The impact of surgical repair on left ventricular outflow tract in atrioventricular septal defect with common atrioventricular valve orifice

Objective: Although a narrow left ventricular outflow tract (LVOT) in atrioventricular septal defect (AVSD) is related to its intrinsic morphology, the contribution from repair technique remains to be quantified. Methods: 108 AVSD patients with common atrio-ventricular valve orifice were divided into 2 groups: two-patch (N=67) and modified 1-patch (N=41) repair. LVOT morphometric was analysed by quantifying the degree of disproportion between subaortic:aortic annular dimensions (disproportionate morphometrics ratio was defined as ≤ 0.9). Z-scores (median, interquartile range) were further analysed in a subset of 80 patients with immediate pre- and post-operative echocardiography. 44 subjects with VSD served as controls. Results: Pre-repair, 13(12%) AVSD had disproportionate morphometrics (vs 6(14%) VSD p=0.79); but subaortic Z-score (-0.53, -1.07 - 0.06) was lower than VSD (0.07, -0.57 - 1.17; p<0.001). Post-repair, both two-patch (8(12%) pre-op vs 25(37%) post-op; p=0.001) and modified 1-patch (5(12%) vs 21(51%), p<0.001) showed greater degree of disproportionate morphometrics. Both two-patch (post-op -0.73, -1.56 - 0.08 vs pre-op -0.43, -0.98 - 0.28; p=0.011) and modified 1-patch (-1.42, -2.63-(-0.78) vs -0.70, -1.18 - (-0.25); p=0.001) also had lower subaortic z-scores post-repair. The post-repair subaortic z-scores were lower in modified 1-patch [-1.42 (-2.63 - (-0.78)] compared to two-patch [-0.73 (-1.56 - 0.08); p=0.004]. Low post-repair subaortic Z-scores (under -2) were observed in 12(41%) modified 1-patch and 6(12%) two-patch (p=0.004). Conclusions: Surgical correction resulted in greater disproportionate morphometrics seen immediately post-repair. The impact on the LV outflow tract was observed in all repair techniques, with a greater burden seen following modified 1-patch repair

The 1.2 A resolution crystal structure of TcpG, the Vibrio cholerae DsbA disulfide-forming protein required for pilus and cholera-toxin production

The enzyme TcpG is a periplasmic protein produced by the Gram-negative pathogen Vibrio cholerae. TcpG is essential for the production of ToxR-regulated proteins, including virulence-factor pilus proteins and cholera toxin, and is therefore a target for the development of a new class of anti-virulence drugs. Here, the 1.2 Å resolution crystal structure of TcpG is reported using a cryocooled crystal. This structure is compared with a previous crystal structure determined at 2.1 Å resolution from data measured at room temperature. The new crystal structure is the first DsbA crystal structure to be solved at a sufficiently high resolution to allow the inclusion of refined H atoms in the model. The redox properties of TcpG are also reported, allowing comparison of its oxidoreductase activity with those of other DSB proteins. One of the defining features of the Escherichia coli DsbA enzyme is its destabilizing disulfide, and this is also present in TcpG. The data presented here provide new insights into the structure and redox properties of this enzyme, showing that the binding mode identified between E. coli DsbB and DsbA is likely to be conserved in TcpG and that the [beta]5-[alpha]7 loop near the proposed DsbB binding site is flexible, and suggesting that the tense oxidized conformation of TcpG may be the consequence of a short contact at the active site that is induced by disulfide formation and is relieved by reduction

The structure of the bacterial oxidoreductase enzyme DsbA in complex with a peptide reveals a basis for substrate specificity in the catalytic cycle of DsbA enzymes

Oxidative protein folding in Gram-negative bacteria results in the formation of disulfide bonds between pairs of cysteine residues. This is a multistep process in which the dithiol-disulfide oxidoreductase enzyme, DsbA, plays a central role. The structure of DsbA comprises an all helical domain of unknown function and a thioredoxin domain, where active site cysteines shuttle between an oxidized, substrate-bound, reduced form and a DsbB-bound form, where DsbB is a membrane protein that reoxidizes DsbA. Most DsbA enzymes interact with a wide variety of reduced substrates and show little specificity. However, a number of DsbA enzymes have now been identified that have narrow substrate repertoires and appear to interact specifically with a smaller number of substrates. The transient nature of the DsbA-substrate complex has hampered our understanding of the factors that govern the interaction of DsbA enzymes with their substrates. Here we report the crystal structure of a complex between Escherichia coli DsbA and a peptide with a sequence derived from a substrate. The binding site identified in the DsbA-peptide complex was distinct from that observed for DsbB in the DsbA-DsbB complex. The structure revealed details of the DsbA-peptide interaction and suggested a mechanism by which DsbA can simultaneously show broad specificity for substrates yet exhibit specificity for DsbB. This mode of binding was supported by solution nuclear magnetic resonance data as well as functional data, which demonstrated that the substrate specificity of DsbA could be modified via changes at the binding interface identified in the structure of the comple

The multidrug resistance IncA/C transferable plasmid encodes a novel domain swapped dimeric protein disulfide isomerase

Background: Bacterial IncA/C plasmids distribute antibiotic resistance genes and encode a conserved thioredoxin-fold protein (DsbP). Results: DsbP shuffles incorrect disulfide bonds in misfolded proteins, and its structure diverges from previously characterized disulfide isomerases. Conclusion: Plasmid-encoded DsbP is a novel domain-swapped protein-disulfide isomerase. Significance: IncA/C plasmids may encode this protein proofreading machinery to ensure horizontal gene transfer of antibiotic resistance genes

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

How does mutual fund flow respond to oil market volatility?

We comprehensively study the impact of oil market volatility on mutual fund flow. In particular, using an extensive dataset on Saudi Arabia covering virtually all equity funds over 2006-2017, this paper provides the first analysis of the linkages between fund flow and oil market volatility. Our main findings show that investors shift substantially their asset allocation to the equity mutual fund sector in periods of high volatility. Our further evidence suggests that flow to high oil-exposed funds is more sensitive to oil volatility than low oil-exposed funds. This is consistent with investors valuing professional management highly during risky periods in a setting where alternatives to equity investment are limited. Our study provides new evidence for a fast-growing market and reveals important implications for the mutual fund market which helps investors, academics and regulators to better understand the behaviour of this market

Sovereign CDS and mutual funds: global evidence

In this paper, we study the impact of sovereign CDS on equity mutual funds across 24 developed and emerging market countries. Our investigation builds on the premise that mutual funds flow and performance respond negatively to increased default risk as measured via sovereign CDS entities. As predicted by our theory, we find that i) sovereign CDS spreads are indeed associated with decreased mutual funds return performance and ii) sovereign CDS spreads covary negatively with subsequent fund flow. This is consistent with investors being sensitive to the pricing information conveyed by the sovereign CDS market. Finally, we find that the impact of sovereign CDS spreads on mutual funds’ performance and flow is more pronounced among emerging market countries. Overall, these findings imply that mutual funds players could make extensive use of the information arising from CDS trading activity. In explaining these results, we emphasize the important implications for investors in mutual funds’ assets portfolios and for country-specific equity funds

Myocardial revascularization using on-pump beating heart among patients with left ventricular dysfunction

Abstract Objectives On-pump beating heart technique for myocardial revascularization has been used successfully among both low and high risk patients. Its application among low ejection fraction patients is limited. The aim of our study is to evaluate this technique among patients with low ejection fraction and to compare results with off-pump bypass technique. Methods This retrospective study includes 137 patients with ejection fraction below 0.35 who underwent isolated coronary artery bypass surgery. 39 patients underwent myocardial revascularization using on-pump beating heart (ONCAB/BH), while 98 patients had off-pump beating heart (OPCAB). Different preoperative, operative and postoperative variables were evaluated among both groups. Results Patients profiles and risk factors were similar among both groups, except for the number of patients undergoing redo CABG which was significantly higher among ONCAB/BH (13% vs 3%; p = 0.025). Ejection fraction (EF) varied from 10-34%. The mean EF for patients who underwent ONCAB/BH was 28 ± 6 in comparison to 26 ± 5 for OPCAB patients (P = 0.093). Predicted risk for surgery according to EuroSCORE was similar among both groups (P = 0.443). The number of grafts performed per patient was significantly more among patients who underwent ONCAB/BH (2.2 ± 0.7 Vs 1.7 ± 0.7; P = 0.002). Completeness of revascularization was significantly greater in the ONCAB/BH patients (72% Vs 46%, P = 0.015). The incidence of hospital mortality and combined major morbidity was more among ONCAB/BH in comparison to OPCAB, but the difference was not significant. However, the incidence of blood loss, ventricular arrythmias, inotropic support, ICU, hospital stay and blood transfusion were significantly greater among patients who underwent ONCAB/BH. Conclusions On-pump beating heart technique can be used in myocardial revascularization among patients with left ventricular dysfunction. The technique was found to be associated with better myocardial revascularization when compared with OPCAB technique. However, the incidence of morbidity and mortality was more than OPCAB.</p