Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy - a meta-analysis

WSTĘP. Inhibitory konwertazy angiotensyny (ACEI) i blokery receptora angiotensyny (ARB) zapobiegają progresji nefropatii cukrzycowej (DN). Wyniki badań sugerują, że połączenie układu renina-angiotensyna-aldosteron (RAAS) i czynników hamujących działa addytywnie w procesie leczenia DN. Ponieważ badania te obejmowały niewielkie grupy chorych, autorzy niniejszej pracy przeprowadzili metaanalizę prób dotyczących leczenia skojarzonego DN. METODY. Badania do metaanalizy wybrano na podstawie baz danych MEDLINE, EMBASE, CINAHL i Cochrane. Włączono wszystkie próby dotyczące skojarzonego leczenia za pomocą ACEI i ARB. Głównym punktem końcowym było dobowe wydalanie białka z moczem, a dodatkowe punkty końcowe obejmowały: wartości ciśnienia tętniczego, stężenia potasu we krwi i współczynnika przesączania kłębuszkowego (GFR). WYNIKI. W 10 włączonych do analizy badaniach 156 chorych otrzymało ACEI i ARB, a 159 jedynie ACEI. Większość badań trwało 8-12 tygodni. U osób leczonych ACEI i ARB uzyskano zmniejszenie proteinurii (p = 0,01), co wiązało się ze znaczną statystyczną heterogenicznością (p = 0,005). Terapia ACEI i ARB była związana ze zmniejszeniem GFR [3,87 ml/min (7,32-0,42); p = 0,03] i tendencją do wzrostu stężenia kreatyniny w surowicy (6,86 umol/l 95% CI -0,76-13,73; p = 0,09). Stężenie potasu zwiększyło się o 0,2 (0,08-0,32) mmol/l (p < 0,01) u chorych leczonych ACEI i ARB. Skurczowe i rozkurczowe ciśnienie krwi obniżyło się odpowiednio o 5,2 mm Hg (2,1-8,4) (p < 0,01) i 5,3 mm Hg (2,2-8,4) (p < 0,01). WNIOSKI. Wyniki metaanalizy sugerują, że łączne stosowanie ACEI + ARB w większym stopniu zmniejsza 24-godzinne wydalanie białka z moczem niż przyjmowanie jedynie ACEI. Korzystne efekty terapii skojarzonej są wynikiem niewielkiego wpływu leków na GFR, stężenie kreatyniny i potasu w surowicy oraz ciśnienie tętnicze. Rezultaty te należy interpretować ostrożnie, ponieważ większość analizowanych badań charakteryzowała się krótkim czasem obserwacji, a w kilku długoterminowych próbach (12 miesięcy) nie wykazano korzystnego wpływu leczenia.AIMS. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) prevent the progression of diabetic nephropathy (DN). Studies suggest that combination renin-angiotensin-aldosterone system (RAAS)-inhibiting therapy provides additive benefit in DN. However, these studies are small in size. We performed a meta-analysis of studies investigating combination therapy for DN. METHODS. Studies were identified through a search of MEDLINE, EMBASE, CINAHL and the Cochrane Database. All trials involving combined ACEI and ARB for slowing progression of DN were included. The primary end point was 24- Blood pressure, serum potassium and glomerular filtration rate (GFR) were secondary end points. RESULTS. In the 10 included trials, 156 patients received ACEI + ARB and 159 received ACEI only. Most studies were 8&#8211;12 weeks in duration. Proteinuria was reduced with ACEI + ARB (p = 0.01). This was associated with significant statistical heterogeneity (p = 0.005). ACEI + ARB was associated with a reduction in GFR [3.87 ml/min (7.32-0.42); p = 0.03] and a trend towards an increase in serum creatinine (6.86 umol/l 95% CI: -0.76-13.73; p = 0.09). Potassium was increased by 0.2 (0.08-0.32) mmol/l (p < 0.01) with ACEI + ARB. Systolic and diastolic blood pressure were reduced by 5.2 (2.1-8.4) mm Hg (p < 0.01) and 5.3 (2.2-8.4) mm Hg (p < 0.01), respectively. CONCLUSIONS. This meta-analysis suggests that ACEI + + ARB reduces 24-h proteinuria to a greater extent than ACEI alone. This benefit is associated with small effects on GFR, serum creatinine, potassium and blood pressure. These results should be interpreted cautiously as most of the included studies were of short duration and the few long-term studies (12 months) have not demonstrated benefi

Hydrocarbon-based statistical copolymers outperform block copolymers for stabilization of ethanol–water Foams

Well-defined block copolymers have been widely used as emulsifiers, stabilizers, and dispersants in the chemical industry for at least 50 years. In contrast, nature employs amphiphilic proteins as polymeric surfactants whereby the spatial distribution of hydrophilic and hydrophobic amino acids within the polypeptide chains is optimized for surface activity. Herein, we report that polydisperse statistical copolymers prepared by conventional free-radical copolymerization can provide superior foaming performance compared to the analogous diblock copolymers. A series of predominantly (meth)acrylic comonomers are screened to identify optimal surface activity for foam stabilization of aqueous ethanol solutions. In particular, all-acrylic statistical copolymers comprising trimethylhexyl acrylate and poly(ethylene glycol) acrylate, P(TMHA-stat-PEGA), confer strong foamability and also lower the surface tension of a range of ethanol–water mixtures to a greater extent than the analogous block copolymers. For ethanol-rich hand sanitizer formulations, foam stabilization is normally achieved using environmentally persistent silicone-based copolymers or fluorinated surfactants. Herein, the best-performing fully hydrocarbon-based copolymer surfactants effectively stabilize ethanol-rich foams by a mechanism that resembles that of naturally-occurring proteins. This ability to reduce the surface tension of low-surface-energy liquids suggests a wide range of potential commercial applications

Genome-Wide Association Mapping of Correlated Traits in Cassava: Dry Matter and Total Carotenoid Content

Article purchased; Published online: 3 August 2017Cassava (Manihot esculenta (L.) Crantz) is a starchy root crop cultivated in the tropics for fresh consumption and commercial processing. Dry matter content and micronutrient density, particularly of provitamin A, traits that are negatively correlated, are among the primary selection objectives in cassava breeding. This study aimed at identifying genetic markers associated with these traits and uncovering the potential underlying cause of their negative correlation - whether linkage and/or pleiotropy. A genome-wide association mapping using 672 clones genotyped at 72,279 SNP loci was carried out. Root yellowness was used indirectly to assess variation in carotenoid content. Two major loci for root yellowness was identified on chromosome 1 at positions 24.1 and 30.5 Mbp. A single locus for dry matter content that co-located with the 24.1 Mbp peak for carotenoid content was identified. Haplotypes at these loci explained a large proportion of the phenotypic variability. Evidence of mega-base-scale linkage disequilibrium around the major loci of the two traits and detection of the major dry matter locus in independent analysis for the white- and yellow-root subpopulations suggests that physical linkage rather that pleiotropy is more likely to be the cause of the negative correlation between the target traits. Moreover, candidate genes for carotenoid (phytoene synthase) and starch biosynthesis (UDP-glucose pyrophosphorylase and sucrose synthase) occurred in the vicinity of the identified locus at 24.1 Mbp. These findings elucidate on the genetic architecture of carotenoids and dry matter in cassava and provides an opportunity to accelerate genetic improvement of these traits

Experimental Lagos bat virus infection in straw-colored fruit bats: A suitable model for bat rabies in a natural reservoir species

Rabies is a fatal neurologic disease caused by lyssavirus infection. Bats are important natural reservoir hosts of various lyssaviruses that can be transmitted to people. The epidemiology and pathogenesis of rabies in bats are poorly understood, making it difficult to prevent zoonotic transmission. To further our understanding of lyssavirus pathogenesis in a natural bat host, an experimental model using straw-colored fruit bats (Eidolon helvum) and Lagos bat virus, an endemic lyssavirus in this species, was developed. To determine the lowest viral dose resulting in 100% productive infection, bats in five groups (four bats per group) were inoculated intramuscularly with one of five doses, ranging from 100.1 to 104.1 median tissue culture infectious dose (TCID50). More bats died due to the development of rabies after the middle dose (102.1 TCID50, 4/4 bats) than after lower (101.1, 2/4; 101.1, 2/4) or higher (103.1, 2/4; 104.1, 2/4) doses of virus. In the two highest dose groups, 4/8 bats developed rabies. Of those bats that remained healthy 3/4 bats seroconverted, suggesting that high antigen loads can trigger a strong immune response that abrogates a productive infection. In contrast, in the two lowest dose groups, 3/8 bats developed rabies, 1/8 remained healthy and seroconverted and 4/8 bats remained healthy and did not seroconvert, suggesting these doses are too low to reliably induce infection. The main lesion in all clinically affected bats was meningoencephalitis associated with lyssavirus-positive neurons. Lyssavirus antigen was detected in tongue epithelium (5/11 infected bats) rather than in salivary gland epithelium (0/11), suggesting viral excretion via the tongue. Thus, intramuscular inoculation of 102.1 TCID50 of Lagos bat virus into straw-colored fruit bats is a suitable m

Distinct clinical symptom patterns in patients hospitalised with COVID-19 in an analysis of 59,011 patients in the ISARIC-4C study

COVID-19 is clinically characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. However, it is the clinical associations of different patterns of symptoms which influence diagnostic and therapeutic decision-making. In this study, we applied clustering techniques to a large prospective cohort of hospitalised patients with COVID-19 to identify clinically meaningful sub-phenotypes. We obtained structured clinical data on 59,011 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 25,477 cases according to symptoms reported at recruitment. We validated our findings in a second group of 33,534 cases recruited to ISARIC-4C, and in 4,445 cases recruited to a separate study of community cases. Unsupervised clustering identified distinct sub-phenotypes. First, a core symptom set of fever, cough, and dyspnoea, which co-occurred with additional symptoms in three further patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were also identified, alongside a sub-phenotype of patients reporting few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom sub-phenotypes were highly consistent in replication analysis within the ISARIC-4C study. Similar patterns were externally verified in patients from a study of self-reported symptoms of mild disease. The large scale of the ISARIC-4C study enabled robust, granular discovery and replication. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four sub-phenotypes are usefully distinct from the core symptom group: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms

Delayed mucosal antiviral responses despite robust peripheral inflammation in fatal COVID-19

Background While inflammatory and immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished coronavirus disease 2019 (COVID-19) severity categories, and relate these to disease progression and peripheral inflammation. Methods We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalized with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0–5 days after symptom onset) or late (6–20 days after symptom onset) phase. Results Patients that survived severe COVID-19 showed interferon (IFN)-dominated mucosal immune responses (IFN-γ, CXCL10, and CXCL13) early in infection. These early mucosal responses were absent in patients who would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by interleukin 2 (IL-2), IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions Defective early mucosal antiviral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely