A SARS-CoV-2 RBD vaccine fused to the chemokine MIP-3α elicits sustained murine antibody responses over 12 months and enhanced lung T-cell responses.

Background: Previous studies have demonstrated enhanced efficacy of vaccine formulations that incorporate the chemokine macrophage inflammatory protein 3α (MIP-3α) to direct vaccine antigens to immature dendritic cells. To address the reduction in vaccine efficacy associated with a mutation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants, we have examined the ability of receptor-binding domain vaccines incorporating MIP-3α to sustain higher concentrations of antibody when administered intramuscularly (IM) and to more effectively elicit lung T-cell responses when administered intranasally (IN). Methods: BALB/c mice aged 6-8 weeks were immunized intramuscularly or intranasally with DNA vaccine constructs consisting of the SARS-CoV-2 receptor-binding domain alone or fused to the chemokine MIP-3α. In a small-scale (n = 3/group) experiment, mice immunized IM with electroporation were followed up for serum antibody concentrations over a period of 1 year and for bronchoalveolar antibody levels at the termination of the study. Following IN immunization with unencapsulated plasmid DNA (n = 6/group), mice were evaluated at 11 weeks for serum antibody concentrations, quantities of T cells in the lungs, and IFN-γ- and TNF-α-expressing antigen-specific T cells in the lungs and spleen. Results: At 12 months postprimary vaccination, recipients of the IM vaccine incorporating MIP-3α had significantly, approximately threefold, higher serum antibody concentrations than recipients of the vaccine not incorporating MIP-3α. The area-under-the-curve analyses of the 12-month observation interval demonstrated significantly greater antibody concentrations over time in recipients of the MIP-3α vaccine formulation. At 12 months postprimary immunization, only recipients of the fusion vaccine had concentrations of serum-neutralizing activity deemed to be effective. After intranasal immunization, only recipients of the MIP-3α vaccine formulations developed T-cell responses in the lungs significantly above those of PBS controls. Low levels of serum antibody responses were obtained following IN immunization. Conclusion: Although requiring separate IM and IN immunizations for optimal immunization, incorporating MIP-3α in a SARS-CoV-2 vaccine construct demonstrated the potential of a stable and easily produced vaccine formulation to provide the extended antibody and T-cell responses that may be required for protection in the setting of emerging SARS-CoV-2 variants. Without electroporation, simple, uncoated plasmid DNA incorporating MIP-3α administered intranasally elicited lung T-cell responses.

The heme oxygenase-1 metalloporphyrin inhibitor stannsoporfin enhances the bactericidal activity of a novel regimen for multidrug-resistant tuberculosis in a murine model.

Multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) poses significant challenges to global tuberculosis (TB) control efforts. Host-directed therapies (HDTs) offer a novel approach to TB treatment by enhancing immune-mediated clearance of Mtb. Prior preclinical studies found that the inhibition of heme oxygenase-1 (HO-1), an enzyme involved in heme metabolism, with tin-protoporphyrin IX (SnPP) significantly reduced mouse lung bacillary burden when co-administered with the first-line antitubercular regimen. Here, we evaluated the adjunctive HDT activity of a novel HO-1 inhibitor, stannsoporfin (SnMP), in combination with a novel MDR-TB regimen comprising a next-generation diarylquinoline, TBAJ-876 (S), pretomanid (Pa), and a new oxazolidinone, TBI-223 (O) (collectively, SPaO), in Mtb-infected BALB/c mice. After 4 weeks of treatment, SPaO + SnMP 5mg/kg reduced mean lung bacillary burden by an additional 0.69 log10 (P = 0.01) relative to SPaO alone. As early as 2 weeks post-treatment initiation, SnMP adjunctive therapy differentially altered the expression of pro-inflammatory cytokine genes and CD38, a marker of M1 macrophages. Next, we evaluated the sterilizing potential of SnMP adjunctive therapy in a mouse model of microbiological relapse. After 6 weeks of treatment, SPaO + SnMP 10mg/kg reduced lung bacterial burdens to 0.71 ± 0.23 log10 colony-forming units (CFUs), a 0.78 log-fold greater decrease in lung CFU compared to SpaO alone (P = 0.005). However, adjunctive SnMP did not reduce microbiological relapse rates after 5 or 6 weeks of treatment. SnMP was well tolerated and did not significantly alter gross or histological lung pathology. SnMP is a promising HDT candidate requiring further study in combination with regimens for drug-resistant TB.

HIV/Tuberculosis Coinfection in Pregnancy and the Postpartum Period.

The convergence of Human Immunodeficiency Virus (HIV) and tuberculosis (TB) represents a considerable global public health challenge. The concurrent infection of HIV and TB in pregnant women not only intensifies the transmission of HIV from mother to fetus but also engenders adverse outcomes for maternal health, pregnancy, and infant well-being, necessitating the implementation of integrated strategies to effectively address and manage both diseases. In this article, we review the pathophysiology, clinical presentation, treatment, and management of HIV/TB coinfection during pregnancy, the postpartum period, and lactation and highlight the differences compared to the general population.

The heme oxygenase-1 metalloporphyrin inhibitor stannsoporfin enhances the bactericidal activity of a novel regimen for multidrug-resistant tuberculosis in a murine model.

Multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) poses significant challenges to global tuberculosis (TB) control efforts. Host-directed therapies (HDT) offer a novel approach for TB treatment by enhancing immune-mediated clearance of Mtb. Prior preclinical studies found that inhibition of heme oxygenase-1 (HO-1), an enzyme involved in heme metabolism, with tin-protoporphyrin IX (SnPP) significantly reduced mouse lung bacillary burden when co-administered with the first-line antitubercular regimen. Here we evaluated the adjunctive HDT activity of a novel HO-1 inhibitor, stannsoporfin (SnMP), in combination with a novel MDR-TB regimen comprising a next-generation diarylquinoline, TBAJ-876 (S), pretomanid (Pa), and a new oxazolidinone, TBI-223 (O) (collectively, SPaO) in Mtb-infected BALB/c mice. After 4 weeks of treatment, SPaO + SnMP 5 mg/kg reduced mean lung bacillary burden by an additional 0.69 log10 (P=0.01) relative to SPaO alone. As early as 2 weeks post-treatment initiation, SnMP adjunctive therapy differentially altered the expression of pro-inflammatory cytokine genes, and CD38, a marker of M1 macrophages. Next, we evaluated the sterilizing potential of SnMP adjunctive therapy in a mouse model of microbiological relapse. After 6 weeks of treatment, SPaO + SnMP 10 mg/kg reduced lung bacterial burdens to 0.71 ± 0.23 log10 CFU, a 0.78 log-fold greater decrease in lung CFU compared to SpaO alone (P=0.005). However, adjunctive SnMP did not reduce microbiological relapse rates after 5 or 6 weeks of treatment. SnMP was well tolerated and did not significantly alter gross or histological lung pathology. SnMP is a promising HDT candidate requiring further study in combination with regimens for drug-resistant TB.

Combination of a MIP3α-antigen fusion therapeutic DNA vaccine with treatments of IFNα and 5-Aza-2'Deoxycytidine enhances activated effector CD8+ T cells expressing CD11c in the B16F10 melanoma model.

Previous studies in the B16F10 mouse melanoma model have demonstrated that combining a DNA vaccine comprised of regions of gp100 and tyrosinase-related protein 2 fused to Macrophage-inflammatory protein 3-alpha (MIP3α) with recombinant Interferon alpha (IFN) and 5-Aza-2'-Deoxycytidine (5Aza) treatments resulted in significantly greater anti-tumor activity and immunogenicity in the tumor microenvironment (TME). This brief report details that the combination of vaccine with treatments IFN and 5Aza results in both the upregulation of genes expressing CD11c-interacting proteins and an increase in the TME of a distinct CD11c+ CD8+ T cell population. This cell population correlates with tumor size, is primarily comprised of effector or effector memory T cells, and has a more robust response to ex vivo stimulation as compared to CD11c- CD8+ T cells as measured by surface activation markers 4-1BB (CD137) and KLRG1 (Killer cell lectin-like receptor G1) and intracellular IFNγ production. In conclusion, this combination therapy results in greater presence of highly active effector CD8+ T-cells expressing CD11c in the TME that correlate with and are likely primary contributors to treatment efficacy.

Human Immunodeficiency Virus and Clonal Hematopoiesis.

The evolution of antiretroviral therapies (ART) has tremendously improved the life expectancy of people living with human immunodeficiency virus (HIV) (PLWH), which is currently similar to the general population. However, as PLWH are now living longer, they exhibit various comorbidities such as a higher risk of cardiovascular disease (CVD) and non-acquired immunodeficiency syndrome (AIDS)-defined malignancies. Clonal hematopoiesis (CH) is the acquisition of somatic mutations by the hematopoietic stem cells, rendering them survival and growth benefit, thus leading to their clonal dominance in the bone marrow. Recent epidemiologic studies have highlighted that PLWH have a higher prevalence of CH, which in turn is associated with increased CVD risk. Thus, a link between HIV infection and a higher risk for CVD might be explained through the induction of inflammatory signaling in the monocytes carrying CH mutations. Among the PLWH, CH is associated with an overall poorer control of HIV infection; an association that requires further mechanistic evaluation. Finally, CH is linked to an increased risk of progression to myeloid neoplasms including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), which are associated with particularly poor outcomes among patients with HIV infection. These bidirectional associations require further molecular-level understanding, highlighting the need for more preclinical and prospective clinical studies. This review summarizes the current literature on the association between CH and HIV infection.

Development and Validation of the HIV-CARDIO-PREDICT Score to Estimate the Risk of Cardiovascular Events in HIV-Infected Patients.

IMPORTANCE: Commonly used risk assessment tools for cardiovascular disease might not be accurate for HIV-infected patients. OBJECTIVE: We aimed to develop a model to accurately predict the 10-year cardiovascular disease (CV) risk of HIV-infected patients. DESIGN: In this retrospective cohort study, adult HIV-infected patients seen at Boston Medical Center between March 2012 and January 2017 were divided into model development and validation cohorts. SETTING: Boston Medical Center, a tertiary, academic medical center. PARTICIPANTS: Adult HIV-infected patients, seen in inpatient and outpatient setting. MAIN OUTCOMES AND MEASURES: We used logistic regression to create a prediction risk model for cardiovascular events using data from the development cohort. Using a point-based risk-scoring system, we summarized the relationship between risk factors and cardiovascular disease (CVD) risk. We then used the area under the receiver operating characteristics curve (AUC) to evaluate model discrimination. Finally, we tested the model using a validation cohort. RESULTS: 1914 individuals met the inclusion criteria. The model had excellent discrimination for CVD risk [AUC 0.989; (95% CI: 0.986-0.993)] and included the following 11 variables: male sex (95% CI: 2.53-3.99), African American race/ethnicity (95% CI: 1.50-3.13), current age (95% CI: 0.07-0.13), age at HIV diagnosis (95% CI: -0.10-(-0.02)), peak HIV viral load (95% CI: 9.89 × 10-7-3.00 × 10-6), nadir CD4 lymphocyte count (95% CI: -0.03-(-0.02)), hypertension (95% CI: 0.20-1.54), hyperlipidemia (95% CI: 3.03-4.60), diabetes (95% CI: 0.61-1.89), chronic kidney disease (95% CI: 1.26-2.62), and smoking (95% CI: 0.12-2.39). The eleven-parameter multiple logistic regression model had excellent discrimination [AUC 0.957; (95% CI: 0.938-0.975)] when applied to the validation cohort. CONCLUSIONS AND RELEVANCE: Our novel HIV-CARDIO-PREDICT Score may provide a rapid and accurate evaluation of CV disease risk among HIV-infected patients and inform prevention measures.

An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis.

Lengthy tuberculosis (TB) treatment is required to overcome the ability of a subpopulation of persistent Mycobacterium tuberculosis (Mtb) to remain in a non-replicating, antibiotic-tolerant state characterized by metabolic remodeling, including induction of the RelMtb-mediated stringent response. We developed a novel therapeutic DNA vaccine containing a fusion of the relMtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3α/CCL20. To augment mucosal immune responses, intranasal delivery was also evaluated. We found that intramuscular delivery of the MIP-3α/relMtb (fusion) vaccine or intranasal delivery of the relMtb (non-fusion) vaccine potentiate isoniazid activity more than intramuscular delivery of the DNA vaccine expressing relMtb alone in a chronic TB mouse model (absolute reduction of Mtb burden: 0.63 log10 and 0.5 log10 colony-forming units, respectively; P=0.0002 and P=0.0052), inducing pronounced Mtb-protective immune signatures. The combined approach involving intranasal delivery of the DNA MIP-3α/relMtb fusion vaccine demonstrated the greatest mycobactericidal activity together with isoniazid when compared to each approach alone (absolute reduction of Mtb burden: 1.13 log10, when compared to the intramuscular vaccine targeting relMtb alone; P<0.0001), as well as robust systemic and local Th1 and Th17 responses. This DNA vaccination strategy may be a promising adjunctive approach combined with standard therapy to shorten curative TB treatment, and also serves as proof of concept for treating other chronic bacterial infections.

IFNα and 5-Aza-2'-deoxycytidine combined with a dendritic-cell targeting DNA vaccine alter tumor immune cell infiltration in the B16F10 melanoma model.

Introduction: DNA vaccines containing a fusion of the gene encoding chemokine MIP-3α (CCL20), the ligand for CCR6 on immature dendritic cells (DCs), to melanoma-associated antigen genes have enhanced anti-tumor immunity and efficacy compared to those lacking the chemokine gene. Previous work has shown that type-I interferon (IFNα or IFN) and 5-Aza-2'-deoxycytidine (5Aza) significantly enhance the therapeutic benefit of DNA vaccines as measured by reduced tumor burden and improved mouse survival. Methods: Here, we explored mouse intratumoral immune correlates underlying the therapeutic benefit of this combination regimen (vaccine, IFN, and 5Aza) as compared to vaccine alone and IFN and 5Aza without vaccine, focusing on chemokine mRNA expression by qRT-PCR and inflammatory cellular infiltration into the tumor microenvironment (TME) by flow cytometry and immunohistochemistry (IHC). Results: The combination group significantly upregulated intratumoral mRNA expression of key immune infiltration chemokines XCL1 and CXCL10. Flow cytometric analyses of tumor suspensions exhibited greater tumor infiltration of CD8+ DCs, CCR7+ DCs, and NK cells in the combination group, as well as reduced levels of myeloid-derived suppressor cells (MDSCs) in vaccinated groups. The mice receiving combination therapy also had greater proportions of effector/memory T-cells (Tem), in addition to showing an enhanced infiltration of Tem and central memory CD8+ T-cells, (Tcm). Tem and Tcm populations both correlated with smaller tumor size. Immunohistochemical analysis of tumors confirmed that CD8+ cells were more abundant overall and especially in the tumor parenchyma with combination therapy. Discussion: Efficient targeting of antigen to immature DCs with a chemokine-fusion vaccine offers a potential alternative approach to classic and dendritic cell-based vaccines. Combining this approach with IFNα and 5Aza treatments significantly improved vaccine efficacy. This treatment creates an environment of increased inflammatory chemokines that facilitates the trafficking of CD8+ DCs, NK cells, and CD8+ T-cells, especially memory cells, while reducing the number of MDSCs. Importantly, in the combination group, CD8+ cells were more able to penetrate the tumor mass in addition to being more numerous. Further analysis of the pathways engaged by our combination therapy is expected to provide additional insights into melanoma pathogenesis and facilitate the development of novel treatment strategies.

Sex determines the presentation and outcomes in MPN and is related to sex-specific differences in the mutational burden.

The factors underlying the variable presentation and clinical course of myeloproliferative neoplasms (MPNs) remain unclear. The aim of this study was to evaluate the independent effect of sex on MPN presentation and outcomes. A total of 815 patients with essential thrombocytosis, polycythemia vera, or primary myelofibrosis were evaluated between 2005 and 2019, and the association of sex with presenting phenotype, JAK2 V617F burden, progression, and survival was examined. Men presented more often with primary myelofibrosis vs essential thrombocytosis (relative risk, 3.2; P < .001) and polycythemia vera (relative risk, 2.1; P < .001), had higher rates of transformation to secondary myelofibrosis (hazard ratio [HR], 1.55; P = .013) and acute myeloid leukemia (HR, 3.67; P < .001), and worse survival (HR, 1.63; P = .001) independent of age, phenotype at diagnosis, and MPN-specific mutation. Men had higher JAK2 V617F allele burdens in their CD34+ cells (P = .001), acquired more somatic mutations (P = .012) apart from the MPN-specific mutations, and had an increased frequency of 1 (odds ratio, 2.35; P = .017) and 2 (odds ratio, 20.20; P = .011) high-risk mutations independent of age, phenotype, and driver mutation. Male sex is an independent predictor of poor outcomes in MPNs. This seems to be due to an increased risk of non-MPN-specific somatic mutations, particularly high-risk mutations, rather than MPN-specific mutation allele frequency. Conversely, disease progression in female subjects is more dependent on JAK2 mutation allele burden than on acquisition of other somatic mutations. Sex should be considered in prognostic models and when evaluating therapeutic strategies in MPNs.

Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration-resistant prostate cancer models.

Previous studies have shown that increased levels of chemokine receptor CXCR7 are associated with the increased invasiveness of prostate cancer cells. We now show that CXCR7 expression is upregulated in VCaP and C4-2B cells after enzalutamide (ENZ) treatment. ENZ treatment induced apoptosis (sub-G1) in VCaP and C4-2B cells, and this effect was further increased after combination treatment with ENZ and CCX771, a specific CXCR7 inhibitor. The levels of p-EGFR (Y1068), p-AKT (T308) and VEGFR2 were reduced after ENZ and CCX771 combination treatment compared to single agent treatment. In addition, significantly greater reductions in migration were shown after combination treatment compared to those of single agents or vehicle controls, and importantly, similar reductions in the levels of secreted VEGF were also demonstrated. Orthotopic VCaP xenograft growth and subcutaneous MDA133-4 patient-derived xenograft (PDX) tumor growth was reduced by single agent treatment, but significantly greater suppression was observed in the combination treatment group. Although overall microvessel densities in the tumor tissues were not different among the different treatment groups, a significant reduction in large blood vessels (>100 µm2 ) was observed in tumors following combination treatment. Apoptotic indices in tumor tissues were significantly increased following combination treatment compared with vehicle control-treated tumor tissues. Our results demonstrate that significant tumor suppression mediated by ENZ and CXCR7 combination treatment may be due, in part, to reductions in proangiogenic signaling and in the formation of large blood vessels in prostate cancer tumors.

Correlation of Opioid Mortality with Prescriptions and Social Determinants: A Cross-sectional Study of Medicare Enrollees.

BACKGROUND: The opioid epidemic is an escalating health crisis. We evaluated the impact of opioid prescription rates and socioeconomic determinants on opioid mortality rates, and identified potential differences in prescription patterns by categories of practitioners. METHODS: We combined the 2013 and 2014 Medicare Part D data and quantified the opioid prescription rate in a county level cross-sectional study with data from 2710 counties, 468,614 unique prescribers and 46,665,037 beneficiaries. We used the CDC WONDER database to obtain opioid-related mortality data. Socioeconomic characteristics for each county were acquired from the US Census Bureau. RESULTS: The average national opioid prescription rate was 3.86 claims per beneficiary that received a prescription for opioids (95% CI 3.86-3.86). At a county level, overall opioid prescription rates (p < 0.001, Coeff = 0.27) and especially those provided by emergency medicine (p < 0.001, Coeff = 0.21), family medicine physicians (p = 0.11, Coeff = 0.008), internal medicine (p = 0.018, Coeff = 0.1) and physician assistants (p = 0.021, Coeff = 0.08) were associated with opioid-related mortality. Demographic factors, such as proportion of white (p white < 0.001, Coeff = 0.22), black (p black < 0.001, Coeff = - 0.19) and male population (p male < 0.001, Coeff = 0.13) were associated with opioid prescription rates, while poverty (p < 0.001, Coeff = 0.41) and proportion of white population (p white < 0.001, Coeff = 0.27) were risk factors for opioid-related mortality (p model < 0.001, R 2 = 0.35). Notably, the impact of prescribers in the upper quartile was associated with opioid mortality (p < 0.001, Coeff = 0.14) and was twice that of the remaining 75% of prescribers together (p < 0.001, Coeff = 0.07) (p model = 0.03, R 2 = 0.03). CONCLUSIONS: The prescription opioid rate, and especially that by certain categories of prescribers, correlated with opioid-related mortality. Interventions should prioritize providers that have a disproportionate impact and those that care for populations with socioeconomic factors that place them at higher risk.

Androgen receptor inhibitor-induced "BRCAness" and PARP inhibition are synthetically lethal for castration-resistant prostate cancer.

Cancers with loss-of-function mutations in BRCA1 or BRCA2 are deficient in the DNA damage repair pathway called homologous recombination (HR), rendering these cancers exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors. This functional state and therapeutic sensitivity is referred to as "BRCAness" and is most commonly associated with some breast cancer types. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only ~20% of prostate cancer patients. We found that castration-resistant prostate cancer (CRPC) cells showed increased expression of a set of HR-associated genes, including BRCA1, RAD54L, and RMI2 Although androgen-targeted therapy is typically not effective in CRPC patients, the androgen receptor inhibitor enzalutamide suppressed the expression of those HR genes in CRPC cells, thus creating HR deficiency and BRCAness. A "lead-in" treatment strategy, in which enzalutamide was followed by the PARP inhibitor olaparib, promoted DNA damage-induced cell death and inhibited clonal proliferation of prostate cancer cells in culture and suppressed the growth of prostate cancer xenografts in mice. Thus, antiandrogen and PARP inhibitor combination therapy may be effective for CRPC patients and suggests that pharmaceutically inducing BRCAness may expand the clinical use of PARP inhibitors.

The Attributable Burden of Clostridium difficile Infection to Long-Term Care Facilities Stay: A Clinical Study.

BACKGROUND: Advanced age, history of hospitalization, and antibiotic consumption are associated with the pathogenesis of Clostridium difficile infection (CDI). Long-term care facilities (LTCFs) represent a setting where CDI has been increasingly reported. We aimed to estimate the actual attributable burden of CDI to LTCF stay and determine the characteristics of the disease epidemiology in this setting. DESIGN: IRB-approved retrospective cohort study. SETTING: LTCF and community. PARTICIPANTS: One thousand seven hundred and sixty-one patients. MEASUREMENTS/RESULTS: The prevalence of CDI among LTCF residents was 22.4%, whereas the prevalence of CDI among community residents was 6.7% (P < .001). The prevalence of CDI among LTCF residents was significantly higher in both the 18-64 (P < .001) and the ≥65 age groups (P < .010). Measures of hospital exposure and antibiotic consumption between LTCF and community residents prior to CDI diagnosis were non-significant. A strict matching (1:2) between LTCF and community residents adjusting for age, total number of hospital admissions and antibiotic consumption showed that the odds of CDI for an LTCF resident were 6.89 times larger than the odds for a community resident (OR = 6.89, 95%, 4.67-10.17). For an LTCF resident with CDI, the odds of manifesting severe disease were 3.25 times larger than the odds for a community resident with CDI (OR = 3.25, 95%, 1.81-5.86). LTCF residents were more frequently hospitalized (P = .002) required longer hospital stays for their CDI management (P = .03) and had more recurrent CDI cases than community residents (P = .04). CONCLUSIONS: Our study highlights the increased burden of CDI among LTCF residents independently of age, antibiotic, and hospitalization background. Severe CDI disease and recurrences are more frequent in LTCFs.

Prevalence of ESBL-Producing Enterobacteriaceae in Pediatric Bloodstream Infections: A Systematic Review and Meta-Analysis.

BACKGROUND: Pediatric bloodstream infections (BSIs) with Extended-Spectrum Beta-Lactamase- producing Enterobacteriaceae (ESBL-PE) are associated with worse clinical outcomes. We aimed to estimate the prevalence of and the mortality associated with ESBL-PE in this patient population. METHODS: A systematic review and meta-analysis using PubMed and EMBASE and included studies reporting the prevalence of ESBL-PE among confirmed BSIs in patients <19 years old. RESULTS: Twenty three (out of 1,718 non-duplicate reports) studies that provided data on 3,381 pediatric BSIs from 1996 to 2013 were included. The prevalence of ESBL-PE was 9% [95%CI (6, 13)] with an annual increase of 3.2% (P = 0.04). The prevalence was 11% [95%CI (6, 17)] among neonates, compared to 5% [95%CI (0, 14)] among children older than 28 days. The pooled prevalence was 15% in Africa [95%CI (8, 23)], 12% in South America [95%CI (5, 23)], 11% in India [95%CI (7, 17)], 7% in the rest of Asia [95%CI (0, 22)], 4% in Europe [95%CI (1, 7)] and 0% in Oceania [95%CI (0, 3)]. Importantly, the mortality in neonates with BSI due to ESBL-PE was 36% [95%CI (22, 51)], compared to 18% [95%CI (15, 22)] among all other neonates with BSI and this difference was statistically significant (P = 0.01). CONCLUSIONS: In the pediatric population, the prevalence of BSI due to ESBL-PE is significant and is associated with increased mortality in neonates. Further studies are warranted to establish a high-risk group and the evaluation of preventive measures, such as antibiotic stewardship programs and infection control measures, in this population is urgently needed.

Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling.

Cell division cycle 6 (CDC6), an androgen receptor (AR) target gene, is implicated in regulating DNA replication and checkpoint mechanisms. CDC6 expression is increased during prostate cancer (PCa) progression and positively correlates with AR in PCa tissues. AR or CDC6 knockdown, together with AZD7762, a Chk1/2 inhibitor, results in decreased TopBP1-ATR-Chk1 signaling and markedly increased ataxia-telangiectasia-mutated (ATM) phosphorylation, a biomarker of DNA damage, and synergistically increases treatment efficacy. Combination treatment with the AR signaling inhibitor enzalutamide (ENZ) and the Chk1/2 inhibitor AZD7762 demonstrates synergy with regard to inhibition of AR-CDC6-ATR-Chk1 signaling, ATM phosphorylation induction, and apoptosis in VCaP (mutant p53) and LNCaP-C4-2b (wild-type p53) cells. CDC6 overexpression significantly reduced ENZ- and AZD7762-induced apoptosis. Additive or synergistic therapeutic activities are demonstrated in AR-positive animal xenograft models. These findings have important clinical implications, since they introduce a therapeutic strategy for AR-positive, metastatic, castration-resistant PCa, regardless of p53 status, through targeting AR-CDC6-ATR-Chk1 signaling.

ICU Acquisition Rate, Risk Factors, and Clinical Significance of Digestive Tract Colonization With Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the acquisition rate, identify risk factors, and estimate the risk for subsequent infection, associated with the colonization of the digestive tract with extended-spectrum beta-lactamase-producing Enterobacteriaceae during ICU-hospitalization. DATA SOURCES: PubMed, EMBASE, and reference lists of all eligible articles. STUDY SELECTION: Included studies provided data on ICU-acquired colonization with extended-spectrum beta-lactamase-producing Enterobacteriaceae in previously noncolonized and noninfected patients and used the double disk synergy test for extended-spectrum beta-lactamase-producing Enterobacteriaceae phenotypic confirmation. Studies reporting extended-spectrum beta-lactamase-producing Enterobacteriaceae outbreaks or data on pediatric population were excluded. DATA EXTRACTION: Two authors independently assessed study eligibility and performed data extraction. DATA SYNTHESIS: Thirteen studies (with 15,045 ICUs-patients) were evaluated using a random-effect model and a meta-regression analysis. The acquisition rate of digestive tract colonization during ICU stay was 7% (95% CI, 5-10) and it varies from 3% (95% CI, 2-4) and 4% (95% CI, 2-6) in the Americas and Europe to 21% (95% CI, 9-35) in the Western Pacific region. Previous hospitalization (risk ratio, 1.57 [95% CI, 1.07-2.31]) or antibiotic use (risk ratio, 1.65 [95% CI, 1.15-2.37]) and exposure to beta-lactams/beta-lactamase inhibitors (risk ratio, 1.78 [95% CI, 1.24-2.56]) and carbapenems (risk ratio, 2.13 [95% CI, 1.49-3.06]) during the ICU stay were independent risk factors for ICU-acquired colonization. Importantly, colonized patients were more likely to develop an extended-spectrum beta-lactamase-producing Enterobacteriaceae infection (risk ratio, 49.62 [95% CI, 20.42-120.58]). The sensitivity and specificity of prior colonization to predict subsequent extended-spectrum beta-lactamase-producing Enterobacteriaceae infection were 95.1% (95% CI, 54.7-99.7) and 89.2% (95% CI, 77.2-95.3), respectively. CONCLUSIONS: The ICU acquisition rate of extended-spectrum beta-lactamase-producing Enterobacteriaceae ranged from 5% to 10%. Previous use of beta-lactam/beta-lactamase or carbapenems and recent hospitalization were independent risk factors for extended-spectrum beta-lactamase-producing Enterobacteriaceae colonization, and colonization was associated with significantly higher frequency of extended-spectrum beta-lactamase-producing Enterobacteriaceae subsequent infection and increased mortality.

Colonisation with extended-spectrum ß-lactamase-producing Enterobacteriaceae and risk for infection among patients with solid or haematological malignancy: a systematic review and meta-analysis.

Cancer patients are vulnerable to infections, including those with extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE), and most of these infections are associated with colonisation of the gastrointestinal tract. The aim of this study was to estimate the prevalence of gastrointestinal colonisation with ESBL-PE cancer populations and to determine the risk for subsequent bloodstream infection (BSI) with these pathogens. PubMed and EMBASE databases were searched from 1 January 1991 to 1 March 2016 to identify studies regarding ESBL-PE colonisation among patients with malignancies. Ten studies (out of 561 non-duplicate articles) were included, providing data on 2211 patients. The pooled prevalence of ESBL-PE colonisation was 19% [95% confidence interval (CI) 8-32%]. Stratifying per region, the pooled prevalence in Europe was 15% (95% CI 10-21%), whereas in Asia the pooled prevalence was 31% (95% CI 4-69%). In addition, the pooled prevalence was 15% (95% CI 7-24%) among patients with haematological malignancy, whereas no studies were identified that included solely patients with solid tumours. Notably, cancer patients with ESBL-PE colonisation were 12.98 times (95% CI 3.91-43.06) more likely to develop a BSI with ESBL-PE during their hospitalisation compared with non-colonised patients. We found that, overall, one in five patients with cancer is colonised with ESBL-PE and the incidence can be as high as one in three in Asia. This is important because colonisation was associated with an almost 13 times higher risk for developing BSI with ESBL-PE. Screening measures should be evaluated to identify their clinical benefit in patients with malignancy.

Uncontrolled diabetes predicts poor response to novel antiandrogens.

Metabolic abnormalities including hyperglycemia and hyperlipidemia have been associated with worse prognosis of prostate cancer (PCa), but there are limited data regarding their impact on the prognosis of castrate-resistant prostate cancer (CRPC) and the response of novel antiandrogens, namely abiraterone acetate (AA) and enzalutamide. Retrospective analysis of 61 patients with CRPC on AA or enzalutamide, treated at the Boston Medical Center, was performed. We evaluated hemoglobin A1c (HbA1c), HDL, LDL, Triglycerides and BMI within 2months before the initiation of treatment with AA or enzalutamide and progression-free survival (PFS) under this treatment. Regression analysis and analysis of variance were used to evaluate the data. HbA1c levels were found to predict adversely the PFS on the novel agents (df (1, 37), P=0.00, R(2)=0.40, coeff=-3.28). The Kaplan-Meier analysis showed that there is significant difference in survival between the HbA1c 4.7-5.9% compared with patients with HbA1c 7.8-11.6% (6.72±1.3months, log rank test P<0.0001) LDL (P=0.07), HDL (P=0.14), and triglycerides (P=0.33) were not found to predict PFS. BMI predicted PFS positively (df (1.59), P=0.02, R(2)=0.09, coeff=0.03), but not independently of HbA1c (P=0.07). No significant implications of social and family history, previous chemotherapy regimen, and Gleason score with PFS were found. Multiple markers of patients' health state were not associated with HbA1c values. Uncontrolled diabetes can predict for poor response of CRPC patients to AA and enzalutamide determining PFS under this treatment. Elevated BMI can positively affect PFS at this stage of disease.