Internet Use for Health Information among American Indians: Facilitators and Inhibitors

Our research team explored Internet use among a heterogeneous American Indian (AI) population to determine Internet use in relation to health information seeking behaviors. Participants examined an AI culturally-tailored tobacco website as an example to explain what they wanted in an AI Internet health site. Using community-based participatory research, we conducted 10 focus groups with non-college AI men and women (N=96), stratified by age (18-29, 30-49, and 50 and over) to better understand their perceptions of Internet use and health information needs. We found that Internet use varied greatly among all strata. Participants referenced WebMD© more than any other website, but participants were not pleased with the design and navigation. When examining the sample website, participants across strata stressed that recreational and traditional tobacco use should be discussed. Participants in all strata desired a simple website design with easy to read text accompanied by images. In order to gain and maintain cultural respect, participants stated that web designers should be aware that some images hold cultural meaning, particularly tobacco. Baseline data are needed for AI’s use of the Internet to obtain health information; this research is helpful to address health inequalities among AI, particularly access to web-based health information

Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency

BACKGROUND: Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVE: We explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS: Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type vs. mutant LIG4 were performed in LIG4 knock-out Jurkat T cells and DNA damage tolerance was subsequently assessed. RESULTS: A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naïve CD4$^{+}$ T cells and low TCR-Vα7.2$^{+}$ T cells, while T/B-cell receptor repertoires showed only mild alterations. Cohort screening identified two other non-related patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSION: We provide evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency

Deployment of the C-band radar Poldirad on Barbados during EUREC4A

The German polarimetric C-band weather radar Poldirad (Polarization Diversity Radar) was deployed for the international field campaign EUREC4A (Elucidating the role of clouds-circulation coupling in climate) on the island of Barbados where it was operated from February until August 2020. Focus of the installation was monitoring clouds and precipitation in the trade wind region east of Barbados. Different scanning modes were used with a temporal sequence of 5 min and a maximum range of 375 km. In addition to built-in quality control performed by the radar signal processor, it was found that the copoloar correlation coefficient rhoHV can be used to remove contamination of radar products by sea clutter. Radar images were available in real time for all campaign participants and aboard research aircraft. Examples of mesoscale precipitation patterns, rain rate accumulation, diurnal cycle, and vertical distribution are given to show the potential of the radar measurements for further studies on the life cycle of precipitating shallow cumulus clouds and other related aspects. Poldirad data from the EUREC4A campaign are available on the EUREC4A AERIS database: https://doi.org/10.25326/218 (Hagen et al., 2021a) for raw data and https://doi.org/10.25326/217 (Hagen et al., 2021b) for gridded data

Views of the public about Snacktivity™: a small changes approach to promoting physical activity and reducing sedentary behaviour

Background: Many people do not meet the recommended health guidance of participation in a minimum of 150–300 min of moderate intensity physical activity per week, often promoted as at least 30 min of physical activity on 5 days of the week. This is concerning and highlights the importance of finding innovative ways to help people to be physically active each day. Snacktivity™ is a novel approach that aims to encourage people to do small, 2–5 min bouts of physical activity ‘snacks’ throughout the whole day, such that they achieve at least 150 min of moderate intensity activity per week. However, before it can be recommended, there is a need to explore whether the concept is acceptable to the public. Methods: A survey to assess the views of the public about Snacktivity™ was distributed to adult patients registered at six general practices in the West Midlands, UK and to health care employees in the same region. Results: A total of 5989 surveys were sent to patients, of which 558 were returned (9.3%). A further 166 surveys were completed by health care employees. A total of 85% of respondents liked the Snacktivity™ concept. The flexibility of the approach was highly rated. A high proportion of participants (61%) reported that the ability to self-monitor their behaviour would help them to do Snacktivity™ throughout their day. Physically inactive participants perceived that Snacktivity™ would help to increase their physical activity, more than those who were physically active (OR = 0.41, 95% CI: 0.25–0.67). Approximately 90% of respondents perceived that Snacktivity™ was easy to do on a non-working day compared to 60% on a working day. Aerobic activity ‘snacks’ were preferred to those which were strength based. Conclusions: The Snacktivity™ approach to promoting physical activity was viewed positively by the public and interventions to test the merits of such an approach now need to be developed and tested in a variety of everyday contexts

Pravastatin for early-onset pre-eclampsia:a randomised, blinded, placebo-controlled trial

Objective: Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a pre-eclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during pre-eclampsia. Design: Blinded (clinician and participant), proof of principle, placebo-controlled trial. Setting: Fifteen UK maternity units. Population: We used a minimisation algorithm to assign 62 women with early-onset pre-eclampsia (24 +0–31 +6 weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth. Primary outcome: Difference in mean plasma sFlt-1 levels over the first 3 days following randomisation. Results: The difference in the mean maternal plasma sFlt-1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95% CI −1175 to 592; P = 0.5), and over days 1–14 was 48 pg/ml (95% CI −1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50–1.40; P = 0.6). The median time from randomisation to childbirth was 9 days [interquartile range (IQR) 5–14 days] for the pravastatin group and 7 days (IQR 4–11 days) for the placebo group. There were three perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin. Conclusions: We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early-onset pre-eclampsia had developed. Pravastatin appears to have no adverse perinatal effects. Tweetable abstract: Pravastatin does not improve maternal plasma sFlt-1 or placental growth factor levels following a diagnosis of early preterm pre-eclampsia #clinicaltrial finds

Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Abstract: Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors

Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Abstract: Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors