Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one ...can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome.
IntroductionLow vitamin D status is prevalent among women with polycystic ovary syndrome (PCOS). The objective of the study is to assess the effect of vitamin D supplementation on (1) the ovulation ...rate to letrozole and (2) other reproductive, endocrine and metabolic outcomes after 1 year of supplementation in women with PCOS.Methods and analysisThis is a multicentre, randomised, double-blind, controlled clinical trial. A total of 220 anovulatory women with PCOS diagnosed by the Rotterdam criteria will be recruited. They will be randomly assigned to either the (1) vitamin D supplementation group or (2) placebo group. Those in the vitamin D group will take oral Vitamin D3 50 000 IU/week for 4 weeks, followed by 50 000 IU once every 2 weeks for 52 weeks. Those who remain anovulatory after 6 months will be treated with a 6-month course of letrozole (2.5 mg to 7.5 mg for 5 days per cycle titrated according to response) for ovulation induction. The primary outcome is the ovulation rate. All statistical analyses will be performed using intention-to-treat and per protocol analyses.Ethics and disseminationEthics approval was sought from the Institutional Review Board of the participating units. All participants will provide written informed consent before joining the study. The results of the study will be submitted to scientific conferences and peer-reviewed journals.Trial registration number NCT04650880.
− Macrolides can ameliorate inflammation in respiratory diseases, providing clinical benefits. Data in influenza is lacking.
− A randomized, open-label, multicenter trial among adults hospitalized ...for laboratory-confirmed influenza was conducted. Study treatments of oseltamivir and azithromycin (500 mg/day), or oseltamivir alone, both for 5 days, were allocated at 1:1 ratio. The primary outcome was plasma cytokine/chemokine concentration change over time (Day 0–10); secondary outcomes were viral load and symptom score changes. Generalized Estimating Equation (GEE) models were used to analyze longitudinal data.
− Fifty patients were randomized to the oseltamivir-azithromycin or oseltamivir groups, with comparable baseline characteristics (age, 57 ± 18 years; A/H3N2, 70%), complications (72%), and viral load. Pro-inflammatory cytokines IL-6 (GEE: β −0.037, 95%CI-0.067,-0.007, P = 0.016; reduction from baseline −83.4% vs −59.5%), CXCL8/IL-8 (β −0.018, 95%CI-0.037,0.000, P = 0.056; −80.5% vs −58.0%), IL-17 (β −0.064, 95%CI-0.117,-0.012, P = 0.015; −74.0% vs −34.3%), CXCL9/MIG (β −0.010, 95%CI-0.020,0.000, P = 0.043; −71.3% vs −56.0%), sTNFR-1, IL-18, and CRP declined faster in the oseltamivir-azithromycin group. There was a trend toward faster symptom resolution (β −0.463, 95%CI-1.297,0.371). Viral RNA decline (P = 0.777) and culture-negativity rates were unaffected. Additional ex vivo studies confirmed reduced induction of IL-6 (P = 0.017) and CXCL8/IL-8 (P = 0.005) with azithromycin.
− We found significant anti-inflammatory effects with adjunctive macrolide treatment in adults with severe influenza infections. Virus control was unimpaired. Clinical benefits of a macrolide-containing regimen deserve further study.
ClinicalTrials.gov NCT01779570
•In this randomized trial, adjunctive azithromycin significantly downregulated proinflammatory responses in severe influenza.•Viral clearance was not impaired.•Differential inhibition of proinflammatory cytokines was shown ex vivo (adaptive/antiviral cytokines relatively preserved).•Macrolide as a potential anti-inflammatory therapy in influenza should deserve further study for clinical efficacy.
Abstract
Background
There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics and optimal MPA exposure in lupus nephritis (LN) patients during long-term maintenance.
...Methods
We measured blood MPA levels at 1, 2, 4, 8, 10 and 12-h post-dose (i.e. C1, C2, C4, C8, C10 and C12) in 88 stable LN patients receiving maintenance prednisolone and mycophenolate mofetil, repeated every 6 months. The relationship between MPA exposure and single nucleotide polymorphisms (SNPs) of adenosine triphosphate–binding cassette subfamily C member 2 (ABCC2; rs2273697, rs3740066, rs717620 and rs17222723), organic anion-transporting polypeptides (OATPs; rs7311358 and rs4149117) and uridine diphosphate glucuronosyltransferase (UGT; rs17863762, rs6714486, rs17868320 and rs72551330) was also investigated.
Results
C1, C2 and C12 were 8.3 ± 6.6 , 7.2 ± 5.2 and 2.0 ± 1.4 mg/L and all correlated with the 12-h area under the curve (AUC0–12; r = 0.51, 0.85 and 0.73; P = 0.02, <0.001 and <0.001, respectively). C12 inversely correlated with hemoglobin, immunoglobulins and leukocyte levels (P < 0.05 for all). Five renal flares, 11 episodes of infection and 10 episodes of anemia (hemoglobin <10 g/dL) occurred over 96 weeks, with a corresponding C12 of 1.3 ± 0.5, 4.3 ± 2.6 and 2.9 ± 1.5 mg/L, respectively (versus 2.4 ± 1.2, 1.8 ± 1.2 and 1.7 ± 1.1 mg/L in patients without these complications; P = 0.041, <0.001 and 0.004). SNP rs2273697 A/G in the ABCC2 gene was associated with lower MPA exposure compared with G/G (1075.9 ± 239.9 versus 1891.5 ± 918.9 mgh/L per g/kg; P = 0.003). SNPs of OATP and UGT were unrelated to MPA level.
Conclusion
MPA C12 correlates with the AUC0–12 and is related to renal flare, infection and anemia. SNP rs2273697 A/G is associated with lower MPA exposure.
A prospective study among adults hospitalized for polymerase chain reaction-confirmed respiratory syncytial virus infections (n = 123) showed frequent occurrence of lower respiratorytract ...complications causing respiratory insufficiency (52.8%), requirement for assisted ventilation (16.3%), and intensive care unit admission/death (12.2%). High viral RNA concentration was detected at time of hospitalization, including in patients who presented later than 2 days of illness (day 1-2, 7.29 ± 1.47; day 3-4, 7.28 ± 1.41; day 5-8, 6.66 ± 1.87 log 10 copies/mL). RNA concentration was independently associated with risk of complications and respiratory insufficiency (adjusted odds ratio 1.40 per log 10 copies/mL increase, 95% confidence interval, 1.03-1.90; P= .034). Our data indicate the need and provide a basis for clinical research on antiviral therapy in this population.
Summary Objectives We aim to study the disease burden, risk factors and severity of Clostridium difficile infection (CDI) in Hong Kong. Methods We conducted a prospective, case–control study in three ...acute-care hospitals in Hong Kong. Adult inpatients who developed CDI diarrhoea confirmed by PCR (n = 139) were compared with the non-CDI controls (n = 114). Ribotyping of isolates and antimicrobial susceptibility testing were performed. Results The estimated crude annual incidence of CDI was 23–33/100,000 population, and 133–207/100,000 population among those aged ≥65 years. The mean age of CDI patients was 71.5. Nursing home care, recent hospitalization, antibiotics exposure (adjusted OR 3.0, 95% CI 1.3–7.1) and proton-pump inhibitors use (adjusted OR 2.2, 95% CI 1.2–3.9) were risk factors. Severe CDI occurred in 41.7%. Overall mortality was 16.5% (among severe CDI, 26.5%). The commonest ribotypes were 002 (22.8%), 014 (14.1%), 012 and 046 ; ribotype 027 was absent. Ribotype 002 was associated with fluoroquinolone resistance and higher mortality (47.6% vs . 12.7%; adjusted HR 2.8, 95% CI 1.1–7.0). Conclusions Our findings show high morbidity and mortality of CDI in the older adults, and identify ribotype 002 as a possible virulent strain causing serious infections in this cohort.
Geochemical proxies and diatom assemblages were used in combination with grain size characteristics not only to describe the deposit left behind by the 27 February 2010, Maule tsunami at Las Cañas, ...Maule Region, Chile, but also to trace the maximum inundation limit of the event. The sandy deposit was laid down between 160 and 260m inland behind an eroded sand dune and a lagoon but reached only 60% of the total tsunami inundation distance of 380m, which was marked by organic debris, pumice clasts and wooden logs. It consisted of coarse to medium sand that thinned and fined inland. At the most seaward point, the 22cm thick deposit exhibited a fining upward unit overlain by a couplet of coarsening–fining upward units, suggesting deposition by at least two waves, while farther inland the fining upward deposit was probably left behind by only one wave. Chemical proxies (Ca/Ti vs Sr/Ba) allow us to distinguish the deposit from the surrounding soil and indicate that it was sourced from the beach and/or dune area, with diatom assemblages confirming the marine origin of the deposit. Saltwater indicators (e.g. Cl, S) provide evidence for the maximum inundation limit beyond the extent of the sandy deposit, despite dilution and dissolution by 500mm of rainfall in the six months since the tsunami. Marine and marine/brackish diatom assemblages decreased landward but were found up to the inundation limit and immediately beyond, suggesting the effect of diatom-bearing sea spray at the wave front or redistribution of the detrital assemblage associated with tsunami inundation due to wind. While the latter might result in a slight over-estimation of the inundation distance, they can be used in combination with chemical proxies to trace the maximum inundation distance of recent and past tsunamis, thus allowing for a better estimation of the magnitude of past events. Post-depositional processes were found to have affected the thinner sandy deposits (<5cm), suggesting that these are unlikely to be preserved in the geological record. This highlights the need to be able to trace the tsunami inundation limit with geochemical and/or diatom proxies without having to rely on sedimentological evidence, as it is now widely recognised that conventional approaches used by tsunami researchers have led to an under-estimation of previous events.
•First reported combined geochemical-diatom evidence of tsunami inundation limit•Sand deposit extends only 60% of the inundation limit that reached 380m inland.•Chemical signatures can discriminate and identify the source of the tsunami deposit.•Chemical signatures can be preserved in soil beneath coarse sandy deposits.•Chemical proxies may be complex but unlike other proxies are always present.
Large areas of farmland in the Sendai Plain, Japan, were inundated by the 11 March 2011 Tohoku-oki tsunami and covered by a discontinuous 30–0.2cm thick sediment layer consisting of sand and/or mud ...and generally thinning and fining inland. Two months after the tsunami, numerous rice paddy fields and depressions remained ponded with brackish or saline water. A series of field surveys in May, August and October 2011 were carried out north of Sendai airport, in order to assess the environmental impact of the tsunami. While evaporation had resulted in elevated conductivity in ponded water in May (up to 68.2mScm−1), rainfall over the next five months led to dilution, although brackish water was still recorded in depressions and on paddy fields. Tsunami sediments, underlying soil and soil beyond the tsunami inundation limit were collected at 43 sites along and near a transect extending over 5km inland, and analysed for grain size, organic content, water leachable ions, acid leachable metals and exchangeable metalloids. Water leachable anion and cation concentrations were elevated in sandy and muddy tsunami deposits and soils particularly in areas, where seawater had stagnated for a longer period of time after the tsunami, with up to 10.5% Cl, 6.6% Na, 2.8% SO4, 440mgkg−1 Br measured in surface sediments (<0.5cm depth). Vertical variations were also recorded, with higher concentrations often measured in the surface samples. A similar trend could be observed for some of the metalloids (As) and metals (Zn, Cu and Ni), although in general, maximum concentrations of metals and metalloids were not much higher than in soils not inundated by the tsunami and were within background levels for uncontaminated Japanese soils.
The impact of saltwater inundation was documented in the chemistry of soils underlying tsunami sediments, which were affected by salt contamination down to ~15cm depth, and soils not covered by tsunami deposits. The latter implies that the extent of tsunami inundation may successfully be determined using geochemical markers in absence of any sedimentological evidence. Water leachable ions mostly decreased over time, however, they remained high enough to impact on rice farming, which was completely halted in 2011. Although further work is required to assess the longer term impact of tsunami inundation, flushing of salt with freshwater, as well as the possible removal of sandy/muddy sediments and underlying soil are recommended to allow crop production to resume.
► Chemical markers identify tsunami inundation limit beyond sediment deposition. ► Tsunami deposits and underlying soil were contaminated by saltwater. ► Brackish ponded water on land still recorded seven months after tsunami. ► Bioavailable metal/metalloid contents within background levels of Japanese soils. ► Long-term impact of saltwater contamination on rice paddy soils of Sendai Plain.
BACKGROUND—Durable polymers used in drug-eluting stents are considered a potential cause of hypersensitivity inflammatory response adversely affecting stent healing. Using a sequential follow-up with ...optical coherence tomography, we compared the differences in healing profiles of 2 drug-eluting stents with a biodegradable or durable polymer.
METHODS AND RESULTS—Sixty patients with multivessel disease were prospectively enrolled to receive both study stents, which were randomly assigned to 2 individual vessels, a Resolute Integrity zotarolimus-eluting stent with a durable BioLinx polymer and a BioMatrix NeoFlex Biolimus A9–eluting stent with a biodegradable polylactic acid polymer. Optical coherence tomography was performed at baseline, then in 5 randomly assigned monthly groups at 2 to 6 months, and at 9 months in all patients. The primary end point was the difference in optical coherence tomography strut coverage at 9 months. Key secondary end points included angiographic late lumen loss and composite major adverse cardiac events (cardiac death, myocardial infarction, target lesion revascularization, and definite or probable stent thrombosis) at 9 months. Resolute Integrity zotarolimus-eluting stent showed significantly better strut coverage than BioMatrix NeoFlex Biolimus A9–eluting stent at 2 to 6 months (P<0.001) and less variance of percent coverage at 9 months, 99.7% (interquartile range, 99.1–100) versus 99.6% (interquartile range, 96.8–99.9; difference, 0.10; 95% confidence interval, 0.00–1.05; P<0.001). No significant difference was observed in major adverse cardiac events or angiographic end points.
CONCLUSIONS—Despite having a durable polymer, Resolute Integrity zotarolimus-eluting stent exhibited better strut coverage than BioMatrix NeoFlex Biolimus A9–eluting stent having a biodegradable polymer; both showed similar antiproliferative efficacy. This novel, longitudinal, sequential optical coherence tomography protocol using each patient as own control could achieve conclusive results in small sample size.
CLINICAL TRIAL REGISTRATION—URLhttps://www.clinicaltrials.gov. Unique identifierNCT01742507.
Adherence to antihypertensive medications represents a crucial success factor for optimal blood pressure (BP) control in clinical practice. This study evaluated whether an additional pharmacist-led ...medication counseling could achieve better optimal BP control and enhance compliance. In a designated family clinic in a region with similar resident characteristics to Hong Kong, patients taking ≥ one antihypertensive agent with suboptimal compliance were randomly allocated to a brief 3-minute drug advice (control; n = 161) or pharmacist counseling (intervention; n = 113). The two groups were compared by repeated measure ANOVA at 3-months and 6-months with BP control and medication compliance as outcome variables, respectively. The proportions of patients having optimal compliance increased from 0% to 41.1% at 3 months and 61.9% at 6 months (P < 0.001). The proportion of patients having optimal BP control improved from 64.1% at baseline to 74.0% at 3 months and 74.5% at 6 months (P = 0.023). There were no significant differences between the two groups in the changes of BP control and compliance levels. This study implied that even a brief 3-minute drug advice might lead to improved BP levels among patients on antihypertensive medications in general practice, but did not demonstrate additional effects by pharmacist counseling.
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