Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV preexposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) ...in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, crossover pharmacokinetic study of TFV-DP in DBS during 33%, 67%, or 100% of daily dosing under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (25 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady state in 8 weeks. TFV-DP was dose proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1,605 (405) fmol/punch for the 33%, 67%, and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1,250 fmol/punch, which were estimated 25th percentiles for 2, 4, and 7 doses/week. In the present study, corresponding TFV-DP was within 3% of the prior estimates, and subgroups by site, race, and sex were within 14% of prior estimates, although males had 17.6% (95% confidence intervals CIs, 6.5, 27.4%) lower TFV-DP than females. The thresholds of 350, 700, and 1,250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.2, and 6 doses/week and 75% of women taking ≥0.6, 2.0, and 5.3 doses/week, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates and is useful for interpreting PrEP adherence and study outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02022657.).
Children with autism spectrum disorder (ASD) are five times more likely to have feeding difficulties than neurotypical peers, although the majority of evidence describes feeding difficulty in ...children age 2 years and older. The purpose of this study is to systematically review the literature on feeding characteristics of children age 0-24 months who were later diagnosed with ASD with an emphasis on the measurement tools used to assess these feeding behaviors. We conducted a systematic review of the literature using PRISMA guidelines. Using selected keywords, a search was conducted using PubMed, PsycINFO, and CINAHL databases for relevant articles to identify feeding characteristics in infants and toddlers (age 0-24 months) later diagnosed with ASD. Sixteen studies were selected for this review by two independent reviewers. Among the selected studies, feeding difficulties were reported in all infant oral feeding modalities (breastfeeding, bottle feeding, and complementary feeding) by infants later diagnosed with ASD. However, the evidence was conflicting among studies regarding feeding characteristics, such as sucking differences while breastfeeding, use of the spoon with feedings, and preference of solid food texture, that presented in infants later diagnosed with ASD. A lack of consistent measurement of feeding behaviors in infants later diagnosed with ASD contributes to the difficulty in comparison across studies. Future research should focus on developing targeted, validated instruments for measuring feeding difficulty in this population with emphasis on breastfeeding and bottle feeding difficulty.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Fat-associated lymphoid clusters (FALC) are inducible structures that support rapid innate-like B-cell immune responses in the serous cavities. Little is known about the physiological cues that ...activate FALCs in the pleural cavity and more generally the mechanisms controlling B-cell activation in FALCs. Here we show, using separate models of pleural nematode infection with Litomosoides sigmodontis and Altenaria alternata induced acute lung inflammation, that inflammation of the pleural cavity rapidly activates mediastinal and pericardial FALCs. IL-33 produced by FALC stroma is crucial for pleural B1-cell activation and local IgM secretion. However, B1 cells are not the direct target of IL-33, which instead requires IL-5 for activation. Moreover, lung inflammation leads to increased IL-5 production by type 2 cytokine-producing innate lymphoid cells (ILC2) in the FALC. These findings reveal a link between inflammation, IL-33 release by FALC stromal cells, ILC2 activation and pleural B-cell activation in FALCs, resulting in local and antigen-specific IgM production.
Abstract Epithelial ovarian carcinoma spreads via shedding of cells and multicellular aggregates (MCAs) from the primary tumor into peritoneal cavity, with subsequent intraperitoneal tumor ...cell:mesothelial cell adhesion as a key early event in metastatic seeding. Evaluation of human tumor extracts and tissues confirms that well-differentiated ovarian tumors express abundant E-cadherin (Ecad), whereas advanced lesions exhibit upregulated N-cadherin (Ncad). Two expression patterns are observed: “mixed cadherin,” in which distinct cells within the same tumor express either E- or Ncad, and “hybrid cadherin,” wherein single tumor cell(s) simultaneously expresses both cadherins. We demonstrate striking cadherin-dependent differences in cell-cell interactions, MCA formation, and aggregate ultrastructure. Mesenchymal-type Ncad+ cells formed stable, highly cohesive solid spheroids, whereas Ecad+ epithelial-type cells generated loosely adhesive cell clusters covered by uniform microvilli. Generation of “mixed cadherin” MCAs using fluorescently tagged cell populations revealed preferential sorting into cadherin-dependent clusters, whereas mixing of cell lines with common cadherin profiles generated homogeneous aggregates. Recapitulation of the “hybrid cadherin” Ecad+/Ncad+ phenotype, via insertion of the CDH2 gene into Ecad+ cells, resulted in the ability to form heterogeneous clusters with Ncad+ cells, significantly enhanced adhesion to organotypic mesomimetic cultures and peritoneal explants, and increased both migration and matrix invasion. Alternatively, insertion of CDH1 gene into Ncad+ cells greatly reduced cell-to-collagen, cell-to-mesothelium, and cell-to-peritoneum adhesion. Acquisition of the hybrid cadherin phenotype resulted in altered MCA surface morphology with increased surface projections and increased cell proliferation. Overall, these findings support the hypothesis that MCA cadherin composition impacts intraperitoneal cell and MCA dynamics and thereby affects ultimate metastatic success.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, ...chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epithelial ovarian cancer (EOC) metastasis occurs by exfoliation of cells and multicellular aggregates (MCAs) from the tumor into the peritoneal cavity, adhesion to and retraction of peritoneal ...mesothelial cells and subsequent anchoring. Elevated levels of lysophosphatidic acid (LPA) have been linked to aberrant cell proliferation, oncogenesis, and metastasis. LPA disrupts junctional integrity and epithelial cohesion in vitro however, the fate of free-floating cells/MCAs and the response of host peritoneal tissues to LPA remain unclear. EOC MCAs displayed significant LPA-induced changes in surface ultrastructure with the loss of cell surface protrusions and poor aggregation, resulting in increased dissemination of small clusters compared to untreated control MCAs. LPA also diminished the adhesive capacity of EOC single cells and MCAs to murine peritoneal explants and impaired MCA survival and mesothelial clearance competence. Peritoneal tissues from healthy mice injected with LPA exhibited enhanced mesothelial surface microvilli. Ultrastructural alterations were associated with restricted peritoneal susceptibility to metastatic colonization by single cells as well as epithelial-type MCAs. The functional consequence is an LPA-induced dissemination of small mesenchymal-type clusters, promoting a miliary mode of peritoneal seeding that complicates surgical removal and is associated with worse prognosis.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Maltreated children experience maltreatment recurrence in foster and adoptive homes.•American Indian children at increased risk for maltreatment recurrence.•American Indian children were more likely ...to report physical maltreatment recurrence.•American Indian children were more likely to report sexual maltreatment recurrence.•American Indian children were more likely to report spiritual maltreatment.
While maltreated children are at risk for recurrent maltreatment, less is known about the maltreatment recurrence of American Indian children in foster and adoptive homes.
This study examined the recurrent maltreatment of American Indian children in foster and adoptive homes, specifically the physical, emotional, sexual, and spiritual abuse subtypes, as well as poly-victimization of American Indian children in comparison to their White peers.
Data originated from the Experiences of Adopted and Fostered Individuals Project. The sample (n = 230) consisted of 99 American Indian and 131 White participants who experienced foster care and/or adoption during childhood.
Chi-square analyses and a t-test were used to test differences in maltreatment recurrence. Ordinary least squares regression analysis was used to examine the factors that contributed to poly-victimization.
Both American Indian and White participants reported high rates of emotional abuse. American Indian participants were particularly vulnerable to maltreatment recurrence in the forms of physical, sexual, and spiritual abuse, as well as poly-victimization in their foster and adoptive homes.
Our findings reflect high rates of maltreatment recurrence in foster care and adoption, which may be the result of retrospective self-report, rather than measures of rereport or substantiated recurrence.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Both T
2-dependent helminth killing and suppression of the T
2 effector response have been attributed to macrophages (MΦ) activated by IL-4 (M(IL-4)). To investigate how M(IL-4) contribute to diverse ...infection outcomes, the MΦ compartment of susceptible BALB/c mice and more resistant C57BL/6 mice was profiled during infection of the pleural cavity with the filarial nematode,
C57BL/6 mice exhibited a profoundly expanded resident MΦ (resMΦ) population, which was gradually replenished from the bone marrow in an age-dependent manner. Infection status did not alter the bone-marrow derived contribution to the resMΦ population, confirming local proliferation as the driver of resMΦ expansion. Significantly less resMΦ expansion was observed in the susceptible BALB/c strain, which instead exhibited an influx of monocytes that assumed an immunosuppressive PD-L2
phenotype. Inhibition of monocyte recruitment enhanced nematode killing. Thus, the balance of monocytic vs. resident M(IL-4) numbers varies between inbred mouse strains and impacts infection outcome.
The majority of women with epithelial ovarian cancer (OvCa) are diagnosed with metastatic disease, resulting in a poor 5-year survival of 31%. Obesity is a recognized non-infectious pandemic that ...increases OvCa incidence, enhances metastatic success and reduces survival. We have previously demonstrated a link between obesity and OvCa metastatic success in a diet-induced obesity mouse model wherein a significantly enhanced tumor burden was associated with a decreased M1/M2 tumor-associated macrophage ratio (Liu Y et al. Can, Res. 2015; 75:5046-57).
The objective of this study was to use pre-clinical murine models of diet-induced obesity to evaluate the effect of a high fat diet (HFD) on response to standard of care chemotherapy and to assess obesity-associated changes in the tumor microenvironment. Archived tumor tissues from ovarian cancer patients of defined body mass index (BMI) were also evaluated using multiplexed immunofluorescence analysis of immune markers.
We observed a significantly diminished response to standard of care paclitaxel/carboplatin chemotherapy in HFD mice relative to low fat diet (LFD) controls. A corresponding decrease in the M1/M2 macrophage ratio and enhanced tumor fibrosis were observed both in murine DIO studies and in human tumors from women with BMI > 30.
Our data suggest that the reported negative impact of obesity on OvCa patient survival may be due in part to the effect of the altered M1/M2 tumor-associated macrophage ratio and enhanced fibrosis on chemosensitivity. These data demonstrate a contribution of host obesity to ovarian tumor progression and therapeutic response and support future combination strategies targeting macrophage polarization and/or fibrosis in the obese host.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
OBJECTIVE:The aim of this study was to identify and compare common reasons and risk factors for 30-day readmission after pancreatic resection.
BACKGROUND:Hospital readmission after pancreatic ...resection is common and costly. Many studies have evaluated this problem and numerous discrepancies exist regarding the primary reasons and risk factors for readmission.
METHODS:Multiple electronic databases were searched from 2002 to 2016, and 15 relevant articles identified. Overall readmission rate was calculated from individual study estimates using a random-effects model. Study data were combined and overall estimates of odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each risk factor. Multivariable data were qualitatively synthesized.
RESULTS:The overall 30-day readmission rate was 19.1% (95% CI 17.4–20.7) across all studies. Infectious complications and gastrointestinal disorders, such as failure to thrive and delayed gastric emptying, together accounted for 58.9% of all readmissions. Demographic factors did not predict readmission. Heart disease (OR 1.37, 95% CI 1.12–1.67), hypertension (OR 1.44, 95% CI 1.09–1.91), and intraoperative blood transfusion (OR 1.45, 95% CI 1.15–1.83) were weak predictors of readmission, while any postoperative complications (OR 2.22, 95% CI 1.55–3.18) or severe complications (OR 2.84, 95% CI 1.65–4.89) were stronger predictors.
CONCLUSIONS:Readmission after pancreatic resection is common and can largely be attributed to infectious complications and inability to maintain adequate hydration and nutrition. Focus on outpatient resources and follow-up to address these issues will prove valuable in reducing readmissions.
PDF
