A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung.

BACKGROUND: Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy is showing promising efficacy for treatment of cystic fibrosis (CF) and is becoming more widely available since recent FDA approval. However, little is known about how these drugs will affect lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF). METHODS: We analyzed sputum microbiome and metabolome data from pwCF (n=24) before and after ETI therapy using 16S rRNA gene sequencing and untargeted metabolomics. RESULTS: The sputum microbiome diversity, particularly its evenness, was increased (p=0.036) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes remained more similar within an individual than across the sampled population. No specific microbial taxa differed in relative abundance before and after therapy, but the collective log-ratio of classic CF pathogens to anaerobes significantly decreased (p=0.013). The sputum metabolome also showed changes associated with ETI (PERMANOVA F=4.22, p=0.002) and was characterized by greater variation across subjects while on treatment. Changes in the metabolome were driven by a decrease in peptides, amino acids, and metabolites from the kynurenine pathway, which were associated with a decrease in CF pathogens. Metabolism of the three small molecules that make up ETI was extensive, including previously uncharacterized structural modifications. CONCLUSIONS: ETI therapy is associated with a changing microbiome and metabolome in airway mucus. This effect was stronger on sputum biochemistry, which may reflect changing niche space for microbial residency in lung mucus as the drug's effects take hold. FUNDING: This project was funded by a National Institute of Allergy and Infectious Disease Grant R01AI145925.

Hmong participants' reactions to return of individual and community pharmacogenetic research results: "A positive light for our community".

Pharmacogenetic research has historically lacked racial and ethnic diversity, limiting the application of findings to minority populations. Recent studies, including the Hmong, have gauged communities' interest in participating in genomic research and receiving their individual results. This study was conducted to create a culturally and linguistically appropriate format to return pharmacogenomic results and identify Minnesota Hmong research participants' reactions to their personal and collective results. Using a community-based participatory research approach, researchers collaborated with Hmong community members to format the pharmacogenetic disclosure process. Three focus groups were completed with 24 Hmong participants and three major themes emerged using thematic analysis. Many Hmong focus group participants viewed the results positively, finding them useful for themselves and their community as a means to optimize responses to and avoid harms from medicines. However, some participants expressed concerns about harms that the pharmacogenetic information could bring, including anxiety, misunderstanding, discrimination, exploitation, and lack of a clinician involvement in interpreting and applying the result. Many participants interpreted their results through an experiential lens, trusting their experience of medicines more than trusting genetic information, and through a cultural lens, expressing the belief that environmental factors may influence how people's bodies respond to medicines by influencing their inherited flesh and blood (roj ntsha). Lastly, participants stressed the importance of disseminating the information while acknowledging the complex linguistic, educational, and cultural factors that limit understanding of the results. Researchers, genetic counselors, pharmacists, and healthcare providers should strive to return results in meaningful ways to all members of society.

Author Correction: Emerging trends in global freshwater availability.

In Fig. 2 of this Analysis, the tick-mark labels on the colour bars in the second and third images from the top were inadvertently swapped. In addition, the citation at the end of the sentence, "On a monthly basis GRACE can resolve TWS changes with sufficient accuracy over scales that range from approximately 200,000 km2 at low latitudes to about 90,000 km2 near the poles" should be to ref. 4 not ref. 1. These errors have been corrected online.

Emerging trends in global freshwater availability.

Freshwater availability is changing worldwide. Here we quantify 34 trends in terrestrial water storage observed by the Gravity Recovery and Climate Experiment (GRACE) satellites during 2002-2016 and categorize their drivers as natural interannual variability, unsustainable groundwater consumption, climate change or combinations thereof. Several of these trends had been lacking thorough investigation and attribution, including massive changes in northwestern China and the Okavango Delta. Others are consistent with climate model predictions. This observation-based assessment of how the world's water landscape is responding to human impacts and climate variations provides a blueprint for evaluating and predicting emerging threats to water and food security.

CLOCK 3111T/C genetic variant influences the daily rhythm of autonomic nervous function: relevance to body weight control.

BACKGROUND/OBJECTIVES: Humans carrying the genetic risk variant C at the circadian CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C have been shown to have more difficulties to achieve desired weight loss than TT carriers. We tested the hypothesis that the daily rhythm of autonomic nervous function differs in CLOCK 3111C carriers, leading to reduced effectiveness in weight control. SUBJECTS/METHODS: We recruited 40 overweight/obese Caucasian women (body mass index>25), 20 carrying CLOCK 3111C (CC and TC) and 20 non-carriers with matched age and body mass index who participated in a dietary obesity treatment program of up to 30 weeks. Following the treatment, ambulatory electrocardiography was continuously monitored for up to 3.5 days when subjects underwent their normal daily activities. To assess autonomic function, heart rate variability analysis (HRV) was performed hourly to obtain mean inter-beat interval between two consecutive R waves (mean RR) and s.d. of normal-to-normal heartbeat intervals (SDNN), and two parasympathetic measures, namely, proportion of differences between adjacent NN intervals that are >50 ms (pNN50), and high-frequency (HF: 0.15-0.4 Hz) power. RESULTS: In the TT carriers, all tested HRV indices showed significant daily rhythms (all P-values <0.0001) with lower mean RR, SDNN, pNN50, and HF during the daytime as compared with the nighttime. The amplitudes of these rhythms except for SDNN were reduced significantly in the C carriers (mean RR: ~19.7%, P=0.001; pNN50: 58.1%, P=0.001; and HF: 41.1%, P=0.001). In addition, subjects with less weight loss during the treatment program had smaller amplitudes in the rhythms of mean RR (P<0.0001), pNN50 (P=0.007) and HF (P=0.003). Furthermore, the rhythmicity-weight loss associations were much stronger in the C carriers as compared to the TT carriers (mean RR: P=0.028, pNN50: P=0.0002; HF: P=0.015). CONCLUSIONS: The daily rhythm of parasympathetic modulation may play a role in the influence of the CLOCK variation on body weight control.

The antenatal urinary tract dilation classification system accurately predicts severity of kidney and urinary tract abnormalities.

BACKGROUND: Urinary tract dilation (UTD) is a commonly diagnosed prenatal condition; however, it is currently unknown which features lead to benign and resolving or pathologic abnormalities. A consensus UTD classification system (antenatal UTD classification, UTD-A) was created by Nguyen et al. in 2014 [1], but has not yet been validated. OBJECTIVE: To evaluate the ability of the UTD-A system to identify kidney and urinary tract (KUT) abnormalities, assess whether UTD-A can predict severity of KUT conditions, and perform a cost analysis of screening ultrasound (US). METHODS: A retrospective single-center study was conducted at an academic medical center. Inclusion criteria were: neonates in the well or sick nursery who had a complete abdominal or limited renal US performed in the first 30 days of life between January 01, 2011 and December 31, 2013. Data were collected on prenatal US characteristics from which UTD-A classification was retrospectively applied, and postnatal data were collected up to 2 years following birth. RESULTS: A total of 203 patients were identified. Of the 36 abnormal postnatal KUT diagnoses, 90% were identified prenatally as UTD A1 or UTD A2-3. The remaining 10% developed postnatal KUT abnormalities due to myelomeningocele, such as VUR or UTD, which were not evident prenatally. Overall sensitivity and specificity of the UTD-A system was 0.767 (95% CI 0.577, 0.901) and 0.836 (95% CI 0.758, 0.897), respectively, when resolved UTD was counted as a normal diagnosis. Postnatal diagnoses differed by UTD-A classification as shown in the Summary fig. Of all the obstructive uropathies, 90.9% occurred in the UTD A2-3 class and none occurred in UTD-A Normal. Rate of postnatally resolved UTD was significantly higher in the UTD A1 group (78%) compared with UTD A2-3 (31%) or UTD-A Normal (12%, all P < 0.001). There was a notable trend towards more UT surgeries, UTI, and positive VUR among UTD A2-3 patients, but statistical significance was limited by a small number of patients. CONCLUSIONS: This study found that the UTD-A classification system revealed important differences in the severity of UTD abnormalities. With repeated validation in larger cohorts, the UTD-A classification may be used to offer a prognosis for parents regarding prenatally diagnosed KUT conditions. Larger prospective studies should be designed to validate whether the UTD-A system can predict postnatal events related to UTD morbidity such as need for UT-related surgery or UTI.

Separating decadal global water cycle variability from sea level rise.

Under a warming climate, amplification of the water cycle and changes in precipitation patterns over land are expected to occur, subsequently impacting the terrestrial water balance. On global scales, such changes in terrestrial water storage (TWS) will be reflected in the water contained in the ocean and can manifest as global sea level variations. Naturally occurring climate-driven TWS variability can temporarily obscure the long-term trend in sea level rise, in addition to modulating the impacts of sea level rise through natural periodic undulation in regional and global sea level. The internal variability of the global water cycle, therefore, confounds both the detection and attribution of sea level rise. Here, we use a suite of observations to quantify and map the contribution of TWS variability to sea level variability on decadal timescales. In particular, we find that decadal sea level variability centered in the Pacific Ocean is closely tied to low frequency variability of TWS in key areas across the globe. The unambiguous identification and clean separation of this component of variability is the missing step in uncovering the anthropogenic trend in sea level and understanding the potential for low-frequency modulation of future TWS impacts including flooding and drought.

Peste Des Petits Ruminants in Benin: Persistence of a Single Virus Genotype in the Country for Over 42 Years.

Peste des petits ruminants (PPR) is a contagious and often fatal disease affecting sheep and goats. Currently, it is endemic in Africa, the Middle and Near East, the Indian subcontinent and China. Understanding the molecular epidemiology and evolution of PPR virus (PPRV) can assist in the control of the transboundary spread of this economically important disease. We isolated PPRV from pathological and swab samples collected 42 years apart (1969 and 2011) in Benin, West Africa, and sequenced the full genome of two isolates (Benin/B1/1969 and Benin/10/2011). Phylogenetic analysis showed that all of the characterized isolates clustered within viral lineage II and that the 2011 isolates fell into two distinct subgroups. Comparison of the full genome sequences revealed a 95.3% identity at the nucleotide level, while at the protein level, the matrix protein was the most conserved between the two viruses with an identity of 99.7% and only one amino acid substitution over the 42-year sampling period. An analysis of specific amino acid residues of known or putative function did not identify any significant changes between the two viruses. A molecular clock analysis of complete PPRV genomes revealed that the lineage II viruses sampled here arose in the early 1960s and that these viruses have likely persisted in Benin since this time.

Association of dementia in patients with benign paroxysmal positional vertigo.

OBJECTIVE: We conducted a cohort study to investigate whether benign paroxysmal positional vertigo (BPPV) is correlated with an increased risk of dementia. METHODS: We established a case cohort comprising 7818 patients aged over 20 years who were diagnosed with BPPV from 2000 to 2010. In addition, we formed a control cohort by randomly selecting 31,272 people without BPPV and matched them with the BPPV patients according to gender, age, and index year. Cox proportional hazard regressions were performed to compute the hazard ratio (HR) of dementia after we adjusted for demographic characteristics and comorbidity. RESULTS: The prevalence of comorbidity was higher among patients with BPPV than among those without BPPV. In addition, patients with BPPV exhibited a 1.24-fold (95% confidence interval, CI 1.09-1.40; P < 0.001) higher risk of dementia than those without BPPV after we adjusted for age, gender, and comorbidity. An analysis stratified according to demographic factors revealed that women with BPPV exhibited a 1.36-fold (95% CI 1.16-1.59; P < 0.001) higher risk of dementia. Patients with BPPV aged over 65 years exhibited a significantly higher risk of dementia (adjusted HR: 1.26; 95% CI 1.10-1.43; P < 0.001) than those without BPPV. CONCLUSIONS: Patients with BPPV exhibited a higher risk of dementia than those without BPPV.

Restoration of MYC-repressed targets mediates the negative effects of GM-CSF on RUNX1-ETO leukemogenicity.

Granulocyte macrophage-colony-stimulating factor (GM-CSF) signaling regulates hematopoiesis and immune responses. CSF2RA, the gene encoding the α-subunit for GM-CSF, is significantly downregulated in t(8;21) (RUNX1-ETO or RE) leukemia patients, suggesting that it may serve as a tumor suppressor. We previously reported that GM-CSF signaling is inhibitory to RE leukemogenesis. Here we conducted gene expression profiling of primary RE hematopoietic stem/progenitor cells (HSPCs) treated with GM-CSF to elucidate the mechanisms mediating the negative effects of GM on RE leukemogenicity. We observed that GM treatment of RE HSPCs resulted in a unique gene expression profile that resembles primary human cells undergoing myelopoiesis, which was not observed in control HSPCs. Additionally, we discovered that GM-CSF signaling attenuates MYC-associated gene signatures in RE HSPCs. In agreement with this, a functional screen of a subset of GM-CSF-responsive genes demonstrated that a MYC inhibitor, MXI1 (Max interactor 1), reduced the leukemic potential of RE HSPCs and t(8;21) acute myeloid leukemia (AML) cells. Furthermore, MYC knockdown and treatment with the BET (bromodomain and extra terminal domain) inhibitor JQ1 reduced the leukemic potential of t(8;21) cell lines. Altogether, we discovered a novel molecular mechanism mediating the GM-CSF-induced reduction in leukemic potential of RE cells, and our findings support MYC inhibition as an effective strategy for reducing the leukemogenicity of t(8;21) AML.

Acclimation potential of Arctic cod (Boreogadus saida) from the rapidly warming Arctic Ocean.

As a consequence of the growing concern about warming of the Arctic Ocean, this study quantified the thermal acclimation responses of Boreogadus saida, a key Arctic food web fish. Physiological rates for cardio-respiratory functions as well as critical maximum temperature (Tc,max) for loss of equilibrium (LOE) were measured. The transition temperatures for these events (LOE, the rate of oxygen uptake and maximum heart rate) during acute warming were used to gauge phenotypic plasticity after thermal acclimation from 0.5°C up to 6.5°C for 1 month (respiratory and Tc,max measurements) and 6 months (cardiac measurements). Tc,max increased significantly by 2.3°C from 14.9°C to 17.1°C with thermal acclimation, while the optimum temperature for absolute aerobic scope increased by 4.5°C over the same range of thermal acclimation. Warm acclimation reset the maximum heart rate to a statistically lower rate, but the first Arrhenius breakpoint temperature during acute warming was unchanged. The hierarchy of transition temperatures was quantified at three acclimation temperatures and was fitted inside a Fry temperature tolerance polygon to better define ecologically relevant thermal limits to performance of B. saida We conclude that B. saida can acclimate to 6.5°C water temperatures in the laboratory. However, at this acclimation temperature 50% of the fish were unable to recover from maximum swimming at the 8.5°C test temperature and their cardio-respiratory performance started to decline at water temperatures greater than 5.4°C. Such costs in performance may limit the ecological significance of B. saida acclimation potential.

A decade of sea level rise slowed by climate-driven hydrology.

Climate-driven changes in land water storage and their contributions to sea level rise have been absent from Intergovernmental Panel on Climate Change sea level budgets owing to observational challenges. Recent advances in satellite measurement of time-variable gravity combined with reconciled global glacier loss estimates enable a disaggregation of continental land mass changes and a quantification of this term. We found that between 2002 and 2014, climate variability resulted in an additional 3200 ± 900 gigatons of water being stored on land. This gain partially offset water losses from ice sheets, glaciers, and groundwater pumping, slowing the rate of sea level rise by 0.71 ± 0.20 millimeters per year. These findings highlight the importance of climate-driven changes in hydrology when assigning attribution to decadal changes in sea level.

Immunotherapy for peanut allergy.

Peanut allergy is one of the commonest food hypersensitivities causing fatal or near-fatal reactions. There is, currently, no preventive treatment and the incidence of severe allergic reactions during peanut desensitisation has limited its clinical use. Anti-immunoglobulin E therapy has been shown to be effective in preventing peanut-induced reactions but it does not result in long-term tolerance. Two important advances have recently been reported. One involves gradual oral introduction of peanut protein to desensitise, whereas the other approach uses a combination of anti-immunoglobulin E and oral peanut immunotherapy. Both approaches could offer a way to desensitise with a far greater margin of safety than has, hitherto, been reported. This article provides an overview of the literature on peanut immunotherapy and describes the experience in a small group of children in Hong Kong who were treated successfully using anti-immunoglobulin E combined with oral peanut desensitisation.

[Reemergence of contagious bovine pleuropneumonia in Senegal]. / Réémergence de la péripneumonie contagieuse bovine au Sénégal.

The authors have described an epizootic infection of contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides biotype Small Colony (MmmSC), that has affected Ndama bovine in Lounthy village, a locality based in Bala city in the Eastern part of Senegal, during the post-rainy season in November 2012. After the cessation of vaccination, a hotbed of suspicion of CBPP was identified on November 3rd 2012 in the village of Lounthy: out of the total of 98 cattle, 13 animals were sick and 5 of them died. These studies have been done according to clinical aspects, serological, bacteriological and molecular analysis of the samples. This reemergent disease will give new orientations for CBPP control in Senegal, where it was supposed the disease has been eradicated since 2005.

JAK inhibitors suppress t(8;21) fusion protein-induced leukemia.

Oncogenic mutations in components of the JAK/STAT pathway, including those in cytokine receptors and JAKs, lead to increased activity of downstream signaling and are frequently found in leukemia and other hematological disorders. Thus, small-molecule inhibitors of this pathway have been the focus of targeted therapy in these hematological diseases. We previously showed that t(8;21) fusion protein acute myeloid leukemia (AML)1-ETO and its alternatively spliced variant AML1-ETO9a (AE9a) enhance the JAK/STAT pathway via downregulation of CD45, a negative regulator of this pathway. To investigate the therapeutic potential of targeting JAK/STAT in t(8;21) leukemia, we examined the effects of a JAK2-selective inhibitor TG101209 and a JAK1/2-selective inhibitor INCB18424 on t(8;21) leukemia cells. TG101209 and INCB18424 inhibited proliferation and promoted apoptosis of these cells. Furthermore, TG101209 treatment in AE9a leukemia mice reduced tumor burden and significantly prolonged survival. TG101209 also significantly impaired the leukemia-initiating potential of AE9a leukemia cells in secondary recipient mice. These results demonstrate the potential therapeutic efficacy of JAK inhibitors in treating t(8;21) AML.