A Community-Based Intervention for Managing Hypertension in Rural South Asia.

BACKGROUND: The burden of hypertension is escalating, and control rates are poor in low- and middle-income countries. Cardiovascular mortality is high in rural areas. METHODS: We conducted a cluster-randomized, controlled trial in rural districts in Bangladesh, Pakistan, and Sri Lanka. A total of 30 communities were randomly assigned to either a multicomponent intervention (intervention group) or usual care (control group). The intervention involved home visits by trained government community health workers for blood-pressure monitoring and counseling, training of physicians, and care coordination in the public sector. A total of 2645 adults with hypertension were enrolled. The primary outcome was reduction in systolic blood pressure at 24 months. Follow-up at 24 months was completed for more than 90% of the participants. RESULTS: At baseline, the mean systolic blood pressure was 146.7 mm Hg in the intervention group and 144.7 mm Hg in the control group. At 24 months, the mean systolic blood pressure fell by 9.0 mm Hg in the intervention group and by 3.9 mm Hg in the control group; the mean reduction was 5.2 mm Hg greater with the intervention (95% confidence interval [CI], 3.2 to 7.1; P<0.001). The mean reduction in diastolic blood pressure was 2.8 mm Hg greater in the intervention group than in the control group (95% CI, 1.7 to 3.9). Blood-pressure control (<140/90 mm Hg) was achieved in 53.2% of the participants in the intervention group, as compared with 43.7% of those in the control group (relative risk, 1.22; 95% CI, 1.10 to 1.35). All-cause mortality was 2.9% in the intervention group and 4.3% in the control group. CONCLUSIONS: In rural communities in Bangladesh, Pakistan, and Sri Lanka, a multicomponent intervention that was centered on proactive home visits by trained government community health workers who were linked with existing public health care infrastructure led to a greater reduction in blood pressure than usual care among adults with hypertension. (Funded by the Joint Global Health Trials scheme; COBRA-BPS ClinicalTrials.gov number, NCT02657746.).

Comparison of Supreme laryngeal mask airway versus endotracheal intubation for airway management during general anesthesia for cesarean section: a randomized controlled trial.

BACKGROUND: The obstetric airway is a significant cause of maternal morbidity and mortality. Endotracheal intubation is considered the standard of care but the laryngeal mask airway (LMA) has gained acceptance as a rescue airway and has been incorporated into the obstetric airway management guidelines. In this randomized controlled equivalence trial, we compared the Supreme LMA (SLMA) with endotracheal intubation (ETT) in managing the obstetric airway during cesarean section. METHODS: Parturients who underwent elective cesarean section under general anesthesia were randomized to receive either an SLMA or ETT as their airway device. Our primary outcome was first-attempt insertion success. Successful insertion was defined as adequate bilateral air entry with auscultation and the presence of end-tidal carbon dioxide on the capnogram. The first-attempt insertion success rate was compared using the Chi-Square test. Secondary outcomes included time-to-ventilation, seal pressure, ventilation/hemodynamic parameters, occurrence of clinical aspiration, fetal outcomes, and maternal side effects associated with the airway device. RESULTS: We recruited 920 parturients (460 SLMA, 460 ETT) who underwent elective cesarean section under general anesthesia. Patient characteristics were similar between the groups. First attempt success was similar (Odds Ratio--ORSLMA/ETT: 1.00 (95%CI: 0.25, 4.02), p = 1.0000). SLMA was associated with reduced time to effective ventilation (Mean Difference--MD -22.96; 95%CI: - 23.71, - 22.21 s) compared to ETT group (p <  0.0001). Ventilation parameters, maternal and fetal outcomes were similar between the groups, and there was no aspiration. CONCLUSIONS: SLMA could be an alternative airway management technique for a carefully selected low-risk obstetric population, with similar insertion success rates, reduced time to ventilation and less hemodynamic changes compared with ETT. Our findings are consistent with the airway guidelines in recommending the second-line use of LMA in the management of the obstetric airway. TRIAL REGISTRATION: The study was registered at http://www.clinicaltrials.gov , identifier: NCT01858467 , retrospectively registered. Date of registration: May 21, 2013.

Automated mandatory bolus versus basal infusion for maintenance of epidural analgesia in labour.

BACKGROUND: Childbirth may cause the most severe pain some women experience in their lifetime. Epidural analgesia is an effective form of pain relief during labour and is considered to be the reference standard. Traditionally epidural analgesia has been delivered as a continuous infusion via a catheter in the epidural space, with or without the ability for the patient to supplement the analgesia received by activating a programmable pump to deliver additional top-up doses, known as patient-controlled epidural analgesia (PCEA). There has been interest in delivering maintenance analgesic medication via bolus dosing (automated mandatory bolus - AMB) instead of the traditional continuous basal infusion (BI); recent randomized controlled trials (RCTs) have shown that the AMB technique leads to improved analgesia and maternal satisfaction. OBJECTIVES: To assess the effects of automated mandatory bolus versus basal infusion for maintaining epidural analgesia in labour. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the World Health Organization International Clinial Trials Registry Platform (WHO-ICTRP) and ClinicalTrials.gov on 16 January 2018. We screened the reference lists of all eligible trials and reviews. We also contacted authors of included studies in this field in order to identify unpublished research and trials still underway, and we screened the reference lists of the included articles for potentially relevant articles. SELECTION CRITERIA: We included all RCTs that compared the use of bolus dosing AMB with continuous BI for providing pain relief during epidural analgesia for labour in women. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were: risk of breakthrough pain with the need for anaesthetic intervention; risk of caesarean delivery; risk of instrumental delivery. Secondary outcomes included: duration of labour; local anaesthetic consumption. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included 12 studies with a total of 1121 women. Ten studies enrolled healthy nulliparous women only and two studies enrolled healthy parous women at term as well. All studies excluded women with complicated pregnancies. There were variations in the technique of initiation of epidural analgesia. Seven studies utilized the combined spinal epidural (CSE) technique, and the other five studies only placed an epidural catheter without any intrathecal injection. Seven studies utilized ropivacaine: six with fentanyl and one with sufentanil. Two studies used levobupivacaine: one with sufentanil and one with fentanyl. Three used bupivacaine with or without fentanyl. The overall risk of bias of the studies was low.AMB probably reduces the risk of breakthrough pain compared with BI for maintaining epidural analgesia for labour (from 33% to 20%; risk ratio (RR) 0.60; 95% confidence interval (CI) 0.39 to 0.92, 10 studies, 797 women, moderate-certainty evidence). AMB may make little or no difference to the risk of caesarean delivery compared to BI (15% and 16% respectively; RR 0.92; 95% CI 0.70 to 1.21, 11 studies, 1079 women, low-certainty evidence).AMB may make little or no difference in the risk of instrumental delivery compared to BI (12% and 9% respectively; RR 0.75; 95% CI 0.54 to 1.06, 11 studies, 1079 women, low-certainty evidence). There is probably little or no difference in the mean duration of labour with AMB compared to BI (mean difference (MD) -10.38 min; 95% CI -26.73 to 5.96, 11 studies, 1079 women, moderate-certainty evidence). There is probably a reduction in the hourly consumption of local anaesthetic with AMB compared to BI for maintaining epidural analgesia during labour (MD -1.08 mg/h; 95% CI -1.78 to -0.38, 12 studies, 1121 women, moderate-certainty evidence). Five out of seven studies reported an increase in maternal satisfaction with AMB compared to BI for maintaining epidural analgesia for labour; however, we did not pool these data due to their ordinal nature. Seven studies reported Apgar scores, though there was significant heterogeneity in reporting. None of the studies showed any significant difference between Apgar scores between groups. AUTHORS' CONCLUSIONS: There is predominantly moderate-certainty evidence that AMB is similar to BI for maintaining epidural analgesia for labour for all measured outcomes and may have the benefit of decreasing the risk of breakthrough pain and improving maternal satisfaction while decreasing the amount of local anaesthetic needed.

Estimating Information Processing in a Memory System: The Utility of Meta-analytic Methods for Genetics.

Genetic studies in Drosophila reveal that olfactory memory relies on a brain structure called the mushroom body. The mainstream view is that each of the three lobes of the mushroom body play specialized roles in short-term aversive olfactory memory, but a number of studies have made divergent conclusions based on their varying experimental findings. Like many fields, neurogenetics uses null hypothesis significance testing for data analysis. Critics of significance testing claim that this method promotes discrepancies by using arbitrary thresholds (α) to apply reject/accept dichotomies to continuous data, which is not reflective of the biological reality of quantitative phenotypes. We explored using estimation statistics, an alternative data analysis framework, to examine published fly short-term memory data. Systematic review was used to identify behavioral experiments examining the physiological basis of olfactory memory and meta-analytic approaches were applied to assess the role of lobular specialization. Multivariate meta-regression models revealed that short-term memory lobular specialization is not supported by the data; it identified the cellular extent of a transgenic driver as the major predictor of its effect on short-term memory. These findings demonstrate that effect sizes, meta-analysis, meta-regression, hierarchical models and estimation methods in general can be successfully harnessed to identify knowledge gaps, synthesize divergent results, accommodate heterogeneous experimental design and quantify genetic mechanisms.

Supreme™ laryngeal mask airway use in general Anesthesia for category 2 and 3 Cesarean delivery: a prospective cohort study.

BACKGROUND: The Supreme™ laryngeal mask airway (SLMA) is a single-use LMA with double lumen design that allows separation of the respiratory and the alimentary tract, hence potentially reducing the gastric volume and risk of aspiration. The purpose of this prospective cohort study is to evaluate the the role of the SLMA as an airway technique for women undergoing category 2 and 3 Cesarean delivery under general anesthesia. METHODS: We recruited 584 parturients who underwent category 2 or 3 Cesarean delivery under general anesthesia, in which 193 parturients underwent category 2 and 391 parturients underwent category 3 Cesarean delivery. The primary outcome was insertion success rate at 1st attempt in SLMA insertion. The secondary outcomes included anaesthetic, obstetric outcomes and maternal side effects associated with airway device. RESULTS: The 1st attempt insertion success rate was 98.3%, while the overall insertion success rate was 100%. The mean (Standard deviation) time to effective ventilation was 15.6 (4.4) seconds. Orogastric tube insertion was successful at the 1st attempt in all parturients. There was no clinical evidence of aspiration or regurgitation. No episodes of hypoxemia, laryngospasm or bronchospasm were observed intra-operatively. The incidence of complications was low and with good maternal satisfaction reported. CONCLUSIONS: The SLMA could be an alternative effective airway in category 2 and 3 parturients emergency Cesarean Delivery under general anesthesia in a carefully-selected obstetric population. TRIAL REGISTRATION: Clinical Trials Registration: Clinicaltrials.gov Registration NCT02026882 . Registered on December 31, 2013.

Hyperbaric versus isobaric bupivacaine for spinal anaesthesia for caesarean section.

BACKGROUND: Bupivacaine is an amide local anaesthetic used in hyperbaric and isobaric forms. These are administered intrathecally into the spine to provide regional anaesthesia for caesarean section. Several trials have compared hyperbaric and isobaric bupivacaine but none have conclusively shown the benefit of either. This review was first published in 2013 and updated in 2016. OBJECTIVES: Our objectives were to:1. Determine the effectiveness of hyperbaric bupivacaine compared to isobaric bupivacaine for spinal anaesthesia in women undergoing caesarean section;2. Determine the safety of hyperbaric bupivacaine compared to isobaric bupivacaine for spinal anaesthesia in women undergoing caesarean section. SEARCH METHODS: We originally searched the following databases to January 2011: CENTRAL, MEDLINE and Embase.For this update, we reran our search in the above databases from January 2011 to March 2016; two studies are awaiting a response from authors for assessment and will be dealt with when we next update the review.We imposed no language restriction. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) involving parturients undergoing spinal anaesthesia for elective caesarean section that compared the use of hyperbaric with isobaric bupivacaine. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data. The data that were extracted included the number of events and the sample sizes in both the intervention and control groups. For continuous outcomes, we extracted mean and standard deviation.We reported odds ratios (ORs) and risk ratios (RRs) for binary outcomes, and mean differences (MDs) for continuous outcomes. MAIN RESULTS: We included three new RCTs in this update, which now comprises 10 studies with a total of 614 participants. We judged most trials as having uncertain risk of bias regarding randomization. Other than this, the overall risk of bias was low. Most included trials had small sample sizes. All of the trials assessed the primary outcome of conversion to general anaesthesia. Ten trials comparing anaesthesia performed with hyperbaric and isobaric bupivacaine failed to show any difference in need for conversion to general anaesthesia (RR 0.33, 95% CI 0.09 to 1.17, 614 participants, very low quality of evidence). Nine trials also failed to show a difference in the need for supplemental analgesics (RR 0.61, 95% CI 0.26 to 1.41, 554 participants, very low quality of evidence). Four trials comparing requirement for ephedrine did not show any difference (RR 0.89, 95% CI 0.57 to 1.38, 256 participants, very low quality of evidence). Seven trials did not provide convincing evidence of difference in nausea and vomiting (RR 0.99, 95% CI 0.57 to 1.72, 433 participants, low quality of evidence). Three trials failed to show a difference in headache (OR 1.82, 95% CI 0.47 to 6.99, 234 participants, low quality of evidence). Two trials showed that the time until sensory block to the thoracic 4th (T4) spinal level was shorter with hyperbaric bupivacaine (MD -1.06 minutes, 95% CI -1.80 to -0.31, 128 participants, moderate quality of evidence). Six trials showed no difference in the amount of ephedrine used (RR 0.23, 95% CI -1.65 to 2.12, 386 participants, moderate quality of evidence). Three trials failed to show any difference in high block (RR 0.88, 95% CI 0.16 to 4.90, 205 participants). AUTHORS' CONCLUSIONS: Data are limited for some of the outcomes. Reporting of the included trials is less than optimal. For these reasons the overall quality of evidence is low or very low for most of the outcomes, based on the GRADE method of assessment. This review found that intrathecal hyperbaric bupivacaine had a more rapid onset of sensory blockade at the 4th thoracic vertebra (T4) level than isobaric bupivacaine. Hower, despite incorporating more data in the analysis, we found little evidence that the need for conversion to general anaesthesia and supplemental analgesia differed between the hyperbaric or isobaric bupivacaine groups. This is mainly due to the rarity of these outcomes, variability in the dose, use of adjuvant drugs and differences in the technique used for regional anaesthesia. There were no differences in the adverse effects studied. Any possible advantage of hyperbaric bupivacaine needs to be confirmed in larger randomized trials. In future research, criteria for conversion to general anaesthesia need to be defined objectively and applied uniformly.

Femoral nerve blocks for acute postoperative pain after knee replacement surgery.

BACKGROUND: Total knee replacement (TKR) is a common and often painful operation. Femoral nerve block (FNB) is frequently used for postoperative analgesia. OBJECTIVES: To evaluate the benefits and risks of FNB used as a postoperative analgesic technique relative to other analgesic techniques among adults undergoing TKR. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 1, MEDLINE, EMBASE, CINAHL, Web of Science, dissertation abstracts and reference lists of included studies. The date of the last search was 31 January 2013. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing FNB with no FNB (intravenous patient-controlled analgesia (PCA) opioid, epidural analgesia, local infiltration analgesia, and oral analgesia) in adults after TKR. We also included RCTs that compared continuous versus single-shot FNB. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection and data extraction. We undertook meta-analysis (random-effects model) and used relative risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) or standardized mean differences (SMDs) for continuous outcomes. We interpreted SMDs according to rule of thumb where 0.2 or smaller represents a small effect, 0.5 a moderate effect and 0.8 or larger, a large effect. MAIN RESULTS: We included 45 eligible RCTs (2710 participants) from 47 publications; 20 RCTs had more than two allocation groups. A total of 29 RCTs compared FNB (with or without concurrent treatments including PCA opioid) versus PCA opioid, 10 RCTs compared FNB versus epidural, five RCTs compared FNB versus local infiltration analgesia, one RCT compared FNB versus oral analgesia and four RCTs compared continuous versus single-shot FNB. Most included RCTs were rated as low or unclear risk of bias for the aspects rated in the risk of bias assessment tool, except for the aspect of blinding. We rated 14 (31%) RCTs at high risk for both participant and assessor blinding and rated eight (18%) RCTs at high risk for one blinding aspect.Pain at rest and pain on movement were less for FNB (of any type) with or without a concurrent PCA opioid compared with PCA opioid alone during the first 72 hours post operation. Pooled results demonstrated a moderate effect of FNB for pain at rest at 24 hours (19 RCTs, 1066 participants, SMD -0.72, 95% CI -0.93 to -0.51, moderate-quality evidence) and a moderate to large effect for pain on movement at 24 hours (17 RCTs, 1017 participants, SMD -0.94, 95% CI -1.32 to -0.55, moderate-quality evidence). Pain was also less in each FNB subgroup: single-shot FNB, continuous FNB and continuous FNB + sciatic block, compared with PCA. FNB also was associated with lower opioid consumption (IV morphine equivalent) at 24 hours (20 RCTs, 1156 participants, MD -14.74 mg, 95% CI -18.68 to -10.81 mg, high-quality evidence) and at 48 hours (MD -14.53 mg, 95% CI -20.03 to -9.02 mg), lower risk of nausea and/or vomiting (RR 0.47, 95% CI 0.33 to 0.68, number needed to treat for an additional harmful outcome (NNTH) four, high-quality evidence), greater knee flexion (11 RCTs, 596 participants, MD 6.48 degrees, 95% CI 4.27 to 8.69 degrees, moderate-quality evidence) and greater patient satisfaction (four RCTs, 180 participants, SMD 1.06, 95% CI 0.74 to 1.38, low-quality evidence) compared with PCA.We could not demonstrate a difference in pain between FNB (any type) and epidural analgesia in the first 72 hours post operation, including pain at 24 hours at rest (six RCTs, 328 participants, SMD -0.05, 95% CI -0.43 to 0.32, moderate-quality evidence) and on movement (six RCTs, 317 participants, SMD 0.01, 95% CI -0.21 to 0.24, high-quality evidence). No difference was noted at 24 hours for opioid consumption (five RCTs, 341 participants, MD -4.35 mg, 95% CI -9.95 to 1.26 mg, high-quality evidence) or knee flexion (six RCTs, 328 participants, MD -1.65, 95% CI -5.14 to 1.84, high-quality evidence). However, FNB demonstrated lower risk of nausea/vomiting (four RCTs, 183 participants, RR 0.63, 95% CI 0.41 to 0.97, NNTH 8, moderate-quality evidence) and higher patient satisfaction (two RCTs, 120 participants, SMD 0.60, 95% CI 0.23 to 0.97, low-quality evidence), compared with epidural analgesia.Pooled results of four studies (216 participants) comparing FNB with local infiltration analgesia detected no difference in analgesic effects between the groups at 24 hours for pain at rest (SMD 0.06, 95% CI -0.61 to 0.72, moderate-quality evidence) or pain on movement (SMD 0.38, 95% CI -0.10 to 0.86, low-quality evidence). Only one included RCT compared FNB with oral analgesia. We considered this evidence insufficient to allow judgement of the effects of FNB compared with oral analgesia.Continuous FNB provided less pain compared with single-shot FNB (four RCTs, 272 participants) at 24 hours at rest (SMD -0.62, 95% CI -1.17 to -0.07, moderate-quality evidence) and on movement (SMD -0.42, 95% CI -0.67 to -0.17, high-quality evidence). Continuous FNB also demonstrated lower opioid consumption compared with single-shot FNB at 24 hours (three RCTs, 236 participants, MD -13.81 mg, 95% CI -23.27 to -4.35 mg, moderate-quality evidence).Generally, the meta-analyses demonstrated considerable statistical heterogeneity, with type of FNB, allocation concealment and blinding of participants, personnel and outcome assessors reducing heterogeneity in the analyses. Available evidence was insufficient to allow determination of the comparative safety of the various analgesic techniques. Few RCTs reported on serious adverse effects such as neurological injury, postoperative falls or thrombotic events. AUTHORS' CONCLUSIONS: Following TKR, FNB (with or without concurrent treatments including PCA opioid) provided more effective analgesia than PCA opioid alone, similar analgesia to epidural analgesia and less nausea/vomiting compared with PCA alone or epidural analgesia. The review also found that continuous FNB provided better analgesia compared with single-shot FNB. RCTs were insufficient to allow definitive conclusions on the comparison between FNB and local infiltration analgesia or oral analgesia.

Early versus late initiation of epidural analgesia for labour.

BACKGROUND: Pain during childbirth is arguably the most severe pain some women may experience in their lifetime. Epidural analgesia is an effective form of pain relief during labour. Many women have concerns regarding its safety. Furthermore, epidural services and anaesthetic support may not be available consistently across all centres. Observational data suggest that early initiation of epidural may be associated with an increased risk of caesarean section, but the same findings were not seen in recent randomised controlled trials. More recent guidelines suggest that in the absence of a medical contraindication, maternal request is a sufficient medical indication for pain relief during labour. The choice of analgesic technique, agent, and dosage is based on many factors, including patient preference, medical status, and contraindications. There is no systematically reviewed evidence on the maternal and foetal outcomes and safety of this practice. OBJECTIVES: This systematic review aimed to summarise the effectiveness and safety of early initiation versus late initiation of epidural analgesia in women. We considered the obstetric and fetal outcomes relevant to women and side effects of the treatments, including risk of caesarean section, instrumental birth and time to birth. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (12 February 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE (January 1966 to February 2014), Embase (January 1980 to February 2014) and reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials involving women undergoing epidural labour analgesia that compared early initiation versus late initiation of epidural labour analgesia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted the data and assessed the trial quality. Data were checked for accuracy. MAIN RESULTS: We included nine studies with a total of 15,752 women.The overall risk of bias of the studies was low, with the exception of performance bias (blinding of participants and personnel).The nine studies showed no clinically meaningful difference in risk of caesarean section with early initiation versus late initiation of epidural analgesia for labour (risk ratio (RR) 1.02; 95% confidence interval (CI) 0.96 to 1.08, nine studies, 15,499 women, high quality evidence). There was no clinically meaningful difference in risk of instrumental birth with early initiation versus late initiation of epidural analgesia for labour (RR 0.93; 95% CI 0.86 to 1.01, eight studies, 15,379 women, high quality evidence). The duration of second stage of labour showed no clinically meaningful difference between early initiation and late initiation of epidural analgesia (mean difference (MD) -3.22 minutes; 95% CI -6.71 to 0.27, eight studies, 14,982 women, high quality evidence). There was significant heterogeneity in the duration of first stage of labour and the data were not pooled.There was no clinically meaningful difference in Apgar scores less than seven at one minute (RR 0.96; 95% CI 0.84 to 1.10, seven studies, 14,924 women, high quality evidence). There was no clinically meaningful difference in Apgar scores less than seven at five minutes (RR 0.96; 95% CI 0.69 to 1.33, seven studies, 14,924 women, high quality evidence). There was no clinically meaningful difference in umbilical arterial pH between early initiation and late initiation (MD 0.01; 95% CI -0.01 to 0.03, four studies, 14,004 women, high quality evidence). There was no clinically meaningful difference in umbilical venous pH favouring early initiation (MD 0.01; 95% CI -0.00 to 0.02, four studies, 14,004 women, moderate quality evidence). AUTHORS' CONCLUSIONS: There is predominantly high-quality evidence that early or late initiation of epidural analgesia for labour have similar effects on all measured outcomes. However, various forms of alternative pain relief were given to women who were allocated to delayed epidurals to cover that period of delay, so that is it hard to assess the outcomes clearly. We conclude that for first time mothers in labour who request epidurals for pain relief, it would appear that the time to initiate epidural analgesia is dependent upon women's requests.

Efficacy and Safety of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler in Chinese Patients with COPD: A Subgroup Analysis of KRONOS.

INTRODUCTION: This pre-specified subgroup analysis evaluated the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) triple therapy versus corresponding dual therapies in the China subgroup of the phase III, double-blind KRONOS study in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). METHODS: Patients were randomized 2:2:1:1 to BGF MDI 320/18/9.6 µg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 µg twice daily for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over weeks 12-24. Secondary endpoints included symptoms, health-related quality of life, and safety. Rate of moderate/severe COPD exacerbations was an additional efficacy endpoint. RESULTS: In the China subgroup (n = 432; 22.7% of the KRONOS population), BGF MDI demonstrated nominally significant improvements in the primary endpoint versus BFF MDI (least squares mean (LSM) difference 68 mL; P = 0.0035) and BUD/FORM DPI (LSM difference 78 mL; P = 0.0010) but not GFF MDI (LSM difference - 4 mL; P = 0.8316). BGF MDI demonstrated at least numerical improvements versus comparators in secondary lung function and symptom endpoints. BGF MDI reduced the rate of moderate/severe COPD exacerbations versus GFF MDI (rate ratio 0.41; P = 0.0030), with numerical benefits versus BFF MDI and BUD/FORM DPI. All treatments were well tolerated. CONCLUSIONS: Results demonstrated that BGF MDI showed benefits on lung function (vs inhaled corticosteroid/long-acting ß2-agonist), as well as symptoms and exacerbations relative to dual therapies. Findings support BGF MDI use in Chinese patients with moderate to very severe COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02497001.

Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD.

Background: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) is a long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination therapy delivered by MDI, formulated using innovative co-suspension delivery technology. The PINNACLE-4 study evaluated the efficacy and safety of GFF MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) from Asia, Europe, and the USA. This article presents the results from the China subpopulation of PINNACLE-4. Methods: In this randomized, double-blind, placebo-controlled, parallel-group Phase III study (NCT02343458), patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second at Week 24. Secondary lung function endpoints and patient-reported outcome measures were also assessed. Safety was monitored throughout the study. Results: Overall, 466 patients from China were included in the intent-to-treat population (mean age 63.6 years, 95.7% male). Treatment with GFF MDI improved the primary endpoint compared to GP MDI, FF MDI, and placebo MDI (least squares mean differences: 98, 104, and 173 mL, respectively; all P≤0.0001). GFF MDI also improved daily total symptom scores and time to first clinically important deterioration versus monocomponents and placebo MDI, and Transition Dyspnea Index focal score versus placebo MDI. Rates of treatment-emergent adverse events were similar across the active treatment groups and slightly higher in the placebo MDI group. Conclusion: GFF MDI improved lung function and daily symptoms versus monocomponents and placebo MDI and improved dyspnea versus placebo MDI. All treatments were well tolerated with no unexpected safety findings. Efficacy and safety results were generally consistent with the global PINNACLE-4 population, supporting the use of GFF MDI in patients with COPD from China.

Control of blood pressure and risk attenuation: a public health intervention in rural Bangladesh, Pakistan, and Sri Lanka: feasibility trial results.

BACKGROUND: High blood pressure (BP) is the leading attributable risk for cardiovascular disease globally. There is little information on effective and sustainable public health system strategies for managing hypertension in South Asian countries. We conducted a feasibility study to gather preliminary data to optimize BP-lowering strategies for a public health intervention in rural communities in Bangladesh, Pakistan, and Sri Lanka. METHODS: A mixed method feasibility study comprised a 3-month pre and postevaluation of a multicomponent intervention (MCI), including BP screening and home health education by trained government community health worker (CHW); providers trained in hypertension management, and compensation of CHW for additional services. Checklists were used to document care. Stakeholder interviews were also conducted. Individuals aged 40 years and above with high BP (systolic ≥140 mmHg or diastolic ≥90 mmHg based on two readings from 2 separate days, or receiving antihypertensive medications) were enrolled from rural communities in Bangladesh, Pakistan, and Sri Lanka. BP was measured at baseline and 3 months postintervention. RESULTS: A total of 412 (90%) of the 454 eligible individuals were recruited. Of those recruited, 90% received home health education session by trained CHWs, 80% were referred to trained providers, of whom 83% completed the management checklist. A follow-up rate of 95.6% was achieved. The mean SBP declined significantly by 4.5 mmHg 95% confidence interval (2.3, 6.7) mmHg (P < 0.001) in the overall pooled analysis in three countries; however, it varied among countries. BP decline was 10.5 mmHg (8.1, 13.0 mmHg) (P < 0.001) in the pooled analysis of individuals with uncontrolled hypertension at baseline, and was also significant each of the three countries. All 98 stakeholders strongly supported upscaling the proposed MCI strategies. CONCLUSION: The proposed MCI is feasible for implementation and requires long-term, large-scale evaluation in the rural public health infrastructure in South Asian countries to determine sustainability of health system changes and BP control. If these long-term effects are confirmed, MCI may be a long-term strategy for tackling rising rates of cardiovascular disease in low-resourced countries.Clintrial.gov NCT02341651.

Thyroid Autoimmune Antibodies and Major Depressive Disorder in Women.

INTRODUCTION: Anti-thyroid antibodies are associated with extra-thyroid diseases such as Graves' ophthalmopathy and Hashimoto's encephalopathy. Some evidence suggests that anti-thyroid antibodies are also associated with depression. Interleukin (IL)-17 appears to play an important role in autoimmune thyroid disease. This study investigated whether specific thyroid autoantibodies and IL-17 distinguished persons with depression from non-depressed controls. MATERIALS AND METHODS: Forty-seven adult females with non-psychotic, current major depressive disorder and 80 healthy female controls participated in this study. Thyroid peroxidase antibodies, thyroglobulin antibodies, thyroid-stimulating hormone (TSH) receptor antibodies, free T3 and T4, TSH and IL-17 were measured from the serum. Measurements were repeated to assess test-retest reliability. Receiver operating characteristic (ROC) curves were used to estimate discriminatory values of the measurements. Differences between groups and associations between the clinical and biochemical assessments were analysed. RESULTS: Median TSH receptor antibody concentration was significantly higher in the depressed than control group (P <0.001). Area under the ROC curve was 0.80 (95% CI, 0.73 to 0.88). Higher TSH receptor antibody titres were associated with greater depression severity scores (r = 0.33, P <0.05). IL-17 levels were not associated with TSH receptor antibody levels or depression severity scores. Thyroid function and other thyroid autoantibodies were not associated with depression severity. CONCLUSION: TSH receptor antibodies might be a biomarker of immune dysfunction in depression.

Functional discharge readiness and mobility following total knee arthroplasty for osteoarthritis: a comparison of analgesic techniques.

OBJECTIVE: To determine if functional discharge readiness and mobility following total knee arthroplasty (TKA) for osteoarthritis is delayed after femoral nerve block (FNB) with or without patient-controlled analgesia (PCA) opioid compared with PCA opioid alone. METHODS: We analyzed secondary outcomes from a randomized controlled trial with 200 patients undergoing unilateral TKA. Experimental group 1 received single-injection FNB with intravenous PCA opioid, experimental group 2 received continuous FNB, and the control group received PCA opioid alone. FNB was administered using bupivacaine. Patients followed a structured TKA pathway. Discharge readiness outcomes included achievement of 90° knee flexion, independent walking, and stair climbing, and were assessed daily before discharge or day 6, whichever came first. Mobility outcomes included the Timed Up and Go (TUG) test, the 6-Minute Walk Distance (6MWD), and self-reported physical function, and were assessed at weeks 2 and 12. TUG was also assessed on days 3 to 6, postoperation. RESULTS: Both FNB groups (77%) were more likely to achieve 90° knee flexion compared with the control group (59%); odds ratio (OR) 2.3, 95% confidence interval (95% CI) 1.1, 4.8 for single-injection FNB, and OR 2.3, 95% CI 1.1, 4.9 for continuous FNB. There were no significant differences in independent walking and stair-climbing ability before discharge, TUG, 6MWD, or self-reported physical function, between the FNB groups compared with the control group. CONCLUSION: After TKA, FNB (single-injection with PCA opioid or continuous) does not delay achievement of 90° knee flexion or other measures of functional discharge readiness and mobility compared with PCA opioid alone.