Evaluation of high dose N- Acetylcysteine on airway inflammation and quality of life outcomes in adults with bronchiectasis: A randomised placebo-controlled pilot study.

BACKGROUND: High dose N acetylcysteine (NAC), a mucolytic, anti-inflammatory and antioxidant agent has been shown to significantly reduce exacerbations, and improve quality of life in placebo controlled, double blind randomised (RCT) studies in patients with COPD, and in an open, randomised study in bronchiectasis. In this pilot, randomised, double-blind, placebo-controlled study, we wished to investigate the feasibility of a larger clinical trial, and the anti-inflammatory and clinical benefits of high dose NAC in bronchiectasis. AIMS: Primary outcome: to assess the efficacy of NAC 2400 mg/day at 6 weeks on sputum neutrophil elastase (NE), a surrogate marker for exacerbations. Secondary aims included assessing the efficacy of NAC on sputum MUC5B, IL-8, lung function, quality of life, and adverse effects. METHODS: Participants were randomised to receive 2400 mg or placebo for 6 weeks. They underwent 3 visits: at baseline, week 3 and week 6 where clinical and sputum measurements were assessed. RESULTS: The study was stopped early due to the COVID pandemic. In total 24/30 patients were recruited, of which 17 completed all aspects of the study. Given this, a per protocol analysis was undertaken: NAC (n = 9) vs placebo (n = 8): mean age 72 vs 62 years; male gender: 44% vs 50%; baseline median FEV11.56 L (mean 71.5 % predicted) vs 2.29L (mean 82.2% predicted). At 6 weeks, sputum NE fell by 47% in the NAC group relative to placebo (mean fold difference (95%CI: 0.53 (0.12,2.42); MUC5B increased by 48% with NAC compared with placebo. Lung function, FVC improved significantly with NAC compared with placebo at 6 weeks (mean fold difference (95%CI): 1.10 (1.00, 1.20), p = 0.045. Bronchiectasis Quality of life measures within the respiratory and social functioning domains demonstrated clinically meaningful improvements, with social functioning reaching statistical significance. Adverse effects were similar in both groups. CONCLUSION: High dose NAC exhibits anti-inflammatory benefits, and improvements in aspects of quality of life and lung function measures. It is safe and well tolerated. Further larger placebo controlled RCT's are now warranted examining its role in reducing exacerbations.

High-volume patient-controlled epidural vs. programmed intermittent epidural bolus for labour analgesia: a randomised controlled study.

The aim of neuraxial analgesia is to achieve excellent pain relief with the fewest adverse effects. The most recently introduced technique for epidural analgesia maintenance is the programmed intermittent epidural bolus. In a recent study, we compared this with patient-controlled epidural analgesia without a background infusion and found that a programmed intermittent epidural bolus was associated with less breakthrough pain, lower pain scores, higher local anaesthetic consumption and comparable motor block. However, we had compared 10 ml programmed intermittent epidural boluses with 5 ml patient-controlled epidural analgesia boluses. To overcome this potential limitation, we designed a randomised, multicentre non-inferiority trial using 10 ml boluses in each group. The primary outcome was the incidence of breakthrough pain and total analgesic intake. Secondary outcomes included motor block; pain scores; patient satisfaction; and obstetric and neonatal outcomes. The trial was considered positive if two endpoints were met: non-inferiority of patient-controlled epidural analgesia with respect to breakthrough pain; and superiority of patient-controlled epidural analgesia with respect to local anaesthetic consumption. A total of 360 nulliparous women were allocated randomly to patient-controlled epidural analgesia-only or programmed intermittent epidural bolus groups. The patient-controlled group received 10 ml boluses of ropivacaine 0.12% with sufentanil 0.75 µg.ml-1 ; the programmed intermittent group received 10 ml boluses supplemented by 5 ml patient-controlled boluses. The lockout period was 30 min in each group and the maximum allowed hourly local anaesthetic/opioid consumption was identical between the groups. Breakthrough pain was similar between groups (11.2% patient controlled vs. 10.8% programmed intermittent, p = 0.003 for non-inferiority). Total ropivacaine consumption was lower in the PCEA-group (mean difference 15.3 mg, p < 0.001). Motor block, patient satisfaction scores and maternal and neonatal outcomes were similar across both groups. In conclusion, patient-controlled epidural analgesia is non-inferior to programmed intermittent epidural bolus if equal volumes of patient-controlled epidural analgesia are used to maintain labour analgesia and superior with respect to local anaesthetic consumption.

Complete Genome Sequence of Micrococcus luteus Strain CW.Ay, Isolated from Indoor Air in a Hong Kong School.

Micrococcus luteus strain CW.Ay was isolated from indoor air in Hong Kong. The complete genome (2,543,764 bp; GC content, 72.93%) was established by hybrid assembly and comprised a linear plasmid and a single chromosome featuring many genes to account for its broad distribution in very diverse habitats.

Refractory uterine atony: still a problem after all these years.

Postpartum hemorrhage is a leading cause of maternal morbidity and mortality, and uterine atony is the leading cause of postpartum hemorrhage. Risk factors for uterine atony include induced or augmented labor, preeclampsia, chorio-amnionitis, obesity, multiple gestation, polyhydramnios, and prolonged second stage of labor. Although a risk assessment is recommended for all parturients, many women with uterine atony do not have risk factors, making uterine atony difficult to predict. Oxytocin is the first-line drug for prevention and treatment of uterine atony. It is a routine component of the active management of the third stage of labor. An oxytocin bolus dose as low as 1 IU is sufficient to produce satisfactory uterine tone in almost all women undergoing elective cesarean delivery. However, a higher bolus dose (3 IU) or infusion rate is recommended for women undergoing intrapartum cesarean delivery. Carbetocin, available in many countries, is a synthetic oxytocin analog with a longer duration than oxytocin that allows bolus administration without an infusion. Second line uterotonic agents include ergot alkaloids (ergometrine and methylergonovine) and the prostaglandins, carboprost and misoprostol. These drugs work by a different mechanism to oxytocin and should be administered early for uterine atony refractory to oxytocin. Rigorous studies are lacking, but methylergonovine and carboprost are likely superior to misoprostol. Currently, the choice of second-line agent should be based on their adverse effect profile and patient comorbidities. Surgical and radiologic management of uterine atony includes uterine tamponade using balloon catheters and compression sutures, and percutaneous transcatheter arterial embolization.

High-throughput human primary cell-based airway model for evaluating influenza, coronavirus, or other respiratory viruses in vitro.

Influenza and other respiratory viruses present a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as from COVID-19. A barrier to the development of effective therapeutics is the absence of a robust and predictive preclinical model, with most studies relying on a combination of in vitro screening with immortalized cell lines and low-throughput animal models. Here, we integrate human primary airway epithelial cells into a custom-engineered 96-device platform (PREDICT96-ALI) in which tissues are cultured in an array of microchannel-based culture chambers at an air-liquid interface, in a configuration compatible with high resolution in-situ imaging and real-time sensing. We apply this platform to influenza A virus and coronavirus infections, evaluating viral infection kinetics and antiviral agent dosing across multiple strains and donor populations of human primary cells. Human coronaviruses HCoV-NL63 and SARS-CoV-2 enter host cells via ACE2 and utilize the protease TMPRSS2 for spike protein priming, and we confirm their expression, demonstrate infection across a range of multiplicities of infection, and evaluate the efficacy of camostat mesylate, a known inhibitor of HCoV-NL63 infection. This new capability can be used to address a major gap in the rapid assessment of therapeutic efficacy of small molecules and antiviral agents against influenza and other respiratory viruses including coronaviruses.

Programmed intermittent epidural bolus vs. patient-controlled epidural analgesia for maintenance of labour analgesia: a two-centre, double-blind, randomised study†.

The programmed intermittent epidural bolus technique has shown superiority to continuous epidural infusion techniques, with or without patient-controlled epidural analgesia for pain relief, reduced motor block and patient satisfaction. Many institutions still use patient-controlled epidural analgesia without a background infusion, and a comparative study between programmed intermittent epidural bolus and patient-controlled epidural analgesia without a background infusion has not yet been performed. We performed a randomised, two-centre, double-blind, controlled trial of these two techniques. The primary outcome was the incidence of breakthrough pain requiring a top-up dose by an anaesthetist. Secondary outcomes included: motor block; pain scores; patient satisfaction; local anaesthetic consumption; and obstetric and neonatal outcomes. We recruited 130 nulliparous women who received initial spinal analgesia, and then epidural analgesia was initiated and maintained with either programmed intermittent epidural bolus or patient-controlled epidural analgesia using ropivacaine 0.12% with sufentanil 0.75 µg·ml-1 . The programmed intermittent epidural bolus group had a programmed bolus of 10 ml every hour, with on-demand patient-controlled epidural analgesia boluses of 5 ml with a 20 min lockout, and the patient-controlled epidural analgesia group had a 5 ml bolus with a 12 min lockout interval; the potential maximum volume per hour was the same in both groups. The patients in the programmed intermittent epidural bolus group had less frequent breakthrough pain compared with the patient-controlled epidural analgesia group, 7 (10.9%) vs. 38 (62.3%; p < 0.0001), respectively. There was a significant difference in motor block (modified Bromage score ≤ 4) frequency between groups, programmed intermittent epidural bolus group 1 (1.6%) vs. patient-controlled epidural analgesia group 8 (13.1%); p = 0.015. The programmed intermittent epidural bolus group had greater local anaesthetic consumption with fewer patient-controlled epidural analgesia boluses. Patient satisfaction scores and obstetric or neonatal outcomes were not different between groups. In conclusion, we found that a programmed intermittent epidural bolus technique using 10 ml programmed boluses and 5 ml patient-controlled epidural analgesia boluses was superior to a patient-controlled epidural analgesia technique using 5 ml boluses and no background infusion.

A randomised comparison of bolus phenylephrine and ephedrine for the management of spinal hypotension in patients with severe preeclampsia and fetal compromise.

BACKGROUND: Studies in healthy patients undergoing elective caesarean delivery show that, compared with phenylephrine, ephedrine used to treat spinal hypotension is associated with increased fetal acidosis. This has not been investigated prospectively in women with severe preeclampsia. METHODS: Patients with preeclampsia requiring caesarean delivery for a non-reassuring fetal heart tracing were randomised to receive either bolus ephedrine (7.5-15mg) or phenylephrine (50-100µg), to treat spinal hypotension. The primary outcome was umbilical arterial base excess. Secondary outcomes were umbilical arterial and venous pH and lactate concentration, venous base excess, and Apgar scores. RESULTS: Among 133 women, 64 who required vasopressor treatment were randomised into groups of 32 with similar patient characteristics. Pre-delivery blood pressure changes were similar. There was no difference in mean [standard deviation] umbilical artery base excess (-4.9 [3.7] vs -6.0 [4.6] mmol/L for ephedrine and phenylephrine respectively; P=0.29). Mean umbilical arterial and venous pH and lactate concentrations did not significantly differ between groups (7.25 [0.08] vs 7.22 [0.10], 7.28 [0.07] vs 7.27 [0.10], and 3.41 [2.18] vs 3.28 [2.44] mmol/L respectively). Umbilical venous oxygen tension was higher in the ephedrine group (2.8 [0.7] vs 2.4 [0.62]) kPa, P=0.02). There was no difference in 1- or 5-min Apgar scores, numbers of neonates with 1-min Apgar scores <7 or with a pH <7.2. CONCLUSIONS: In patients with severe preeclampsia and fetal compromise, fetal acid-base status is independent of the use of bolus ephedrine versus phenylephrine to treat spinal hypotension.

Impact of a third stage of labor oxytocin protocol on cesarean delivery outcomes.

BACKGROUND: There are currently no standard recommendations regarding the dose, rate, or duration of intravenous oxytocin administration for the active management of the third stage of labor in the USA. In 2008, we initiated a standardized postpartum oxytocin protocol for active management of the third stage of labor. In cesarean deliveries, upon clamping of the umbilical cord, an oxytocin infusion of 18 U/h was started and adjusted upward if there was ongoing uterine atony. The aim of this study was to compare intraoperative data on oxytocin dose, estimated blood loss, supplemental uterotonic use and vasopressor use before and after the implementation of this protocol. We hypothesized that implementation of the protocol would result in lower intraoperative oxytocin doses without increasing estimated blood loss. METHODS: In this retrospective study, patient characteristics, estimated blood loss, vasopressor administration, and supplemental uterotonic use during two time periods were compared: the two-month interval before initiation of the oxytocin protocol and the two-month interval after initiation. Data were compared using the chi-squared test, t-test, or Mann-Whitney U test as appropriate. P < 0.05 was considered significant. RESULTS: Data for 901 deliveries were analyzed. The amount of intraoperative oxytocin administered decreased after implementation of the protocol (median difference 8.4 U, 95% CI 7.4 to 9.4). Although there was an increase in estimated blood loss, there were no differences in the percentage of patients experiencing intraoperative blood loss >1000 mL or the need for additional uterotonic mediations between the two time periods. CONCLUSIONS: We found that the use of an oxytocin management protocol reduced the amount of intraoperative oxytocin administered without increasing the rate of postpartum hemorrhage or the need for additional uterotonics. Clinicians may consider using a rate of 18 U/h as a starting point for administration of oxytocin to achieve adequate uterine tone in healthy parturients for prevention of postpartum hemorrhage.

Effect of ritonavir-induced cytochrome P450 3A4 inhibition on plasma fentanyl concentrations during patient-controlled epidural labor analgesia: a pharmacokinetic simulation.

BACKGROUND: Ritonavir inhibition of cytochrome P450 3A4 decreases the elimination clearance of fentanyl by 67%. We used a pharmacokinetic model developed from published data to simulate the effect of sample patient-controlled epidural labor analgesic regimens on plasma fentanyl concentrations in the absence and presence of ritonavir-induced cytochrome P450 3A4 inhibition. METHODS: Fentanyl absorption from the epidural space was modeled using tanks-in-series delay elements. Systemic fentanyl disposition was described using a three-compartment pharmacokinetic model. Parameters for epidural drug absorption were estimated by fitting the model to reported plasma fentanyl concentrations measured after epidural administration. The validity of the model was assessed by comparing predicted plasma concentrations after epidural administration to published data. The effect of ritonavir was modeled as a 67% decrease in fentanyl elimination clearance. Plasma fentanyl concentrations were simulated for six sample patient-controlled epidural labor analgesic regimens over 24 h using ritonavir and control models. Simulated data were analyzed to determine if plasma fentanyl concentrations producing a 50% decrease in minute ventilation (6.1 ng/mL) were achieved. RESULTS: Simulated plasma fentanyl concentrations in the ritonavir group were higher than those in the control group for all sample labor analgesic regimens. Maximum plasma fentanyl concentrations were 1.8 ng/mL and 3.4 ng/mL for the normal and ritonavir simulations, respectively, and did not reach concentrations associated with 50% decrease in minute ventilation. CONCLUSION: Our model predicts that even with maximal clinical dosing regimens of epidural fentanyl over 24 h, ritonavir-induced cytochrome P450 3A4 inhibition is unlikely to produce plasma fentanyl concentrations associated with a decrease in minute ventilation.

A qualitative analysis of parturients' perspectives on neuraxial labor analgesia.

BACKGROUND: The decision to use, or not use, neuraxial analgesia is complex and likely multi-factorial. The objectives of this study were to understand parturients' concerns about neuraxial analgesia, and the reasons for not anticipating the use of neuraxial analgesia using qualitative methodology. METHODS: English-speaking, term parturients, who had not requested or received labor analgesia, were recruited for this mixed-methods study. In addition to a quantitative survey, the results of which have been published elsewhere, women were asked open-ended questions regarding concerns about neuraxial analgesia and reasons for not anticipating its use. Answers were recorded verbatim and analyzed using qualitative methodology. RESULTS: Interviews were conducted with 509 women. Thirty-nine percent of patients expressed some concern about neuraxial analgesia. These concerns were thematically represented by misunderstandings about neuraxial analgesia, general fears about the procedure, and lack of trust in providers. Many of the concerns were misunderstandings that were not supported by the medical literature. Of the 129 patients who did not anticipate using neuraxial analgesia, 23% stated that this was because they desired a natural childbirth and/or control over their labor experience, whereas 46% cited concerns about the procedure and its complications as the basis for their decision. CONCLUSION: Many women who anticipate not using neuraxial analgesia may be basing their decision on an inaccurate understanding of the risks of the procedure. Improved patient education and counseling that target specific areas of concern may address these misunderstandings.

The effect of intravenous magnesium therapy on the duration of intrathecal fentanyl labor analgesia.

BACKGROUND: Magnesium has been reported to augment the analgesic effects of opioids when co-administered into the cerebrospinal fluid. The purpose of this study was to determine the influence of intravenous magnesium therapy administered for preeclampsia on the duration of intrathecal fentanyl analgesia for labor. METHODS: Thirty-four nulliparous parturients having labor induced for preeclampsia and receiving intravenous magnesium therapy were recruited. Thirty-four nulliparous patients having labor induced for elective or medical reasons were recruited as controls. At request for analgesia, baseline serum magnesium levels were obtained and combined spinal-epidural analgesia was initiated with intrathecal fentanyl 25µg. Before injection of fentanyl, a sample of cerebrospinal fluid was obtained for magnesium assay. An epidural catheter was sited but no additional medications were administered until the second request for analgesia. The primary outcome was duration of intrathecal fentanyl analgesia. RESULTS: There was no difference in the median duration of analgesia between the magnesium [79min (95% CI 76 to 82)] and control groups [69min (95% CI 56 to 82)] (difference between medians: 10min (95% CI -4 to 21min; P=0.16). There was neither a relationship between the serum and cerebrospinal fluid magnesium concentrations nor the cerebrospinal magnesium concentration and duration of intrathecal fentanyl analgesia. CONCLUSIONS: Intravenous magnesium therapy at doses typically used for seizure prophylaxis in preeclampsia did not influence the duration of intrathecal fentanyl labor analgesia. However, this study may have been underpowered to detect a difference and future study is warranted.

[In vitro antibiotic susceptibility to fluoroquinolones]. / Susceptibilidad antibiótica in vitro a fluoroquinolonas.

OBJECTIVE: To determine the antibiotic susceptibility of bacteria recovered from cultures of ocular infections in the Fundación Oftalmológica de Santander - Clínica Carlos Ardila Lulle (FOSCAL). MATERIALS AND METHODS: Retrospective descriptive study of a series of registries of cultures of samples from ocular surfaces and intraocular fluids from the OCULAB-FOSCAL laboratory in Floridablanca (Colombia) made between January and December of 2007. Antibiotic sensitivity screening by the method of Kirby-Bauer with impregnated Sensi-Discs™ of determined antibiotic concentrations was performed. RESULTS: A total of 352 samples were studied: 160 from conjunctiva, 150 from cornea and 42 from intraocular fluids. Of the total of the samples more than one microorganism was recovered 45.65% of the samples. Gram positive and Gram negative bacteria were identified in 78.7 and 18.4%, respectively. Resistance to gatifloxacin, moxifloxacin, ciprofloxacin and levofloxacin was observed in 6.3, 8.9, 33.2 and 35.6%, respectively, of Gram positive bacteria. Resistance to gatifloxacin, moxifloxacin, ciprofloxacin and levofloxacin was also observed in 7.4, 16.7, 16.7%and 25.9%, respectively, of Gram negative bacteria. The overall bacterial resistance (Gram positive and Gram negative) to moxifloxacin was 10.15%, and to gatifloxacin it was 6.46%, being which showed a statistically significant difference (P<.05). CONCLUSIONS: In our study the development of bacterial resistance to fourth generation fluoroquinolones was demonstrated in ocular samples. However, lower levels of resistance to fourth generation fluoroquinolones compared with that of third and second generation were found, particularly to Gram positive. Gatifloxacin showed lower resistance levels than moxifloxacin. Nevertheless, interpretation of this superiority must be made with caution in the clinical field, since other factors, like tissue penetration and in vivo activity, must be taken into account.

Socioeconomic deprivation, readmissions, mortality and acute exacerbations of bronchiectasis.

BACKGROUND: Bronchiectasis is known to cause significant morbidity in children in New Zealand. Little is known of the disease in adults. AIM: Our objective was to characterise a cohort of adults who presented to hospital with acute exacerbations of the disease. METHODS: We retrospectively collected information on all exacerbations treated as inpatients from a single hospital in South Auckland, New Zealand during 2002. RESULTS: We collected information on 307 exacerbations in 152 patients. Twenty-seven per cent were of Maaori ethnic origin, and 44% Pacific. Seventy per cent lived in areas categorised as the 20% most deprived in New Zealand. Comorbid conditions were present in 80% of patients - most commonly chronic obstructive pulmonary disease, asthma, diabetes and cardiac disease. Seventy (46%) patients had at least one readmission and 32 patients (21%) died within 12 months of admission to hospital. Greater deprivation was associated with increased mortality at 12 months after admission after adjusting for other factors (OR 11, 95% CI 2.0-61, P= 0.006). In the subgroup who underwent high-resolution computed tomographic scanning (93), increasing severity of bronchiectasis (modified Bhalla score) was associated with readmission within 12 months (P= 0.004), but not mortality (P= 0.419). CONCLUSIONS: We have shown that exacerbations of bronchiectasis in South Auckland are more common in patients who are predominantly of Maaori or Pacific descent and are socioeconomically deprived. Admission to hospital for an exacerbation is associated with high readmission and mortality rates.