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The aim of this study was to assess dual renin system intervention with the maximum recommended doses of aliskiren and valsartan, compared with each drug alone in patients with hypertension. In this double-blind study, 1797 patients with hypertension (mean sitting diastolic blood pressure 95–109 mm Hg and 8-h daytime ambulatory diastolic blood pressure ≥90 mm Hg) were randomly assigned to receive once-daily aliskiren 150 mg (n=437), valsartan 160 mg (455), a combination of aliskiren 150 mg and valsartan 160 mg (446), or placebo (459) for 4 weeks, followed by forced titration to double the dose to the maximum recommended dose for another 4 weeks. The primary endpoint was change in mean sitting diastolic blood pressure from baseline to week 8 endpoint. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov with the number NCT00219180. 196 (11%) patients discontinued study treatment before the end of the trial (63 in the placebo group, 53 in the aliskiren group, 43 in the valsartan group, and 37 in the aliskiren/valsartan group), mainly due to lack of therapeutic effect. At week 8 endpoint, the combination of aliskiren 300 mg and valsartan 320 mg lowered mean sitting diastolic blood pressure from baseline by 12·2 mm Hg, significantly more than either monotherapy (aliskiren 300 mg 9·0 mm Hg decrease, p<0·0001; valsartan 320 mg, 9·7 mm Hg decrease, p<0·0001), or with placebo (4·1 mm Hg decrease, p<0·0001). Rates of adverse events and laboratory abnormalities were similar in all groups. The combination of aliskiren and valsartan at maximum recommended doses provides significantly greater reductions in blood pressure than does monotherapy with either agent in patients with hypertension, with a tolerability profile similar to that with aliskiren and valsartan alone.

How dividing cells stay in shape Studies of the mechanism of cytokinesis, the process by which a mother cell undergoes cleavage to form two separated daughter cells, often focus on the action of the contractile actomyosin ring at the cell equator. Ewa Paluch and colleagues instead investigate the mechanics of the actomyosin cortex found at the cell poles during cytokinesis. They find that the presence of a contractile polar cortex makes cytokinesis an inherently unstable process that can result in misalignment of the constriction ring. They propose that the membrane blebs forming at the poles of dividing cells stabilize the position by releasing cortical contractility. These findings reveal an inherent instability in the shape of a dividing cell and demonstrate a novel mechanism that helps to limit shape instability. Cytokinesis, the physical separation of daughter cells at the end of mitosis, requires precise regulation of the mechanical properties of the cell periphery 1 , 2 . Although studies of cytokinetic mechanics mostly focus on the equatorial constriction ring 3 , a contractile actomyosin cortex is also present at the poles of dividing cells 2 , 4 . Whether polar forces influence cytokinetic cell shape and furrow positioning remains an open question. Here we demonstrate that the polar cortex makes cytokinesis inherently unstable. We show that limited asymmetric polar contractions occur during cytokinesis, and that perturbing the polar cortex leads to cell shape oscillations, resulting in furrow displacement and aneuploidy. A theoretical model based on a competition between cortex turnover and contraction dynamics accurately accounts for the oscillations. We further propose that membrane blebs, which commonly form at the poles of dividing cells 5 and whose role in cytokinesis has long been enigmatic, stabilize cell shape by acting as valves releasing cortical contractility. Our findings reveal an inherent instability in the shape of the dividing cell and unveil a novel, spindle-independent mechanism ensuring the stability of cleavage furrow positioning.

OBJECTIVE: We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination. RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR). RESULTS: Placebo geometric mean albuminuria was 258 mg/day (range 84-2,361), mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg, and GFR was 89 ± 27 ml/min per 1.73 m². Aliskiren treatment reduced albuminuria by 48% (95% CI 27-62) compared with placebo (P < 0.001), not significantly different from the 58% (42-79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3-8.8) ml/min per 1.73 m² by aliskiren, 8.0 (3.6-12.3) ml/min per 1.73 m² by irbesartan, and 11.7 (7.4-15.9) ml/min per 1.73 m² by the combination. CONCLUSIONS: The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.

Objectives The GETAFIX trial will test the hypothesis that favipiravir is a more effective treatment for COVID-19 infection in patients who have early stage disease, compared to current standard of care. This study will also provide an important opportunity to investigate the safety and tolerability of favipiravir, the pharmacokinetic and pharmacodynamic profile of this drug and mechanisms of resistance in the context of COVID-19 infection, as well as the effect of favipiravir on hospitalisation duration and the post COVID-19 health and psycho-social wellbeing of patients recruited to the study. Trial design GETAFIX is an open label, parallel group, two arm phase II/III randomised trial with 1:1 treatment allocation ratio. Patients will be randomised to one of two arms and the primary endpoint will assess the superiority of favipiravir plus standard treatment compared to standard treatment alone. Participants This trial will recruit adult patients with confirmed positive valid COVID-19 test, who are not pregnant or breastfeeding and have no prior major co-morbidities. This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Patients must meet all of the following criteria: 1. Age 16 or over at time of consent 2. Exhibiting symptoms associated with COVID-19 3. Positive for SARS-CoV-2 on valid COVID-19 test 4. Point 1, 2, 3, or 4 on the WHO COVID-19 ordinal severity scale at time of randomisation. (Asymptomatic with positive valid COVID-19 test, Symptomatic Independent, Symptomatic assistance needed, Hospitalized, with no oxygen therapy) 5. Have >=10% risk of death should they be admitted to hospital as defined by the ISARIC4C risk index: https://isaric4c.net/risk 6. Able to provide written informed consent 7. Negative pregnancy test (women of childbearing potential*) 8. Able to swallow oral medication Patients will be excluded from the trial if they meet any of the following criteria: 1. Renal impairment requiring, or likely to require, dialysis or haemofiltration 2. Pregnant or breastfeeding 3. Of child bearing potential (women), or with female partners of child bearing potential (men) who do not agree to use adequate contraceptive measures for the duration of the study and for 3 months after the completion of study treatment 4. History of hereditary xanthinuria 5. Other patients judged unsuitable by the Principal Investigator or sub-Investigator 6. Known hypersensitivity to favipiravir, its metabolites or any excipients 7. Severe co-morbidities including: patients with severe hepatic impairment, defined as:  • greater than Child-Pugh grade A  • AST or ALT > 5 x ULN  • AST or ALT >3 x ULN and Total Bilirubin > 2xULN 8. More than 96 hours since first positive COVID-19 test sample was taken 9. Unable to discontinue contra-indicated concomitant medications This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Intervention and comparator Patients randomised to the experimental arm of GETAFIX will receive standard treatment for COVID-19 at the discretion of the treating clinician plus favipiravir. These patients will receive a loading dose of favipiravir on day 1 of 3600mg (1800mg 12 hours apart). On days 2-10, patients in the experimental arm will receive a maintenance dose of favipiravir of 800mg 12 hours apart (total of 18 doses). Patients randomised to the control arm of the GETAFIX trial will receive standard treatment for COVID-19 at the discretion of the treating clinician. Main outcomes The primary outcome being assessed in the GETAFIX trial is the efficacy of favipiravir in addition to standard treatment in patients with COVID-19 in reducing the severity of disease compared to standard treatment alone. Disease severity will be assessed using WHO COVID 10 point ordinal severity scale at day 15 +/- 48 hours. All randomised participants will be followed up until death or 60 days post-randomisation (whichever is sooner). Randomisation Patients will be randomised 1:1 to the experimental versus control arm using computer generated random sequence allocation. A minimisation algorithm incorporating a random component will be used to allocate patients. The factors used in the minimisation will be: site, age (16-50/51-70/71+), history of hypertension or currently obsess (BMI>30 or obesity clinically evident; yes/no), 7 days duration of symptoms (yes/no/unknown), sex (male/female), WHO COVID-19 ordinal severity score at baseline (1/2or 3/4). Blinding (masking) No blinding will be used in the GETAFIX trial. Both participants and those assessing outcomes will be aware of treatment allocation. Numbers to be randomised (sample size) In total, 302 patients will be randomised to the GETAFIX trial: 151 to the control arm and 151 to the experimental arm. There will be an optional consent form for patients who may want to contribute to more frequent PK and PD sampling. The maximum number of patients who will undergo this testing will be sixteen, eight males and eight females. This option will be offered to all patients who are being treated in hospital at the time of taking informed consent, however only patients in the experimental arm of the trial will be able to undergo this testing. Trial Status The current GETAFIX protocol is version 4.0 12 th September 2020. GETAFIX opened to recruitment on 26 th October 2020 and will recruit patients over a period of approximately six months. Trial registration GETAFIX was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT) Database on 15 th April 2020; Reference number 2020-001904-41 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001904-41/GB ). GETAFIX was registered on ISRCTN on 7 th September 2020; Reference number ISRCTN31062548 ( https://www.isrctn.com/ISRCTN31062548 ). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (see Additional file 2 ).

Abstract Introduction: Renin-angiotensin system inhibitors have been reported to exert protective effects against organ damage and failure; however, the impact of the direct renin inhibitor as monotherapy has not been assessed. Here, we investigated the effects of 24-week monotherapy with aliskiren compared to amlodipine in hypertensive patients with type 2 diabetes or obesity. Methods: In this randomized intervention study, 62 adult hypertensive patients with visceral obesity (defined as a body mass index [BMI] greater than 25 kg/m2 and a visceral adipose tissue area [VFA] greater than 100 cm2) or type 2 diabetes mellitus (age 57 ± 13, 65% men, BMI 28.8 ± 4.8 kg/m2, VFA 134.8 ± 47.0 cm2, blood pressure 141 ± 16/86 ± 13 mm Hg) were randomized to receive 24-week treatment with aliskiren (max. 300 mg) or amlodipine (max. 10 mg). The primary outcome was the change in VFA at 24 weeks post-treatment. Results: Change in VFA did not differ significantly from baseline in either group. Systolic blood pressure significantly decreased at 12 weeks (−10 mm Hg, p = 0.001) and 24 weeks (−10 mm Hg, p = 0.001) in the amlodipine group and at 24 weeks (−11 mm Hg, p = 0.001) in the aliskiren group. Diastolic blood pressure significantly decreased at 24 weeks (−6 mm Hg, p = 0.009) only in the amlodipine group. Although the estimated glomerular filtration rates did not significantly change in either group, the logarithm of urinary albumin excretion significantly decreased at 24 weeks only in the aliskiren group (−0.60, p < 0.001). The 24-week changes in the urinary albumin excretion significantly correlated with the changes in the plasma renin activity in the aliskiren group (r = 0.51, p = 0.008). Conclusion: Aliskiren monotherapy did not show any superiority to amlodipine monotherapy on VFA, estimated glomerular filtration rates, or urinary albumin excretion in obese or type 2 diabetic hypertensive patients.

The transversus abdominis plane (TAP) block is a relatively straightforward regional technique used for postoperative analgesia in patients undergoing abdominal surgeries. Various adjuvants have been used in past to prolong the duration of action of analgesia in peripheral nerve blocks. Several studies investigating the analgesic efficacy of dexamethasone added to local anesthetic agents, such as bupivacaine, have shown promising results. However, there are few studies comparing the efficacy of dexamethasone with ropivacaine. To determine if the addition of dexamethasone 8 mg to ropivacaine 0.2% in a TAP block would prolong the analgesic effect when compared with ropivacaine 0.2% alone after inguinal hernia repair and spermatocelectomy. A randomized, double blinded, placebo-controlled, prospective study. Teaching hospital. A total of 82 patients undergoing inguinal hernia repair or spermatocelectomy were enrolled in the study, of which 41 patients received TAP block with ropivacaine with saline, and the other 41 received ropivacaine with dexamethasone immediately following surgery. Both the proceduralist (resident) and the patient were blinded to the solution used. Visual analog pain scores (0 - 10) were obtained pre-block and immediately post block. Our primary endpoint was visual analog pain score at 12 hours, with 24 and 48-hour pain scores as the secondary endpoints. The averaged pre-block pain score was 7.6 ± 1.7 in the saline group and 7.7 ± 2.2 in the dexamethasone group. There was an improvement in the pain scores from the baseline, at 12 hours after the administration of the block in both the groups. Although the dexamethasone group had a greater change in pain score (-3.2) than the saline group (-2.2), the difference between the 2 groups was not statistically significant (0.08). We did not observe significant differences in change from baseline at 24 hours and 48 hours between the 2 groups (P value = 0.74 and 0.44, respectively). We did not assess the total dose of analgesics used during the surgery with the assumption that the effect of intraoperative analgesics should wear off by the time we collect the 12-hour pain score. We did not control for the expertise of the provider that performed the block, as some of the providers may have been junior residents with limited experience and expertise in the area. Additionally, we were unable to include postoperative opioid consumption due to concerns of inconsistencies during patient reporting and data quality. In conclusion, we could not show a statistically significant prolongation of analgesia for TAP blocks with ropivacaine when dexamethasone was added, though there was a one point drop in pain score at 12 hours post block when dexamethasone was added to the block solution. This decrease in pain scores at 12 hours may still be beneficial to patient satisfaction given the low side effect profile of dexamethasone. As ropivacaine has a lower pH than other local anesthetic agents, further well designed studies are needed to investigate the combination of this drug with more alkaline drugs like corticosteroids. Regional anesthesia, transversus abdominis plane, dexamethasone, ropivacaine.

Introduction Epidural infusion with low local anesthetic concentrations with opiates decrease the severity of the motor blockade associated. The present study aims to compare the analgesic efficacy and the motor blockade between two local anesthetic epidural infusions: levobupivacaine 0.0625% + fentanyl 2mcg/mL versus ropivacaine 0.075% + fentanyl 2mcg/mL. Materials and methods In a single-blind prospective randomized study, 60 laboring parturient had continuous epidural analgesia as follows: 30 of them received levobupivacaine 0.0625% + fentanyl 2mcg/mL and 30 of them received ropivacaine 0.075% + fentanyl 2mcg/mL and rates of infusion were adjusted to the height. Analgesic, motor blockade and satisfaction records were collected as well as maternal and neonate adverse events. Results After 2 h of the catheter placement, patients who received levobupivacaine showed a mean VAS of 3.2 [1.8–4.6] versus 1.8 [1.2–2.5] ( p = 0.05 ) in patients who received ropivacaine. In addition, patients who received levobupivacaine showed a punctuation in Bromage scale of 0.0 [0.0–1.0] versus 0.0 [0.0–0.0] ( p = 0.04 ) in patients who received ropivacaine. Finally, the parturient who received levobupivacaine scored a mean satisfaction index of 8.1 [7.3–8.9] versus 9.3 [8.7–9.8] ( p = 0.02 ) in those who received ropivacaine. We did not register maternal nor neonate adverse events. Conclusion Both infusions (levobupivacaine 0.0625% + fentanyl 2mcg/mL and ropivacaine 0.075% + fentanyl 2mcg/mL) are effective for labor analgesia. However, ropivacaine would present a better pharmacodynamic profile with less motor blockade and decreased need for analgesic rescue hence improving patient’s satisfaction.

The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

The combination of weight excess and hypertension significantly contributes to cardiovascular risk and progressive kidney damage. An unfavorable renal hemodynamic profile is thought to contribute to this increased risk and may be ameliorated by direct renin inhibition (DRI). The aim of this trial was to assess the effect of DRI on renal and systemic hemodynamics and on RAAS activity, in men with weight excess and hypertension. A randomized, double-blind, cross-over clinical trial to determine the effect of DRI (aliskiren 300 mg/day), with angiotensin converting enzyme inhibition (ACEi; ramipril 10 mg/day) as a positive control, on renal and systemic hemodynamics, and on RAAS activity (n = 15). Mean (SEM) Glomerular filtration rate (101 (5) mL/min/1.73m2) remained unaffected by DRI or ACEi. Effective renal plasma flow (ERPF; 301 (14) mL/min/1.73m2) was increased in response to DRI (320 (14) mL/min/1.73m2, P = 0.012) and ACEi (317 (15) mL/min/1.73m2, P = 0.045). Filtration fraction (FF; 34 (0.8)%) was reduced by DRI only (32 (0.7)%, P = 0.044). Mean arterial pressure (109 (2) mmHg) was reduced by DRI (101 (2) mmHg, P = 0.008) and ACEi (103 (3) mmHg, P = 0.037). RAAS activity was reduced by DRI and ACEi. Albuminuria (20 [9-42] mg/d) was reduced by DRI only (12 [5-28] mg/d, P = 0.030). In men with weight excess and hypertension, DRI and ACEi improved renal and systemic hemodynamics. Both DRI and ACEi reduced RAAS activity. Thus, DRI provides effective treatment in weight excess and hypertension. Dutch trial register, registration number: 2532 www.trialregister.nl.

Background Ultrasound guidance has reduced the amount of local anesthetics to achieve a successful block. Previous studies of the relationship between the volume or concentration of local anesthetics and the effects of the block were based on relatively high doses of local anesthetics. We tested the hypothesis that providing low dose of ropivacaine at three combinations of volumes and concentrations for ultrasound-guided interscalene brachial plexus block would produce different effects in the aspect of onset time, pain control and the incidence of side effects. Methods Ninety-nine patients undergoing elective arthroscopic shoulder surgery were randomized to receive an ultrasound guided combined with nerve stimulator mediated interscalene block with ropivacaine 0.75 % (6.7 ml, Group 0.75), 0.5 % (10 ml, Group 0.5) or 0.25 % (20 ml, Group 0.25). The primary end point was the onset time of the sensory blockade, assessed by using a pinprick in the C5-6 dermatome. The secondary end points included the onset time of the motor blockade, block success rate, postoperative pain rating score, rescue analgesics requirement, sleep quality, strength of the hand on the block side,and the incidence of hemi-diaphragmatic paresis which was evaluated by ultrasonography. Results There was a statistically significant difference of the sensory block median onset times among Group 0.75 (5 min), Group 0.5 (10 min) and Group 0.25 (20 min). One patient in Group 0.5 and 20 patients in Group 0.25 did not achieve a complete motor block within 30 min, which were also significantly different. No significant difference was observed in postoperative analgesia, decrease of handgrip strength and the incidence of hemi-diaphragmatic paresis among the 3 groups. Conclusions This study demonstrates that ropivacaine 50 mg as 0.25, 0.5 or 0.75 % solution for interscalene brachial plexus block before arthroscopic shoulder surgery produces comparable blockade with few side effects, while 0.75 % seems to be more preferable as it is associated with faster onset time. Trial registration ChiCTR-TRC-13004058 . Registered 4 December 2013.