman: None declared, B. Gilburd: None declared, A. Watad: None declared, H. Amital: None declared, P. Langevitz: None declared, N. L. Bragazzi: None declared, M. Adawi: None declared, D. Perez: None declared, M. Blank: None declared, N. K. Biln Employee of: Augurex Life Sciences Corp, A. Marotta Employee of: Augurex Life Sciences Corp, Y. Shoenfeld: None declared

INTRODUCTION: A consistently suppressed viral load enables HIV (+) patients to live longer, healthier lives and reduces the probability of transmitting the virus. Since the prevalence of HIV is four times higher among those with psychiatric disorders than in the general population, it is likely that this group would also have greater difficulty remaining in care and achieving viral suppression. METHODS: A secondary data analysis utilizing screening data from the PATH for Triples (PFT) Study were examined to assess HIV load suppression among 254 psychiatric inpatients with comorbid substance use disorders in Philadelphia. Viral load results from the past 12 months were obtained from medical records for 63 inpatients identified as HIV (+). RESULTS: The sample was predominately African American (76%), male (56%), and the average age was 43 years. Psychiatric disorders included depression (64%), schizophrenia (21%), and bipolar disorder (13%) with patients reporting use of alcohol (73%), cocaine (64%), cannabis (29%) and opioids (16%) prior to admission. Among this high risk sample of HIV (+) patients, about one half (52%) achieved viral suppression, with recent opioid users six times more likely to have a detectable viral load than non-opioid users (OR=6.0; CI=1.1–31.7, p=.035). DISCUSSION: The 52% virial load suppression rate among psychiatric inpatient was higher than expected, given that the CDC’s national suppression rate among those diagnosed with HIV in the general population is 58%. However, individuals with mental illness and substance use disorders require constant surveillance, monitoring, and supportive services to achieve viral suppression. Many of those who were virally suppressed were engaged in Philadelphia’s extensive treatment network, whereas those who were detectable and enrolled in the PFT intervention were often homeless with unstable psychiatric symptoms and current substance use disorders, particularly opioid abuse.

Musculoskeletal involvement, including arthritis and tendinopathy, is a common and important determinant of disability and impaired quality of life in systemic sclerosis. However, the treatment of arthritis in systemic sclerosis has not been studied as a primary outcome in randomized controlled trials, and arthritis-specific outcome measures for systemic sclerosis have not been sufficiently validated to date. Rheumatologists caring for patients with systemic sclerosis must address these complaints regularly despite the fact that the level of evidence for the treatment of systemic sclerosis–related inflammatory arthritis is limited. Consensus statements, based on treatments for related musculoskeletal aspects of rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune diseases, support the use of methotrexate and hydroxychloroquine. Newer biologics, which have efficacy in the treatment of other autoimmune conditions, may show promise in the treatment of arthritis in systemic sclerosis. In this article, we review the current literature on the assessment and treatment of systemic sclerosis arthritis in order to address management considerations.

Summary A‐lamins, encoded by the LMNA gene, are major structural components of the nuclear lamina coordinating essential cellular processes. Mutations in the LMNA gene and/or alterations in its expression levels have been linked to a distinct subset of human disorders, collectively known as laminopathies, and to cancer. Mechanisms regulating A‐lamins are mostly obscure. Here, we identified E3 ubiquitin ligase Smurf2 as a physiological regulator of lamin A and its disease‐associated mutant form progerin (LAΔ50), whose expression underlies the development of Hutchinson‐Gilford progeria syndrome (HGPS), a devastating premature aging syndrome. We show that Smurf2 directly binds, ubiquitinates, and negatively regulates the expression of lamin A and progerin in Smurf2 dose‐ and E3 ligase‐dependent manners. Overexpression of catalytically active Smurf2 promotes the autophagic–lysosomal breakdown of lamin A and progerin, whereas Smurf2 depletion increases lamin A levels. Remarkably, acute overexpression of Smurf2 in progeria fibroblasts was able to significantly reduce the nuclear deformability. Furthermore, we demonstrate that the reciprocal relationship between Smurf2 and A‐lamins is preserved in different types of mouse and human normal and cancer tissues. These findings establish Smurf2 as an essential regulator of lamin A and progerin and lay a foundation for evaluating the efficiency of progerin clearance by Smurf2 in HGPS, and targeting of the Smurf2–lamin A axis in age‐related diseases such as cancer.

A key strategy targeting the metabolic changes underlying tumorigenesis involves inhibiting the glutaminase isozyme GLS to disrupt glutamine catabolism. However, identifying patient groups for this approach remains a challenge. Here, we define the roles of GLS and its less studied counterpart liver-type glutaminase (GLS2) in breast cancer. We find that GLS2 is upregulated and essential for TCA cycle anaplerosis, cell proliferation, and tumorigenesis in luminal-subtype breast cancers, which account for >70% of disease incidence, and that it mediates resistance to GLS-selective inhibitors. Although GLS is overexpressed in basal-subtype breast cancers, sensitivity to GLS inhibitors depends on glutamate efflux through the xCT antiporter. These findings establish an important role for GLS2 in tumorigenesis and suggest patient stratification approaches for glutaminase-targeted therapy.

BACKGROUND Previous analyses identified specific geographic areas in Philadelphia (hotspots) associated with negative outcomes along the HIV care continuum. We examined individual and community factors associated with residing in these hotspots. METHODS Retrospective cohort of 1404 persons newly diagnosed with HIV in 2008-2009 followed for 24 months after linkage to care. Multivariable regression examined associations between individual (age, sex, race/ethnicity, HIV transmission risk, and insurance status) and community (economic deprivation, distance to care, access to public transit, and access to pharmacy services) factors and the outcomes: residence in a hotspot associated with poor retention-in-care and residence in a hotspot associated with poor viral suppression. RESULTS In total, 24.4% and 13.7% of persons resided in hotspots associated with poor retention and poor viral suppression, respectively. For persons residing in poor retention hotspots, 28.3% were retained in care compared with 40.4% of those residing outside hotspots (P < 0.05). Similarly, for persons residing in poor viral suppression hotspots, 51.4% achieved viral suppression compared with 75.3% of those outside hotspots (P < 0.0.05). Factors significantly associated with residence in poor retention hotspots included female sex, lower economic deprivation, greater access to public transit, shorter distance to medical care, and longer distance to pharmacies. Factors significantly associated with residence in poor viral suppression hotspots included female sex, higher economic deprivation, and shorter distance to pharmacies. CONCLUSIONS Individual and community-level associations with geographic hotspots may inform both content and delivery strategies for interventions designed to improve retention-in-care and viral suppression.

Copyright: © 2014 Blank MB. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Volume 1 : Issue 1 Article Ref. #: 1000HARTOJ1e001 Mahatma Gandhi once said that the measure of a country’s greatness is in how it treats its least fortunate members. In his last public speech, Hubert Humphrey echoed the same sentiment when he said “...the moral test of government is how that government treats those who are in the dawn of life, the children; those who are in the twilight of life, the elderly; those who are in the shadows of life; the sick, the needy and the handicapped” (Remarks at the dedication of the Hubert H. Humphrey Building, November 1, 1977, Congressional Record, November 4, 1977, vol 123, p. 37287). The obligation of a civilization to care for the sick and downtrodden goes back in history at least to Aristotle.

To determine if an escalating HIV treatment adherence intervention would be considered by participants from a caring or coercive perspective, perceived coercion was examined in 238 community-based dually diagnosed individuals (HIV+ and a serious mental illness) randomized to a treatment-as-usual (TAU) control group or preventing AIDS through health for HIV+ persons (PATH+) Intervention that increased intervention intensity when adherence fell below 80 %. Minor differences were observed in perceived coercion between the PATH+ Intervention and Control groups with perceived coercion marginally higher in the PATH+ group. Latent growth curve analyses indicate that perceived coercion was not related to duration of the intervention for either the PATH+ or Control group. The experience of coercion by HIV+ individuals receiving community-based mental health services was not related to the intensity or duration of delivered services.

Background In areas where helminthes infections are common, autoimmune diseases are rare. Treatment with helminthes or their ova, improved clinical findings of several autoimmune diseases. Based on the helminthes biological activity, a novel chimeric be-specific molecule was synthetized of tuftsin-phosphoryl-choline (PC)-TPC. Objectives To study TPC treatment in established collagen induced arthritis (CIA) mice, and the mechanism of activity. Methods Arthritis was induced in DBA male mice by immunization with collagen emulsified in TB-mycobacteria at the tail base. Boost was given 3 weeks later. Treatment with TPC started when the clinical score was 2. Cytokines were measure in culture-fluid of splenocytes in-vitro. T regulatory cells and B regulatory cells were measured by FACS. TPC effect on TLR4 expression was studied using HEKTM-mTLR4 cells system and its inhibitor. M1 shift to M2 was performed in RAW macrophages differentiated to M1 by PMA followed by LPS. TPC was added and IL-6, TNFalpha, IL-10 were tested by ELISA. Results Starting TPC treatment of CIA mice after disease establishment, had a significant lower arthritis score in comparison with control vehicle subjected mice (i.e. TPC-6.8±0.8 vs vehicle-13.8±0.45; p via the phosphorylcholine end. Our data indicated that TPC significantly ameliorated established CIA by anti-inflammatory immunomodulatory activity. Conclusions Our data may lead to a novel bi-specific self small molecule for therapy of patients with advanced RA. Disclosure of Interest None declared

The heightened risk of persons with serious mental illness to contract and transmit human immunodeficiency virus (HIV) is a public health problem. Here we evaluate the interaction between psychiatric diagnosis and response to a community based-intervention targeted at treatment adherence in 236 HIV+ persons with co-occurring mental illness. To examine differential effectiveness of the intervention for categories of patient diagnosis, we reanalyzed the data after stratifying participants into two diagnostic groups: (1) participants with depressive disorders without psychosis and (2) participants with a psychotic or bipolar disorder. Outcomes included viral load and mental health quality of life (SF-12 Mental Health). We found that HIV+ persons with non-psychotic depressive disorders demonstrated a larger decrease in HIV viral load and more improvement in measures of mental health quality of life when compared to HIV+ persons with psychotic and bipolar disorders. We suggest that successful adherence interventions should be informed by psychiatric symptomatology. Trial registration: clinicaltrials.gov 29 identifier NCT00264823.

Non-classical secretory vesicles, collectively referred to as extracellular vesicles (EVs), have been implicated in different aspects of cancer cell survival and metastasis. Here, we describe how a specific class of EVs, called microvesicles (MVs), activates VEGF receptors and tumour angiogenesis through a unique 90 kDa form of VEGF (VEGF90K). We show that VEGF90K is generated by the crosslinking of VEGF165, catalysed by the enzyme tissue transglutaminase, and associates with MVs through its interaction with the chaperone Hsp90. We further demonstrate that MV-associated VEGF90K has a weakened affinity for Bevacizumab, causing Bevacizumab to be ineffective in blocking MV-dependent VEGF receptor activation. However, treatment with an Hsp90 inhibitor releases VEGF90K from MVs, restoring the sensitivity of VEGF90K to Bevacizumab. These findings reveal a novel mechanism by which cancer cell-derived MVs influence the tumour microenvironment and highlight the importance of recognizing their unique properties when considering drug treatment strategies., Extracellular vesicles (EVs) contain VEGF and can contribute to tumour angiogenesis, although the mechanism remains unclear. Here, the authors find that a form of VEGF (VEGF90K) resistant to Bevacizumab but sensitive to HSP90 inhibitors, associates with EVs through its interaction with Hsp90.