Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial

BackgroundThe dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio.Methods and findingsWe undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03532594","term_id":"NCT03532594"}}NCT03532594).Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78–1.14] vs. 0.75 [IQR 0.57–0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75–245] vs. 135 [IQR 94–222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160–210] vs. 280 [IQR 250–300] mg; p < 0.001).Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C).ConclusionsUsing a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients.Trial registrationClinicalTrials.gov Unique identifier {"type":"clinical-trial","attrs":{"text":"NCT03532594","term_id":"NCT03532594"}}NCT03532594.

Lachlan Miles and co-workers report on a randomized controlled trial seeking to optimise protamine dosing after cardiopulmonary bypass.     

Human papillomavirus seroprevalence in pregnant women following gender-neutral and girls-only vaccination programs in Finland: A cross-sectional cohort analysis following a cluster randomized trial

BackgroundCervical cancer elimination through human papillomavirus (HPV) vaccination programs requires the attainment of herd effect. Due to its uniquely high basic reproduction number, the vaccination coverage required to achieve herd effect against HPV type 16 exceeds what is attainable in most populations. We have compared how gender-neutral and girls-only vaccination strategies create herd effect against HPV16 under moderate vaccination coverage achieved in a population-based, community-randomized trial.Methods and findingsIn 2007–2010, the 1992–1995 birth cohorts of 33 Finnish communities were randomized to receive gender-neutral HPV vaccination (Arm A), girls-only HPV vaccination (Arm B), or no HPV vaccination (Arm C) (11 communities per trial arm). HPV16/18/31/33/35/45 seroprevalence differences between the pre-vaccination era (2005–2010) and post-vaccination era (2011–2016) were compared between all 8,022 unvaccinated women <23 years old and resident in the 33 communities during 2005–2016 (2,657, 2,691, and 2,674 in Arms A, B, and C, respectively). Post- versus pre-vaccination-era HPV seroprevalence ratios (PRs) were compared by arm. Possible outcome misclassification was quantified via probabilistic bias analysis. An HPV16 and HPV18 seroprevalence reduction was observed post-vaccination in the gender-neutral vaccination arm in the entire study population (PR₁₆ = 0.64, 95% CI 0.10–0.85; PR₁₈ = 0.72, 95% CI 0.22–0.96) and for HPV16 also in the herpes simplex virus type 2 seropositive core group (PR₁₆ = 0.64, 95% CI 0.50–0.81). Observed reductions in HPV31/33/35/45 seroprevalence (PR_31/33/35/45 = 0.88, 95% CI 0.81–0.97) were replicated in Arm C (PR_31/33/35/45 = 0.79, 95% CI 0.69–0.90).ConclusionsIn this study we only observed herd effect against HPV16/18 after gender-neutral vaccination with moderate vaccination coverage. With only moderate vaccination coverage, a gender-neutral vaccination strategy can facilitate the control of even HPV16. Our findings may have limited transportability to other vaccination coverage levels.Trial registrationClinicalTrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT00534638","term_id":"NCT00534638"}}NCT00534638, https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00534638","term_id":"NCT00534638"}}NCT00534638.     

Integrated treatment of hepatitis C virus infection among people who inject drugs: A multicenter randomized controlled trial (INTRO-HCV)

BackgroundThe standard pathways of testing and treatment for hepatitis C virus (HCV) infection in tertiary healthcare are not easily accessed by people who inject drugs (PWID). The aim of this study was to evaluate the efficacy of integrated treatment of chronic HCV infection among PWID.Methods and findingsINTRO-HCV is a multicenter, randomized controlled clinical trial. Participants recruited from opioid agonist therapy (OAT) and community care clinics in Norway over 2017 to 2019 were randomly 1:1 assigned to the 2 treatment approaches. Integrated treatment was delivered by multidisciplinary teams at opioid agonist treatment clinics or community care centers (CCCs) for people with substance use disorders. This included on-site testing for HCV, liver fibrosis assessment, counseling, treatment, and posttreatment follow-up. Standard treatment was delivered in hospital outpatient clinics. Oral direct-acting antiviral (DAA) medications were administered in both arms. The study was not completely blinded. The primary outcomes were time-to-treatment initiation and sustained virologic response (SVR), defined as undetectable HCV RNA 12 weeks after treatment completion, analyzed with intention to treat, and presented as hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals.Among 298 included participants, 150 were randomized to standard treatment, of which 116/150 (77%) initiated treatment, with 108/150 (72%) initiating within 1 year of referral. Among those 148 randomized to integrated care, 145/148 (98%) initiated treatment, with 141/148 (95%) initiating within 1 year of referral. The HR for the time to initiating treatment in the integrated arm was 2.2 (1.7 to 2.9) compared to standard treatment. SVR was confirmed in 123 (85% of initiated/83% of all) for integrated treatment compared to 96 (83% of initiated/64% of all) for the standard treatment (OR among treated: 1.5 [0.8 to 2.9], among all: 2.8 [1.6 to 4.8]). No severe adverse events were linked to the treatment.ConclusionsIntegrated treatment for HCV in PWID was superior to standard treatment in terms of time-to-treatment initiation, and subsequently, more people achieved SVR. Among those who initiated treatment, the SVR rates were comparable. Scaling up of integrated treatment models could be an important tool for elimination of HCV.Trial registrationClinicalTrials.gov.no {"type":"clinical-trial","attrs":{"text":"NCT03155906","term_id":"NCT03155906"}}NCT03155906

Dr. Fadnes and colleagues conducted a randomized controlled trial to compare the efficacy of integrated treatment using multidisciplinary teams to standard treatment of Hepatitis C virus infection among people who currently inject or formerly injected drugs.     

Pyronaridine–artesunate real-world safety,tolerability, and effectiveness in malaria patients in 5 African countries: A single-arm,open-label,cohort event monitoring study

BackgroundIn Phase II/III randomized controlled clinical trials for the treatment of acute uncomplicated malaria, pyronaridine–artesunate demonstrated high efficacy and a safety profile consistent with that of comparators, except that asymptomatic, mainly mild-to-moderate transient increases in liver aminotransferases were reported for some patients. Hepatic safety, tolerability, and effectiveness have not been previously assessed under real-world conditions in Africa.Methods and findingsThis single-arm, open-label, cohort event monitoring study was conducted at 6 health centers in Cameroon, Democratic Republic of Congo, Gabon, Ivory Coast, and Republic of Congo between June 2017 and April 2019. The trial protocol as closely as possible resembled real-world clinical practice for the treatment of malaria at the centers. Eligible patients were adults or children of either sex, weighing at least 5 kg, with acute uncomplicated malaria who did not have contraindications for pyronaridine–artesunate treatment as per the summary of product characteristics. Patients received fixed-dose pyronaridine–artesunate once daily for 3 days, dosed by body weight, without regard to food intake. A tablet formulation was used in adults and adolescents and a pediatric granule formulation in children and infants under 20 kg body weight. The primary outcome was the hepatic event incidence, defined as the appearance of the clinical signs and symptoms of hepatotoxicity confirmed by a >2× rise in alanine aminotransferase/aspartate aminotransferase (ALT/AST) versus baseline in patients with baseline ALT/AST >2× the upper limit of normal (ULN). As a secondary outcome, this was assessed in patients with ALT/AST >2× ULN prior to treatment versus a matched cohort of patients with normal baseline ALT/AST. The safety population comprised 7,154 patients, of mean age 13.9 years (standard deviation (SD) 14.6), around half of whom were male (3,569 [49.9%]). Patients experienced 8,560 malaria episodes; 158 occurred in patients with baseline ALT/AST elevations >2×ULN. No protocol-defined hepatic events occurred following pyronaridine–artesunate treatment of malaria patients with or without baseline hepatic dysfunction. Thus, no cohort comparison could be undertaken. Also, as postbaseline clinical chemistry was only performed where clinically indicated, postbaseline ALT/AST levels were not systematically assessed for all patients. Adverse events of any cause occurred in 20.8% (1,490/7,154) of patients, most frequently pyrexia (5.1% [366/7,154]) and vomiting (4.2% [303/7,154]). Adjusting for Plasmodium falciparum reinfection, clinical effectiveness at day 28 was 98.6% ([7,369/7,746] 95% confidence interval (CI) 98.3 to 98.9) in the per-protocol population. There was no indication that comorbidities or malnutrition adversely affected outcomes. The key study limitation was that postbaseline clinical biochemistry was only evaluated when clinically indicated.ConclusionsPyronaridine–artesunate had good tolerability and effectiveness in a representative African population under conditions similar to everyday clinical practice. These findings support pyronaridine–artesunate as an operationally useful addition to the management of acute uncomplicated malaria.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03201770","term_id":"NCT03201770"}}NCT03201770.

Gaston Tona Lutete and co-workers report on safety and effectiveness of the antimalarial drug pyronaridine-artesunate in African countries.     

Adherence at 2 years with distribution of essential medicines at no charge: The CLEAN Meds randomized clinical trial

BackgroundAdherence to medicines is low for a variety of reasons, including the cost borne by patients. Some jurisdictions publicly fund medicines for the general population, but many jurisdictions do not, and such policies are contentious. To our knowledge, no trials studying free access to a wide range of medicines have been conducted.Methods and findingsWe randomly assigned 786 primary care patients who reported not taking medicines due to cost between June 1, 2016 and April 28, 2017 to either free distribution of essential medicines (n = 395) or to usual medicine access (n = 391). The trial was conducted in Ontario, Canada, where hospital care and physician services are publicly funded for the general population but medicines are not. The trial population was mostly female (56%), younger than 65 years (83%), white (66%), and had a low income from wages as the primary source (56%). The primary outcome was medicine adherence after 2 years. Secondary outcomes included control of diabetes, blood pressure, and low-density lipoprotein (LDL) cholesterol in patients taking relevant treatments and healthcare costs over 2 years. Adherence to all appropriate prescribed medicines was 38.7% in the free distribution group and 28.6% in the usual access group after 2 years (absolute difference 10.1%; 95% confidence interval (CI) 3.3 to 16.9, p = 0.004). There were no statistically significant differences in control of diabetes (hemoglobin A1c 0.27; 95% CI −0.25 to 0.79, p = 0.302), systolic blood pressure (−3.9; 95% CI −9.9 to 2.2, p = 0.210), or LDL cholesterol (0.26; 95% CI −0.08 to 0.60, p = 0.130) based on available data. Total healthcare costs over 2 years were lower with free distribution (difference in median CAN$1,117; 95% CI CAN$445 to CAN$1,778, p = 0.006). In the free distribution group, 51 participants experienced a serious adverse event, while 68 participants in the usual access group experienced a serious adverse event (p = 0.091). Participants were not blinded, and some outcomes depended on participant reports.ConclusionsIn this study, we observed that free distribution of essential medicines to patients with cost-related nonadherence substantially increased adherence, did not affect surrogate health outcomes, and reduced total healthcare costs over 2 years.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02744963","term_id":"NCT02744963"}}NCT02744963.     

Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study

BackgroundCirculating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD.Methods and findingsThe derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3–5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses.Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799–2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491–1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527–1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362–1.775), renin HR 1.501 (95% CI 1.305–1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297–1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307–1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243–1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131–1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226–1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255–1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316–1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134–1.396), spondin-1 HR 1.295 (95% CI 1.156–1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237–1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129–1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307–1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490–2.056).The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events.ConclusionsProfiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00799903","term_id":"NCT00799903"}}NCT00799903.

Niclas Eriksson and colleagues report associations between 157 cardiovascular plasma biomarkers and cardiovascular death in patients.     

Resistance exercise improves muscle strength,health status and pain intensity in fibromyalgia—a randomized controlled trial

IntroductionFibromyalgia (FM) is characterized by persistent widespread pain, increased pain sensitivity and tenderness. Muscle strength in women with FM is reduced compared to healthy women. The aim of this study was to examine the effects of a progressive resistance exercise program on muscle strength, health status, and current pain intensity in women with FM.MethodsA total of 130 women with FM (age 22–64 years, symptom duration 0–35 years) were included in this assessor-blinded randomized controlled multi-center trial examining the effects of progressive resistance group exercise compared with an active control group. A person-centred model of exercise was used to support the participants’ self-confidence for management of exercise because of known risks of activity-induced pain in FM. The intervention was performed twice a week for 15 weeks and was supervised by experienced physiotherapists. Primary outcome measure was isometric knee-extension force (Steve Strong®), secondary outcome measures were health status (FIQ total score), current pain intensity (VAS), 6MWT, isometric elbow-flexion force, hand-grip force, health related quality of life, pain disability, pain acceptance, fear avoidance beliefs, and patient global impression of change (PGIC). Outcomes were assessed at baseline and immediately after the intervention. Long-term follow up comprised the self-reported questionnaires only and was conducted after 13–18 months. Between-group and within-group differences were calculated using non-parametric statistics.ResultsSignificant improvements were found for isometric knee-extension force (p = 0.010), health status (p = 0.038), current pain intensity (p = 0.033), 6MWT (p = 0.003), isometric elbow flexion force (p = 0.02), pain disability (p = 0.005), and pain acceptance (p = 0.043) in the resistance exercise group (n = 56) when compared to the control group (n = 49). PGIC differed significantly (p = 0.001) in favor of the resistance exercise group at post-treatment examinations. No significant differences between the resistance exercise group and the active control group were found regarding change in self-reported questionnaires from baseline to 13–18 months.ConclusionsPerson-centered progressive resistance exercise was found to be a feasible mode of exercise for women with FM, improving muscle strength, health status, and current pain intensity when assessed immediately after the intervention.

Trial registration

ClinicalTrials.gov identification number: {"type":"clinical-trial","attrs":{"text":"NCT01226784","term_id":"NCT01226784"}}NCT01226784, Oct 21, 2010.     

Effectiveness of Group Problem Management Plus,a brief psychological intervention for adults affected by humanitarian disasters in Nepal: A cluster randomized controlled trial

BackgroundGlobally, 235 million people are impacted by humanitarian emergencies worldwide, presenting increased risk of experiencing a mental disorder. Our objective was to test the effectiveness of a brief group psychological treatment delivered by trained facilitators without prior professional mental health training in a disaster-prone setting.Methods and findingsWe conducted a cluster randomized controlled trial (cRCT) from November 25, 2018 through September 30, 2019. Participants in both arms were assessed at baseline, midline (7 weeks post-baseline, which was approximately 1 week after treatment in the experimental arm), and endline (20 weeks post-baseline, which was approximately 3 months posttreatment). The intervention was Group Problem Management Plus (PM+), a psychological treatment of 5 weekly sessions, which was compared with enhanced usual care (EUC) consisting of a family psychoeducation meeting with a referral option to primary care providers trained in mental healthcare. The setting was 72 wards (geographic unit of clustering) in eastern Nepal, with 1 PM+ group per ward in the treatment arm. Wards were eligible if they were in disaster-prone regions and residents spoke Nepali. Wards were assigned to study arms based on covariate constrained randomization. Eligible participants were adult women and men 18 years of age and older who met screening criteria for psychological distress and functional impairment. Outcomes were measured at the participant level, with assessors blinded to group assignment. The primary outcome was psychological distress assessed with the General Health Questionnaire (GHQ-12). Secondary outcomes included depression symptoms, posttraumatic stress disorder (PTSD) symptoms, “heart–mind” problems, social support, somatic symptoms, and functional impairment. The hypothesized mediator was skill use aligned with the treatment’s mechanisms of action. A total of 324 participants were enrolled in the control arm (36 wards) and 319 in the Group PM+ arm (36 wards). The overall sample (N = 611) had a median age of 45 years (range 18–91 years), 82% of participants were female, 50% had recently experienced a natural disaster, and 31% had a chronic physical illness. Endline assessments were completed by 302 participants in the control arm (36 wards) and 303 participants in the Group PM+ arm (36 wards). At the midline assessment (immediately after Group PM+ in the experimental arm), mean GHQ-12 total score was 2.7 units lower in Group PM+ compared to control (95% CI: 1.7, 3.7, p < 0.001), with standardized mean difference (SMD) of −0.4 (95% CI: −0.5, −0.2). At 3 months posttreatment (primary endpoint), mean GHQ-12 total score was 1.4 units lower in Group PM+ compared to control (95% CI: 0.3, 2.5, p = 0.014), with SMD of −0.2 (95% CI: −0.4, 0.0). Among the secondary outcomes, Group PM+ was associated with endline with a larger proportion attaining more than 50% reduction in depression symptoms (29.9% of Group PM+ arm versus 17.3% of control arm, risk ratio = 1.7, 95% CI: 1.2, 2.4, p = 0.002). Fewer participants in the Group PM+ arm continued to have “heart–mind” problems at endline (58.8%) compared to the control arm (69.4%), risk ratio = 0.8 (95% CI, 0.7, 1.0, p = 0.042). Group PM+ was not associated with lower PTSD symptoms or functional impairment. Use of psychosocial skills at midline was estimated to explain 31% of the PM+ effect on endline GHQ-12 scores. Adverse events in the control arm included 1 suicide death and 1 reportable incidence of domestic violence; in the Group PM+ arm, there was 1 death due to physical illness. Study limitations include lack of power to evaluate gender-specific effects, lack of long-term outcomes (e.g., 12 months posttreatment), and lack of cost-effectiveness information.ConclusionsIn this study, we found that a 5-session group psychological treatment delivered by nonspecialists modestly reduced psychological distress and depression symptoms in a setting prone to humanitarian emergencies. Benefits were partly explained by the degree of psychosocial skill use in daily life. To improve the treatment benefit, future implementation should focus on approaches to enhance skill use by PM+ participants.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03747055","term_id":"NCT03747055"}}NCT03747055.

Mark Jordans and co-workers evaluate a group therapy intervention in adults affected by psychological distress in Nepal.     

Interpersonal psychotherapy delivered by nonspecialists for depression and posttraumatic stress disorder among Kenyan HIV–positive women affected by gender-based violence: Randomized controlled trial

BackgroundHIV–positive women suffer a high burden of mental disorders due in part to gender-based violence (GBV). Comorbid depression and posttraumatic stress disorder (PTSD) are typical psychiatric consequences of GBV. Despite attention to the HIV-GBV syndemic, few HIV clinics offer formal mental healthcare. This problem is acute in sub-Saharan Africa, where the world’s majority of HIV–positive women live and prevalence of GBV is high.Methods and findingsWe conducted a randomized controlled trial at an HIV clinic in Kisumu, Kenya. GBV-affected HIV–positive women with both major depressive disorder (MDD) and PTSD were randomized to 12 sessions of interpersonal psychotherapy (IPT) plus treatment as usual (TAU) or Wait List+TAU. Nonspecialists were trained to deliver IPT inside the clinic. After 3 months, participants were reassessed, and those assigned to Wait List+TAU were given IPT. The primary outcomes were diagnosis of MDD and PTSD (Mini International Neuropsychiatric Interview) at 3 months. Secondary outcomes included symptom measures of depression and PTSD, intimate partner violence (IPV), and disability. A total of 256 participants enrolled between May 2015 and July 2016. At baseline, the mean age of the women in this study was 37 years; 61% reported physical IPV in the past week; 91% reported 2 or more lifetime traumatic events and monthly income was 18USD. Multilevel mixed-effects logistic regression showed that participants randomized to IPT+TAU had lower odds of MDD (odds ratio [OR] 0.26, 95% CI [0.11 to 0.60], p = 0.002) and lower odds of PTSD (OR 0.35, [0.14 to 0.86], p = 0.02) than controls. IPT+TAU participants had lower odds of MDD-PTSD comorbidity than controls (OR 0.36, 95% CI [0.15 to 0.90], p = 0.03). Linear mixed models were used to assess secondary outcomes: IPT+TAU participants had reduced disability (−6.9 [−12.2, −1.5], p = 0.01), and nonsignificantly reduced work absenteeism (−3.35 [−6.83, 0.14], p = 0.06); partnered IPT+TAU participants had a reduction of IPV (−2.79 [−5.42, −0.16], p = 0.04). Gains were maintained across 6-month follow-up. Treatment group differences were observed only at month 3, the time point at which the groups differed in IPT status (before cross over). Study limitations included 35% attrition inclusive of follow-up assessments, generalizability to populations not in HIV care, and data not collected on TAU resources accessed.ConclusionsIPT for MDD and PTSD delivered by nonspecialists in the context of HIV care yielded significant improvements in HIV–positive women’s mental health, functioning, and GBV (IPV) exposure, compared to controls.Trial registrationClinical Trials Identifier {"type":"clinical-trial","attrs":{"text":"NCT02320799","term_id":"NCT02320799"}}NCT02320799.

Susan Meffert and co-workers evaluate interpersonal psychotherapy for treatment of psychiatric disorders in women with HIV infection in Kenya.     

Low numbers of blood and salivary natural killer cells are associated with a better response to belimumab in primary Sj?gren’s syndrome: results of the BELISS study

IntroductionIn this study, we sought to address changes in blood lymphocyte subpopulations and labial salivary gland (LSG) inflammation after belimumab treatment in patients with primary Sjögren’s syndrome (pSS) and to identify predictors of response to treatment.MethodsSequential blood lymphocyte subsets and LSG biopsies were analysed between week 0 (W0) and W28 in 15 patients with pSS treated with belimumab. Systemic response to treatment was defined as a decrease in the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index score of ≥3 points at W28.ResultsAfter belimumab, we observed a decrease in blood B lymphocytes primarily involving CD27-negative/immunoglobulin D–positive naïve B cells (p=0.008). Lymphocytic sialadenitis (focus score >1) that was present in 12 patients (80.0 %) before belimumab treatment became negative in 5 of them after treatment (p=0.03). The median (interquartile range) LSG B-cell/T-cell ratio decreased from 0.58 (0.5–0.67) to 0.50 (0.5–0.5) (p=0.06). B-cell activating factor (BAFF) staining was detected in 11 (78.6 %) of 14 patients before belimumab treatment compared with 7 (50.0 %) of 14 after belimumab therapy (p=0.10). The median percentage of BAFF-positive cells in foci significantly decreased from 27.5 % (10–40) to 5 % (0–20) (p=0.03). A systemic response was achieved in six patients (40 %). The only predictor of response was the presence of a low number of natural killer (NK) cells, both in blood (8.5 % [7–10] vs 11 % [9–21]; p=0.04) and in LSG (20.6/mm³ [20.0–21.4] vs 30.0/mm³ [25.0–100.0], p=0.003). Serum BAFF levels did not influence response to treatment.ConclusionsLow blood and salivary NK cell numbers are associated with a better response to belimumab. This suggests that two distinct subsets of pSS may exist: one with a predominant type I interferon (IFN)–BAFF–B-cell axis, representing good responders to belimumab; and one with a predominant type II IFN–NK cell axis, representing non-responders.

Trial registration

ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01160666","term_id":"NCT01160666"}}NCT01160666. Registered 9 July 2010.     

Effectiveness of a primary care-based integrated mobile health intervention for stroke management in rural China (SINEMA): A cluster-randomized controlled trial

BackgroundManaging noncommunicable diseases through primary healthcare has been identified as the key strategy to achieve universal health coverage but is challenging in most low- and middle-income countries. Stroke is the leading cause of death and disability in rural China. This study aims to determine whether a primary care-based integrated mobile health intervention (SINEMA intervention) could improve stroke management in rural China.Methods and findingsBased on extensive barrier analyses, contextual research, and feasibility studies, we conducted a community-based, two-arm cluster-randomized controlled trial with blinded outcome assessment in Hebei Province, rural Northern China including 1,299 stroke patients (mean age: 65.7 [SD:8.2], 42.6% females, 71.2% received education below primary school) recruited from 50 villages between June 23 and July 21, 2017. Villages were randomly assigned (1:1) to either the intervention or control arm (usual care). In the intervention arm, village doctors who were government-sponsored primary healthcare providers received training, conducted monthly follow-up visits supported by an Android-based mobile application, and received performance-based payments. Participants received monthly doctor visits and automatically dispatched daily voice messages. The primary outcome was the 12-month change in systolic blood pressure (BP). Secondary outcomes were predefined, including diastolic BP, health-related quality of life, physical activity level, self-reported medication adherence (antiplatelet, statin, and antihypertensive), and performance in “timed up and go” test. Analyses were conducted in the intention-to-treat framework at the individual level with clusters and stratified design accounted for by following the prepublished statistical analysis plan. All villages completed the 12-month follow-up, and 611 (intervention) and 615 (control) patients were successfully followed (3.4% lost to follow-up among survivors). The program was implemented with high fidelity, and the annual program delivery cost per capita was US$24.3. There was a significant reduction in systolic BP in the intervention as compared with the control group with an adjusted mean difference: −2.8 mm Hg (95% CI −4.8, −0.9; p = 0.005). The intervention was significantly associated with improvements in 6 out of 7 secondary outcomes in diastolic BP reduction (p < 0.001), health-related quality of life (p = 0.008), physical activity level (p < 0.001), adherence in statin (p = 0.003) and antihypertensive medicines (p = 0.039), and performance in “timed up and go” test (p = 0.022). We observed reductions in all exploratory outcomes, including stroke recurrence (4.4% versus 9.3%; risk ratio [RR] = 0.46, 95% CI 0.32, 0.66; risk difference [RD] = 4.9 percentage points [pp]), hospitalization (4.4% versus 9.3%; RR = 0.45, 95% CI 0.32, 0.62; RD = 4.9 pp), disability (20.9% versus 30.2%; RR = 0.65, 95% CI 0.53, 0.79; RD = 9.3 pp), and death (1.8% versus 3.1%; RR = 0.52, 95% CI 0.28, 0.96; RD = 1.3 pp). Limitations include the relatively short study duration of only 1 year and the generalizability of our findings beyond the study setting.ConclusionsIn this study, a primary care-based mobile health intervention integrating provider-centered and patient-facing technology was effective in reducing BP and improving stroke secondary prevention in a resource-limited rural setting in China.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03185858","term_id":"NCT03185858"}}NCT03185858.

Lijing Yan and colleagues evaluate a mobile health intervention for secondary stroke prevention in China.     

Renal Outcomes of Pioglitazone Compared with Acarbose in Diabetic Patients: A Randomized Controlled Study

ObjectiveTo assess the effect of pioglitazone on renal outcome, including urinary albumin excretion and estimated glomerular filtration rate (eGFR), in diabetic patients.DesignA prospective, randomized, open-labeled, controlled study.SettingTaipei Veterans General Hospital.PatientsSixty type 2 diabetic patients treated with sulfonylureas and metformin, whose glycated hemoglobin (HbA1c) levels were between 7% and 10% and eGFR was between 45 and 125 mL/min/1.73 m².InterventionThe patients were randomized to receive acarbose or pioglitazone and followed up for 6 months. Thirty patients were randomly assigned to receive acarbose, and 30 patients were assigned to receive pioglitazone.MeasurementsThe primary study endpoint was the changes in the urinary albumin-to-creatinine ratio (UACR). The secondary endpoint was the changes in eGFR and other parameters.ResultsAfter 6 months of treatment, the mean changes in UACR were −18 ± 104 and 12 ± 85 (p = 0.25, between groups) for the acarbose and pioglitazone groups, respectively. The mean changes in eGFR were 0 ± 14 and −7 ± 16 mL/min/1.73 m² (p = 0.09, between groups) for the acarbose and pioglitazone groups, respectively. The reductions in HbA1c were similar in both groups. Fasting blood glucose was lower in the pioglitazone group than in the acarbose group. Significant body weight gain was observed in the pioglitazone group as compared with the acarbose group (1.3 ± 2.8 vs. −0.6 ± 1.5 kg, p = 0.002).ConclusionIn type 2 diabetic patients who were treated with sulfonylureas and metformin and possessed HbA1c levels between 7% and 10%, additional acarbose or pioglitazone for 6 months provided similar glycemic control and eGFR and UACR changes. In the pioglitazone group, the patients exhibited significant body weight gain.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01175486","term_id":"NCT01175486"}}NCT01175486     

Diagnostic performance of a Recombinant Polymerase Amplification Test—Lateral Flow (RPA-LF) for cutaneous leishmaniasis in an endemic setting of Colombia

BackgroundControl of cutaneous leishmaniasis by public health systems in the Americas relies on case identification and treatment. Point-of-care diagnostics that can be performed by health workers within or near affected communities could effectively bring the health system to the resource-limited sites providing early diagnosis and treatment, reducing morbidity and the burden of disease.Methodology/principal findingsA cross-sectional study was undertaken to evaluate the diagnostic test performance of Isothermal Recombinase Polymerase Amplification (RPA) targeting Leishmania kinetoplast DNA, coupled with a lateral flow (LF) immunochromatographic strip, in a field setting and a laboratory reference center. Minimally invasive swab and FTA filter paper samples were obtained by community health workers and highly trained technicians from ulcerated lesions of > 2 weeks’ evolution from 118 patients’ ≥ 2 years of age in the municipality of Tumaco, Nariño. Extracted DNA was processed by RPA-LF at a reference center or in a primary health facility in the field. Evaluation was based on a composite “gold standard” that included microscopy, culture, biopsy and real-time polymerase chain reaction detection of Leishmania 18S rDNA. Standard of care routine diagnostic tests were explored as comparators.Sensitivity and specificity of RPA-LF in the reference lab scenario were 87% (95%CI 74–94) and 86% (95%CI 74–97), respectively. In the field scenario, the sensitivity was 75% (95%CI 65–84) and specificity 89% (95%CI 78–99). Positive likelihood ratios in both scenarios were higher than 6 while negative likelihood ratios ranged to 0.2–0.3 supporting the usefulness of RPA-LF to rule-in and potentially to rule-out infection.Conclusions/significanceThe low complexity requirements of RPA-LF combined with non-invasive sampling support the feasibility of its utilization by community health workers with the goal of strengthening the diagnostic capacity for cutaneous leishmaniasis in Colombia.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT04500873","term_id":"NCT04500873"}}NCT04500873.     

Treatment of W. bancrofti (Wb) in HIV/Wb Coinfections in South India

BackgroundThe disease course of human immunodeficiency virus (HIV) is often altered by existing or newly acquired coincident infections.Conclusions/SignificanceWe were unable to find a significant effect of W. bancrofti infection or its treatment on HIV clinical course or surrogate markers of HIV disease progression though we recognized that our study was limited by the smaller than predicted sample size and by the use of ART in half of the patients. Treatment of W. bancrofti coinfection in HIV positive subjects (as is usual in mass drug administration campaigns) did not represent an increased risk to the subjects, and should therefore be considered for PLWHA living in W. bancrofti endemic areas.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00344279","term_id":"NCT00344279"}}NCT00344279     

Comparative palatability of orally disintegrating tablets (ODTs) of Praziquantel (L-PZQ and Rac-PZQ) versus current PZQ tablet in African children: A randomized,single-blind,crossover study

BackgroundPraziquantel (PZQ) is currently the only recommended drug for infection and disease caused by the schistosome species that infects humans; however, the current tablet formulation is not suitable for pre-school age children mainly due to its bitterness and the large tablet size. We assessed the palatability of two new orally disintegrating tablet (ODT) formulations of PZQ.MethodologyThis randomized, single-blind, crossover, swill-and-spit palatability study ({"type":"clinical-trial","attrs":{"text":"NCT02315352","term_id":"NCT02315352"}}NCT02315352) was carried out at a single school in Tanzania in children aged 6–11 years old, with or without schistosomiasis infection as this was not part of the assessment. Children were stratified according to age group (6–8 years or 9–11 years) and gender, then randomized to receive each formulation in a pre-specified sequence. Over 2 days, the children assessed the palatability of Levo-Praziquantel (L-PZQ) ODT 150 mg and Racemate Praziquantel (Rac-PZQ) ODT 150 mg disintegrated in the mouth without water on the first day, and L-PZQ and Rac-PZQ dispersed in water and the currently available PZQ 600 mg formulation (PZQ-Cesol) crushed and dispersed in water on the second day. The palatability of each formulation was rated using a 100 mm visual analogue scale (VAS) incorporating a 5-point hedonic scale, immediately after spitting out the test product (VAS_{t = 0} primary outcome) and after 2–5 minutes (VAS_{t = 2–5}).Principal findingsIn total, 48 children took part in the assessment. Overall, there was no reported difference in the VAS_{t = 0} between the two ODT formulations (p = 0.106) without water. Higher VAS_{t = 0} and VAS_{t = 2–5} scores were reported for L-PZQ ODT compared with Rac-PZQ ODT in older children (p = 0.046 and p = 0.026, respectively). The VAS_{t = 0} and VAS_{t = 2–5} were higher for both ODT formulations compared with the standard formulation (p<0.001 for both time points). No serious adverse events were reported.Conclusions/SignificanceThe new paediatric-friendly formulations dispersed in water were both found to be more palatable than the existing standard formulation of PZQ. There may be gender and age effects on the assessment of palatability. Further research is needed for assessing efficacy and tolerability of the newly ODTs Praziquantel drug in younger children.Trial registrationThe trial was registered on ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT02315352","term_id":"NCT02315352"}}NCT02315352) and in the Pan African Clinical Trials Registry (PACTR201412000959159).     

Miltefosine for the treatment of cutaneous leishmaniasis—A pilot study from Ethiopia

BackgroundCutaneous leishmaniasis (CL) in Ethiopia, caused by Leishmania aethiopica, is often severe and hard to treat compared to CL caused by other species elsewhere. Miltefosine is the only oral anti-leishmanial drug, with a favorable side-effect profile compared to routinely available sodium stibogluconate (SSG), but evidence about its use for L. aethiopica is lacking.Methodology and principal findingsIn an observational cohort study, treatment outcomes, safety and adherence among CL patients who required systemic treatment and received miltefosine for 28 days in Boru Meda Hospital and University of Gondar Hospital were studied. Patient cure was defined as 100% flattening for non-ulcerated lesions and 100% flattening and 100% re-epithelization for ulcerated lesions. Outcomes were documented for day 28, 90 and 180, both per site, and pooled, adjusting for site as a fixed effect with effect coding. Among 94 included patients (32 in Gondar, 62 in Boru Meda), median lesion duration was 12 months, median size six cm, and mucosal involvement (46.8%) and diffuse (30.9%) lesions were common. Adherence to miltefosine was good, and side-effects were tolerable. Initial outcomes at day 28 were promising, with 68.8% and 94.0% of patients having good improvement or cure in Gondar and Boru Meda respectively. In Boru Meda, outcomes were good with 72.7% and 72.9% cure at day 90 and day 180 respectively. In Gondar, results were less promising, with only 12.5% and 26.7% cure at day 90 and day 180, although confidence intervals were wide. In pooled estimates, 48.7% of patients reached cure at day 180, and 32.3% relapsed. Outcomes were better in Boru Meda Hospital, for smaller lesions and for mucosal lesions.Conclusions/SignificanceBased on miltefosine’s good initial response, tolerable side-effects, tablet-form, we propose to include miltefosine for future clinical trials using extended treatment schedules, combination therapy, or targeting specific subgroups.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT04004754","term_id":"NCT04004754"}}NCT04004754.     

Efficacy and safety of apatinib for the treatment of AFP-producing gastric cancer

BackgroundAlpha-fetoprotein-producing gastric cancer (AFPGC) poses a therapeutic challenge worldwide because of its poor prognosis. This study aimed to evaluate the efficacy and safety of antiangiogenic drug apatinib in advanced AFPGC in a real-world setting.MethodsFrom September 2015 to December 2017, twenty-one patients identified with AFPGC from the clinical trial AHEAD-G202, an open-label, prospective, multicenter, non-interventional study of apatinib for advanced metastatic gastric cancer, were enrolled to perform this analysis. Patients received oral apatinib as monotherapy or combination therapy. A treatment cycle was defined as 28 days. The primary outcome was progression-free survival (PFS) and overall survival (OS), and the secondary outcomes included safety, objective response rate (ORR), and disease control rate (DCR).ResultsTwenty patients were evaluated for the apatinib efficacy analysis. The ORR of apatinib was 10%, whereas the DCR was 70%. The median PFS was 3.5 months [95%confidence interval (CI): 2.34–4.66]. The median OS was 4.5 months (95%CI: 3.49–5.51). Median OS of AFPGC patients without carcinoembryonic antigen (CEA) elevation achieved 30.8 months. CEA elevation was considered to be a potential independent predictive factor for OS (P = 0.030) and PFS (P = 0.047) by the analysis of multivariate analysis. The most common grade 3 to 4 adverse events (AEs) were hypertension (4.8%), hand-foot syndrome (4.8%), anorexia (4.8%), and vomiting and nausea (4.8%).ConclusionApatinib showed promising efficacy and an acceptable safety profile in patients with advanced AFPGC. Antiangiogenic therapy may be a good strategy for the treatment of AFPGC as a rare sub-type of gastric cancer.Trial registrationAHEAD-G202 ({"type":"clinical-trial","attrs":{"text":"NCT02668380","term_id":"NCT02668380"}}NCT02668380).     

The 5-HT1A receptor agonist buspirone improves esophageal motor function and symptoms in systemic sclerosis: a 4-week,open-label trial

BackgroundAcute administration of the oral 5-HT₁A receptor agonist buspirone, which is commonly used as an anxiolytic drug, may improve compromised lower esophageal sphincter function. In an open-label trial we assessed the effects of buspirone on esophageal motor function and symptoms in patients with esophageal involvement associated with systemic sclerosis (SSc).MethodsThirty consecutive patients with SSc and symptomatic esophageal involvement, despite treatment with proton pump inhibitors, underwent high resolution manometry and chest computed tomography for assessment of motor function and esophageal dilatation, respectively. Regurgitation, heartburn, dysphagia, and chest pain severity was subjectively scored by visual analog scales. Manometric parameters (primary endpoint) and symptom severity (secondary endpoint) were re-examined after 4-week daily administration of 20 mg buspirone. Other medications remained unchanged.ResultsEight patients did not complete the trial because of buspirone-associated dizziness (n = 2), or nausea (n = 2), or reluctancy to undergo final manometry. In the remaining 22 patients lower esophageal sphincter (LES) resting pressure increased from 7.7 ± 3.9 to 12.2 ± 4.6 mmHg (p = 0.00002) after buspirone administration; other manometric parameters did not change. Statistical analysis revealed negative correlation between individual increases in resting LES pressure and supra-aortic esophageal diameter (r = -0.589, p = 0.017), suggesting a more beneficial effect in patients with less severely affected esophageal function. Heartburn and regurgitation scores decreased at 4 weeks compared to baseline (p = 0.001, and p = 0.022, respectively).ConclusionOur findings warrant more conclusive evaluation with a double-blind controlled study; however, buspirone could potentially be given under observation for objective improvement in all patients with SSc who report reflux symptoms despite undergoing standard treatment.

Trial registration

ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02363478","term_id":"NCT02363478"}}NCT02363478 Registered: 21-02-2014.     

Modeling of In-Utero and Intra-Partum Transmissions to Evaluate the Efficacy of Interventions for the Prevention of Perinatal HIV

BackgroundAntiretroviral treatments decrease HIV mother-to-child transmission through pre/post exposure prophylaxis and reduction of maternal viral load. We modeled in-utero and intra-partum HIV transmissions to investigate the preventive role of various antiretroviral treatments interventions.MethodsWe analysed data from 3,759 women-infant pairs enrolled in 3 randomized clinical trials evaluating (1) zidovudine monotherapy, (2) zidovudine plus perinatal single-dose nevirapine or (3) zidovudine plus lopinavir/ritonavir for the prevention of mother-to-child transmission of HIV in Thailand. All infants were formula-fed. Non-linear mixed effect modeling was used to express the viral load evolution under antiretroviral treatments and the probability of transmission.ResultsMedian viral load was 4 log₁₀ copies/mL (Interquartile range: 3.36–4.56) before antiretroviral treatments initiation. An Emax model described the viral load time-course during pregnancy. Half of the maximum effect of zidovudine (28% decrease) and lopinavir/ritonavir (72% decrease) were achieved after 98 and 12 days, respectively. Adjusted on viral load at baseline (Odds ratio = 1.50 [95% confidence interval: 1.34, 1.68] per log₁₀ copies/mL increment), antiretroviral treatments duration (OR = 0.80 [0.75, 0.84] per week increment) but not the nature of antiretroviral treatments were associated with in-utero transmission. Adjusted on gestational age at delivery (<37 weeks, OR = 2.37 [1.37, 4.10]), baseline CD4 (Odds ratio = 0.79 [0.72, 0.88] per 100 cells/mm3 increment) and predicted viral load at delivery (OR = 1.47 [1.25, 1.64] per log₁₀ copies/mL increment), single-dose nevirapine considerably reduced intra-partum transmission (OR = 0.32 [0.2, 0.51]).ConclusionThese models determined the respective contributions of various antiretroviral strategies on prevention of mother-to-child transmission. This can help predict the efficacy of new antiretroviral treatments and/or prevention of mother-to-child transmission strategies particularly for women with no or late antenatal care who are at high risk of transmitting HIV to their offspring.

Trial Registration

This analysis is based on secondary data obtained from three clinical trials. ClinicalTrials.gov. {"type":"clinical-trial","attrs":{"text":"NCT00386230","term_id":"NCT00386230"}}NCT00386230, {"type":"clinical-trial","attrs":{"text":"NCT00398684","term_id":"NCT00398684"}}NCT00398684, {"type":"clinical-trial","attrs":{"text":"NCT00409591","term_id":"NCT00409591"}}NCT00409591.