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Objectives: Marshallese are a Pacific Islander community that experience a disproportionate rate of type 2 diabetes. The purpose of this study is to evaluate the preliminary effectiveness and feasibility of an Adapted-Family Diabetes Self-Management Education (DSME) intervention among Marshallese adults diagnosed with type 2 diabetes and their family members when delivered in a clinical setting. Methods: Marshallese patients (primary participants) with type 2 diabetes (n = 10) and their family members (n = 10) enrolled in a pilot study deigned to evaluate an Adapted-Family DSME curriculum conducted by community health workers and a certified diabetes educator in a clinical setting. Primary and family participants’ health information and biometric data (HbA1c, blood pressure, cholesterol, and body mass index) were collected at preintervention and 12 weeks postintervention. Results: All 10 primary participants and 8 of the family members received all 10 hours of the education intervention. Nine of the 10 primary participants and 8 of the 10 family members completed the pre- and postintervention data collection events. Primary participants demonstrated a mean decrease in HbA1c of 0.7%, from pre- to postintervention, as well as improved blood pressure and cholesterol. Family members demonstrated minor improvements in HbA1c and blood pressure. Conclusions: Results suggest preliminary effectiveness and feasibility of the Adapted-Family DSME in a clinic setting and will inform implementation of a fully powered study.

Purpose This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax ® ) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. Methods Twenty-one patients with peritoneal malignancies received Nanotax ® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50–275 mg/m 2 ) of Cremophor-free Nanotax ® were administered intraperitoneally for one to six cycles (every 28 days). Results Intraperitoneal (IP) administration of Nanotax ® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration–time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450–2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax ® IP treatment. Conclusions Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax ® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.

The incidence of Lyme borreliosis has risen, accompanied by persistent symptoms. The innate immune system and related cytokines are crucial in the host response and symptom development. We characterized cytokine production capacity before and after antibiotic treatment in 1,060 Lyme borreliosis patients. We observed a negative correlation between antibody production and IL-10 responses, as well as increased IL-1Ra responses in patients with disseminated disease. Genome-wide mapping the cytokine production allowed us to identify 34 cytokine quantitative trait loci (cQTLs), with 31 novel ones. We pinpointed the causal variant at the TLR1-6-10 locus and validated the regulation of IL-1Ra responses at transcritpome level using an independent cohort. We found that cQTLs contribute to Lyme borreliosis susceptibility and are relevant to other immune-mediated diseases. Our findings improve the understanding of cytokine responses in Lyme borreliosis and provide a genetic map of immune function as an expanded resource. Common genetic variants can affect an individual’s immune response to pathogens. Here, the authors uncover and characterize variants regulating cytokine responses in Lyme Borreliosis in 1,060 patients.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1 – 5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need 6 , 7 . Here we report the progressive accumulation of exhausted, unconventionally activated CD8 + PD1 + T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8 + PD1 + T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8 + PD1 + CXCR6 + , TOX + , and TNF + T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 + T cells or TNF neutralization, suggesting that CD8 + T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8 + PD1 + T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment. In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Human respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infection in children under 5 y of age. In the absence of a safe and effective vaccine and with limited options for therapeutic interventions, uncontrolled epidemics of RSV occur annually worldwide. Existing RSV reverse genetics systems have been predominantly based on older laboratory-adapted strains such as A2 or Long. These strains are not representative of currently circulating genotypes and have a convoluted passage history, complicating their use in studies on molecular determinants of viral pathogenesis and intervention strategies. In this study, we have generated reverse genetics systems for clinical isolates of RSV-A (ON1, 0594 strain) and RSV-B (BA9, 9671 strain) in which the full-length complementary DNA (cDNA) copy of the viral antigenome is cloned into a bacterial artificial chromosome (BAC). Additional recombinant (r) RSVs were rescued expressing enhanced green fluorescent protein (EGFP), mScarlet, or NanoLuc luciferase from an additional transcription unit inserted between the P and M genes. Mutations in antigenic site II of the F protein conferring escape from palivizumab neutralization (K272E, K272Q, S275L) were investigated using quantitative cell-fusion assays and rRSVs via the use of BAC recombineering protocols. These mutations enabled RSV-A and -B to escape palivizumab neutralization but had differential impacts on cell-to-cell fusion, as the S275L mutation resulted in an almost-complete ablation of syncytium formation. These reverse genetics systems will facilitate future cross-validation efficacy studies of novel RSV therapeutic intervention strategies and investigations into viral and host factors necessary for virus entry and cell-to-cell spread.

AimsTo determine the prevalence of myopic maculopathy in the general population in Germany and to analyse potential associations with ocular and systemic factors.DesignThe Gutenberg Health Study is a population-based study, including 15 010 participants aged 35–74 years.MethodsMyopic maculopathy was graded in phakic eyes with spherical equivalent ≤−6 D by assessing fundus photographs according to a recent international photographic classification system (META-PM). 801 eyes of 519 participants (mean age 51.0±0.77 years) met the conditions and had gradable fundus photographs. Age-specific prevalence estimates were computed. Multivariable logistic regression analysis was used to assess associated factors with myopic maculopathy.ResultsMyopic maculopathy was present in 10.3% (95% CI 7.9 to 13.3) study participants. The prevalence was 8.6% (95% CI 6.1% to 11.9%) in the 397 right eyes and 8.7% (95% CI 6.2% to 12.0%) in the 404 left eyes. The most common type of pathology was diffuse atrophy (8.1%), followed by patchy atrophy (1.3%) and macular atrophy (0.5%); plus lesions were present in 3% (right eyes). Age (OR 1.07 per year, 95% CI 1.03 to 1.11, p<0.001), higher myopic refractive error (p<0.001), and male gender (p=0.02) were associated with myopic maculopathy, while cardiovascular risk factors and socioeconomic factors were not.ConclusionsThe prevalence of myopic maculopathy in the German population was 0.5%, and 10% in high myopic participants, aged 35–74 years. These population-based data are the first in Europe. Myopic maculopathy was related to severity of myopic refractive error and age.

Abstract Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC 50 : 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.

Background To estimate the burden of diseases, it is important to consider patient-reported outcomes including Quality of Life (QoL). The aim of this study is to provide population-based reference data for the National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25), stratified by sex and age. Methods The Gutenberg Health Study (GHS) is a population-based, prospective, observational cohort study in Germany, including 15,010 participants aged between 35 and 74. The baseline examination was conducted between 2007 and 2012. To overcome known shortcomings of the NEI VFQ-25, we calculated the previously proposed visual functioning scale and the socio-emotional scale based on Rasch-transformed person-level data. We present mean values, standard deviations and percentiles for age decades stratified by sex. We used a linear regression model to assess the influence of age, sex, socioeconomic status, distance-corrected visual acuity (better-seeing eye) and the absolute difference in distance-corrected visual acuity of both eyes on vision-related QoL. Results NEI VFQ-25 data are available from 12,231 participants (82%). Both the long-form visual functioning scale (LFVFS) and the long-form socio-emotional scale (LFSES) showed a clear age dependency, with an average LFVFS score of 92.8 for men and 90.5 for women in the youngest age group and 85.7 and 83.4 in the oldest age group, and a LFSES score of 98.3 for men and 98.1 in women in the youngest and 94.7 and 94.5 in the oldest decade. The largest difference was observed between the youngest age group (35–44 years) and the 45–54 years group. Men tended to have slightly higher scores than women. In the multivariable linear regression analysis, age (per 5 years −0.42), female sex (−1.57), worse distance-corrected visual acuity of the better eye (per 0.1 increase in logMAR −2.92) and the difference between both eyes (per 0.1 increase in logMAR −0.87) were associated with a reduced LFVFS score (all p  < 0.001). For the LFSES score, we showed that the influence of sex was minor, and that age (per 5 years −0.22), visual acuity of the better eye (−1.65), and the difference between both eyes (−0.56) were associated with a lower score (all p  < 0.001). Conclusions We report age- and sex-specific reference data from a large population-based study of mainly Caucasian ethnicity of two unidimensional scores based on Rasch-transformed NEI VFQ-25 data. Vision-related QoL is lower in older and in female individuals. Our results support the association of vision-related QoL not only with the distance-corrected visual acuity of the better eye but also with the difference in visual acuity between each eye. Our findings could be used as a reference for comparison in future studies addressing the influence of eye diseases on vision-related QoL.