A multifaceted risk management program to improve the reporting rate of patient safety incidents in primary care: a cluster-randomised controlled trial.

BACKGROUND: While patient safety incident reporting is of key importance for patient safety in primary care, the reporting rate by healthcare professionals remains low. This study aimed to assess the effectiveness of a risk management program in increasing the reporting rate within multiprofessional primary care facilities. METHODS: A nation-wide cluster-randomised controlled trial was performed in France, with each cluster defined as a primary care facility. The intervention included professional e-learning training, identification of a risk management advisor, and multidisciplinary meetings to address incident analysis. In the first observational period, a patient safety incident reporting system for professionals was implemented in all facilities. Then, facilities were randomised, and the program was implemented. Incidents were reported over the 15-month study period. Quasi-Poisson models were used to compare reporting rates. RESULTS: Thirty-five facilities (intervention, n = 17; control, n = 18) were included, with 169 and 232 healthcare professionals, respectively, involved. Overall, 7 out of 17 facilities carried out the entire program (41.2%), while 6 did not hold meetings (35.3%); 48.5% of professionals logged on to the e-learning website. The relative rate of incidents reported was 2.7 (95% CI = [0.84-11.0]; p = 0.12). However, a statistically significant decrease in the incident rate between the pre-intervention and post-intervention periods was observed for the control arm (HR = 0.2; 95% CI = [0.05-0.54]; p = 0.02), but not for the intervention arm (HR = 0.54; 95% CI = [0.2-1.54]; p = 0.23). CONCLUSION: This program didn't lead to a significant improvement in the patient safety incident reporting rate by professionals but seemed to sustain reporting over time. Considering that the program was fully implemented in only 41% of facilities, this highlights the difficulty of implementing such multidisciplinary programs in primary care despite its adaptation to the setting. A better understanding of how risk management is currently organized in these multiprofessional facilities is of key importance to improve patient safety in primary care. TRIAL REGISTRATIONS: The study has been registered at clinicaltrials.gov (NCT02403388) on 30 March 2015.

Bevacizumab, olaparib, and durvalumab in patients with relapsed ovarian cancer: a phase II clinical trial from the GINECO group.

Most patients with advanced ovarian cancer (AOC) ultimately relapse after platinum-based chemotherapy. Combining bevacizumab, olaparib, and durvalumab likely drives synergistic activity. This open-label phase 2 study (NCT04015739) aimed to assess activity and safety of this triple combination in female patients with relapsed high-grade AOC following prior platinum-based therapy. Patients were treated with olaparib (300 mg orally, twice daily), the bevacizumab biosimilar FKB238 (15 mg/kg intravenously, once-every-3-weeks), and durvalumab (1.12 g intravenously, once-every-3-weeks) in nine French centers. The primary endpoint was the non-progression rate at 3 months for platinum-resistant relapse or 6 months for platinum-sensitive relapse per RECIST 1.1 and irRECIST. Secondary endpoints were CA-125 decline with CA-125 ELIMination rate constant K (KELIM-B) per CA-125 longitudinal kinetics over 100 days, progression free survival and overall survival, tumor response, and safety. Non-progression rates were 69.8% (90%CI 55.9%-80.0%) at 3 months for platinum-resistant relapse patients (N = 41), meeting the prespecified endpoint, and 43.8% (90%CI 29.0%-57.4%) at 6 months for platinum-sensitive relapse (N = 33), not meeting the prespecified endpoint. Median progression-free survival was 4.1 months (95%CI 3.5-5.9) and 4.9 months (95%CI 2.9-7.0) respectively. Favorable KELIM-B was associated with better survival. No toxic deaths or major safety signals were observed. Here we show that further investigation of this triple combination may be considered in AOC patients with platinum-resistant relapse.

Efficacy and safety of one anastomosis gastric bypass versus Roux-en-Y gastric bypass at 5 years (YOMEGA): a prospective, open-label, non-inferiority, randomised extension study.

BACKGROUND: The multicentre randomised trial YOMEGA (NCT02139813) comparing the one anastomosis gastric bypass (OAGB) with the Roux-en-Y gastric bypass (RYGB) confirmed the non-inferiority of OAGB on weight loss outcomes at 24 months. We aimed to report weight loss, metabolic, and safety outcomes at 5 years. METHODS: YOMEGA is a prospective, open-label, non-inferiority, randomised trial conducted at nine centres in France. Inclusion criteria were BMI of 40 kg/m2 or more, or 35 kg/m2 or more with comorbidities. Key exclusion criteria were severe gastro-oesophageal reflux disease or Barrett's oesophagus and previous bariatric surgery. Patients were randomly assigned (1 :1) to OAGB (one gastrojejunal anastomosis with a 200 cm biliopancreatic limb) or RYGB (with a 150 cm alimentary limb and a 50 cm biliary limb), stratified by centre, with blocks of variable size. The primary endpoint of this extension study was percentage excess BMI loss and was analysed in the per-protocol population, including patients with data who were operated on with the technique randomly assigned to them and excluding patients with major deviations from the protocol during the follow-up (change of surgical technique, death, or withdrawal of consent). Non-inferiority was concluded for the primary endpoint if the upper bound of the CI was less than the non-inferiority limit (7 percentage points). YOMEGA is registered with ClinicalTrials.gov, NCT02139813, and the 5-year follow-up of YOMEGA is registered with ClinicalTrials.gov, NCT05549271. FINDINGS: Between May 13, 2014, and March 2, 2016, 253 patients were randomly assigned to OAGB (n=129) or RYGB (n=124), and from these patients 114 in the OAGB group and 118 in the RYGB group were included in the per-protocol analysis. In the per-protocol population, at baseline, mean age was 43·0 years (SD 10·8), mean BMI was 44·0 kg/m2 (5·6), 54 (23%) patients were male and 178 (77%) were female; 55 (27%) of 207 patients had type 2 diabetes. After 5 years, mean percentage excess BMI loss was -75·6% (SD 28·1) in the OAGB group versus -71·4% (SD 29·8) in the RYGB group, confirming non-inferiority (mean difference -4·1% [90% CI -12·0 to 3·7], p=0·0099). Remission of type 2 diabetes was similar in both groups. Nutritional status did not differ; the most common adverse event was clinical gastro-oesophageal reflux disease, occurring in 27 (41%) of 66 patients in the OAGB group versus 14 (18%) of 76 patients in the RYGB group (p=0·0030). Among serious adverse events, ten (8%) of 127 patients converted from OAGB to RYGB. 171 (68%) of 253 patients were followed up. INTERPRETATION: OAGB was not inferior to RYGB regarding percentage excess BMI loss at 5 years with similar metabolic outcomes. The high rate of clinical gastro-oesophageal reflux disease after OAGB raises questions about its long-term consequences, which need to be further investigated. FUNDING: Medtronic.

A Multicenter Cohort Study on 301 Tissue-Level Implants: Cumulative Implant Survival Rate and Marginal Bone Level Change up to 4.5 Years.

PURPOSE: To retrospectively determine the cumulative survival rate (CSR) and marginal bone level change (ΔMBL) around novel hybrid design tissue-level (TL) dental implants that support multiple-screw-retained restorations. MATERIALS AND METHODS: Implant CSRs were analyzed at the implant and patient level using Kaplan-Meier estimates. ΔMBL was measured by comparing the periapical loading and follow-up visit radiographs using an improved standardized digital methodology based on image gray levels. ΔMBL outcomes were subject to linear mixed regression to identify potential risk factors. RESULTS: A total of 301 TL implants in 69 patients with an average age of 62.6 ± 11.7 years (range: 36 to 87 years) at the time of implant placement were considered for the analysis. All 301 implants were successfully restored and loaded. The 54-month CSRs at the implant and patient levels were 98.9% (95% CI: 96.7 to 99.6) and 95.3% (95% CI: 86.1 to 98.5), respectively. ΔMBL after a mean follow-up of 22 ± 10.7 months after loading was 0.00 ± 0.57 mm. None of the implant sites showed marginal bone loss exceeding 1.5 mm. Multivariate regression analysis revealed a significant association between ΔMBL and the loading protocol (P = .027) but not between ΔMBL and age or transgingival height. CONCLUSIONS: The high CSRs and stable peri-implant marginal bone levels support the use of recent TL implants, which have a hybrid design inherited from the bone-level implant-abutment connection, as a suitable treatment option for restoring partially or fully edentulous patients with a good mid-term prognosis. These results should be complemented by further prospective studies in a real-world multicenter private practice setup that represents the daily realities of implant treatment.

Anesthesia practices for management of labor pain and cesarean delivery in France (EPIDOL): A cross-sectional survey.

BACKGROUND: This study aimed to collect obstetric anesthesia practice and patient-reported outcomes as an update to the last French Obstetric Anesthesia survey from 1996. METHODS: Maternity units were randomly selected across France and surveyed for 7 consecutive days from February, 2016, to January, 2017. Data was gathered prospectively by questionnaires filled out by patients and anesthesia providers. RESULTS: There were 1885 questionnaires received from 56 units, with 379 cesarean delivery (CD) and 1506 vaginal delivery (VD) cases analyzed. The overall neuraxial labor analgesia (NLA) rate was 82.5% (95% CI [82.4-82.6]), with 70.3% (95% CI [71.4-71.6]) receiving automated administration (PCEA/PIEB). NLA was effective throughout labor in 68.2% of cases, however, severe pain was reported by 29.4% of patients. The overall rate of alternative approaches for labor analgesia was 19.5% (95%CI [19.2-19.7]). Obesity (OR 2.8; 95% CI [1.0-7.5], p < 0.04) and delivery in level I units (OR 0.6; 95% CI [0.5-0.9], p < 0.01) were associated with severe pain during VD. Satisfaction was found to be similar in patients delivering with or without NLA. The incidence of pain during CD was similar in scheduled versus non-scheduled CD. Failure of NLA during CD was associated with severe pain (OR 10.0; 95% CI [3.1-31.9], p < 0.01) and dissatisfaction (OR 26.2; 95% CI [3.0-225.1], p < 0.01). CONCLUSION: Despite the high NLA rate in France, a significant proportion of women experience severe pain during labor and delivery. This study emphasizes the need for further practice guidelines in obstetric anesthesia to ensure optimal pain management and improve patients' experience during childbirth. CLINICALTRIALS: govNCT02853890.

Lack of reproducibility of histopathological features in MYC-rearranged large B cell lymphoma using digital whole slide images: a study from the Lunenburg lymphoma biomarker consortium.

AIMS: Subclassification of large B cell lymphoma (LBCL) is challenging due to the overlap in histopathological, immunophenotypical and genetic data. In particular, the criteria to separate diffuse large B cell lymphoma (DLBCL) and high-grade B cell lymphoma (HGBL) are difficult to apply in practice. The Lunenburg Lymphoma Biomarker Consortium previously reported a cohort of over 5000 LBCL that included fluorescence in-situ hybridisation (FISH) data. This cohort contained 209 cases with MYC rearrangement that were available for a validation study by a panel of eight expert haematopathologists of how various histopathological features are used. METHODS AND RESULTS: Digital whole slide images of haematoxylin and eosin-stained sections allowed the pathologists to visually score cases independently as well as participate in virtual joint review conferences. Standardised consensus guidelines were formulated for scoring histopathological features and included overall architecture/growth pattern, presence or absence of a starry-sky pattern, cell size, nuclear pleomorphism, nucleolar prominence and a range of cytological characteristics. Despite the use of consensus guidelines, the results show a high degree of discordance among the eight expert pathologists. Approximately 50% of the cases lacked a majority score, and this discordance spanned all six histopathological features. Moreover, none of the histological variables aided in prediction of MYC single versus double/triple-hit or immunoglobulin-partner FISH-based designations or clinical outcome measures. CONCLUSIONS: Our findings indicate that there are no specific conventional morphological parameters that help to subclassify MYC-rearranged LBCL or select cases for FISH analysis, and that incorporation of FISH data is essential for accurate classification and prognostication.

Avelumab in patients with gestational trophoblastic tumors with resistance to polychemotherapy: Cohort B of the TROPHIMMUN phase 2 trial.

PURPOSE: There is a need for innovative treatments in women with gestational trophoblastic tumors (GTT) resistant to chemotherapy. The TROPHIMMUN trial assessed the efficacy of avelumab in patients with resistance to single-agent chemotherapy (cohort A), or to polychemotherapy (cohort B). Cohort B outcomes are reported here. METHODS: In the cohort B of this phase 2 multicenter trial (NCT03135769), women with GTT progressing after polychemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. The primary endpoint was the rate of hCG normalization enabling treatment discontinuation (2-stage Simon design). RESULTS: Between February 2017 and August 2020, 7 patients were enrolled. Median age was 37 years (range: 29-47); disease stage was I or III in 42.9% and 57.1%; FIGO score was 9-10 in 28.6%, 11 in 28.6%, and 16 in 14.3%, respectively. Median follow-up was 18.2 months. One patient (14.3%) experienced hCG normalization enabling treatment discontinuation. However, resistance to avelumab was observed in the remaining 6 patients (85.7%). The cohort B was stopped for futility. Grade 1-2 treatment-related adverse events occurred in 57.1%, most commonly fatigue (42.9%), nausea, diarrhea, infusion-related reaction, muscle pains, dry eyes (each 14.3%). The median resistance-free survival was 1.4 months (95% CI 0.7-5.3). CONCLUSIONS: Although avelumab is active in patients with single-agent chemotherapy-resistant GTT (cohort A), it was associated with limited efficacy in patients with resistance to polychemotherapy (cohort B). The prognosis of patients with polychemotherapy resistance remains poor, and innovative immunotherapy-based therapeutic combinations are needed.

COMPARISON OF PRIMARY AND SECONDARY FORMS OF MULTIPLE EVANESCENT WHITE DOT SYNDROME.

PURPOSE: The aim of this study was to compare primary versus secondary forms of multiple evanescent white dot syndrome (MEWDS) at T0 (baseline) and T1 (1-4 months after the onset of symptoms). METHODS: A total of 101 eyes in 100 patients were included in a multicentric retrospective study. RESULTS: Secondary MEWDS was defined as MEWDS associated with underlying chorioretinal inflammatory pathologies, mainly multifocal choroiditis and punctuate inner choroidopathy. Patients with secondary MEWDS were older (P = 0.011). The proportion of women (P = 0.8), spherical equivalent (P = 0.3), and best-corrected visual acuity at T0 (P = 0.2) were not significantly different between the two groups. The area of MEWDS lesions on late-phase indocyanine green angiography was significantly smaller in secondary MEWDS (P = 0.001) and less symmetrical with respect to both horizontal (P = 0.003) and vertical (P = 0.004) axis. At T0, neither the clinical (P = 0.5) nor the multimodal imaging (P = 0.2) inflammation scores were significantly different between the groups. At T1, the multimodal imaging inflammation score was higher in secondary MEWDS (P = 0.021). CONCLUSION: In secondary MEWDS, outer retinal lesions are less extensive and located close to preexisting chorioretinal lesions. Mild signs of intraocular inflammation on multimodal imaging are more frequent in secondary MEWDS during recovery. These findings suggest that chorioretinal inflammation may trigger secondary MEWDS.

Evaluation of commercial Anti-SARS-CoV-2 neutralizing antibody assays in seropositive subjects.

The virus neutralization test (VNT) is the reference for the assessment of the functional ability of neutralizing antibodies (NAb) to block SARS-CoV-2 entry into cells. New competitive immunoassays measuring antibodies preventing interaction between the spike protein and its cellular receptor are proposed as surrogate VNT (sVNT). We tested three commercial sVNT (a qualitative immunochromatographic test and two quantitative immunoassays named YHLO and TECO) together with a conventional anti-spike IgG assay (bioMérieux) in comparison with an in-house plaque reduction neutralization test (PRNT50) using the original 19A strain and different variants of concern (VOC), on a panel of 306 sera from naturally-infected or vaccinated patients. The qualitative test was rapidly discarded because of poor sensitivity and specificity. Areas under the curve of YHLO and TECO assays were, respectively, 85.83 and 84.07 (p-value >0.05) using a positivity threshold of 20 for PRNT50, and 95.63 and 90.35 (p-value =0.02) using a threshold of 80. However, the performances of YHLO and bioMérieux were very close for both thresholds, demonstrating the absence of added value of sVNT compared to a conventional assay for the evaluation of the presence of NAb in seropositive subjects. In addition, the PRNT50 assay showed a reduction of NAb titers towards different VOC in comparison to the 19A strain that could not be appreciated by the commercial tests. Despite the good correlation between the anti-spike antibody titer and the titer of NAb by PRNT50, our results highlight the difficulty to distinguish true NAb among the anti-RBD antibodies with commercial user-friendly immunoassays.

Polycystic liver: automatic segmentation using deep learning on CT is faster and as accurate compared to manual segmentation.

OBJECTIVE: This study aimed to develop and investigate the performance of a deep learning model based on a convolutional neural network (CNN) for the automatic segmentation of polycystic livers at CT imaging. METHOD: This retrospective study used CT images of polycystic livers. To develop the CNN, supervised training and validation phases were performed using 190 CT series. To assess performance, the test phase was performed using 41 CT series. Manual segmentation by an expert radiologist (Rad1a) served as reference for all comparisons. Intra-observer variability was determined by the same reader after 12 weeks (Rad1b), and inter-observer variability by a second reader (Rad2). The Dice similarity coefficient (DSC) evaluated overlap between segmentations. CNN performance was assessed using the concordance correlation coefficient (CCC) and the two-by-two difference between the CCCs; their confidence interval was estimated with bootstrap and Bland-Altman analyses. Liver segmentation time was automatically recorded for each method. RESULTS: A total of 231 series from 129 CT examinations on 88 consecutive patients were collected. For the CNN, the DSC was 0.95 ± 0.03 and volume analyses yielded a CCC of 0.995 compared with reference. No statistical difference was observed in the CCC between CNN automatic segmentation and manual segmentations performed to evaluate inter-observer and intra-observer variability. While manual segmentation required 22.4 ± 10.4 min, central and graphics processing units took an average of 5.0 ± 2.1 s and 2.0 ± 1.4 s, respectively. CONCLUSION: Compared with manual segmentation, automated segmentation of polycystic livers using a deep learning method achieved much faster segmentation with similar performance. KEY POINTS: • Automatic volumetry of polycystic livers using artificial intelligence method allows much faster segmentation than expert manual segmentation with similar performance. • No statistical difference was observed between automatic segmentation, inter-observer variability, or intra-observer variability.

Evaluation of Commercial Anti-SARS-CoV-2 Antibody Assays and Comparison of Standardized Titers in Vaccinated Health Care Workers.

With the availability of vaccines, commercial assays detecting anti-severe acute respiratory syndrome coronavirus-2 antibodies (Ab) evolved toward quantitative assays directed to the spike glycoprotein or its receptor binding domain (RBD). The main objective of the present study was to compare the Ab titers obtained with quantitative commercial binding Ab assays, after one dose (convalescent individuals) or two doses (naive individuals) of vaccine, in health care workers (HCW). Antibody titers were measured in 255 sera (from 150 HCW) with five quantitative immunoassays (Abbott RBD IgG II quant, bioMérieux RBD IgG, DiaSorin Trimeric spike IgG, Siemens Healthineers RBD IgG, Wantai RBD IgG). One qualitative total antibody anti-RBD detection assay (Wantai) was used to detect previous infection before vaccination. The results are presented in binding Ab units (BAU)/mL after application, when possible, of a conversion factor provided by the manufacturers and established from a World Health Organization internal standard. There was a 100% seroconversion with all assays evaluated after two doses of vaccine. With assays allowing BAU/mL correction, Ab titers were correlated (Pearson correlation coefficient, ρ, range: 0.85-0.94). The titer differences varied by a mean of 10.6% between Siemens and bioMérieux assays to 60.9% between Abbott and DiaSorin assays. These results underline the importance of BAU conversion for the comparison of Ab titer obtained with the different quantitative assays. However, significant differences persist, notably, between kits detecting Ab against the different antigens. A true standardization of the assays would be to include the International Standard in the calibration of each assay to express the results in IU/mL.

Psychological effect of COVID-19 pandemic among women undergoing infertility care, a French cohort - PsyCovART Psychological effect of COVID-19: PsyCovART.

PURPOSE: To assess psychological state of women who experienced postponement of ART care during the first COVID-19 wave in a French public ward of reproductive medicine. METHODS: An online anonymous survey was emailed between July and August 2020 to all women whose infertility care, including the first consultation for infertility, have been delayed at the beginning of the COVID-19 pandemic. Anxiety, depression, and stress were assessed using Hospital Anxiety and Depression Scale (HADS) and Perceived Stress Scale (PSS-10). Feelings about COVID-19 outbreak, lockdown and suspension of fertility care were assessed by Multiple-Choice Questions and Visual Analog Scales. RESULTS: 435 women answered to the survey (response rate 34.6%). Mean levels of the HADS-A (anxiety), HADS-D (depression) and PSS10 were respectively 7.58(±3.85), 4.51(±3.48), and 27(±6.75). Prevalence of stress was 50.8% and almost half of women presented clear or suggestive anxiety symptoms (respectively 21.6% and 25.7%). Stress and anxiety rates were much higher than those expected in infertile population. Increased stress was observed in women above 35 years and those stopped 'in cycle' or during pre-treatment for in-vitro fertilization or frozen embryo transfer. Patient with history of depression or anxiety had a higher prevalence of perceived stress (p = 0.0006). Postponement was perceived as 'unbearable' for women experiencing stress (p = 0.0032). After the first wave of pandemic, pregnancy desire remained the same and 84.3% of women wanted to resume fertility care as soon as possible. CONCLUSION: Stopping fertility care during the COVID-19 pandemic had a significant psychological impact on women with an increase of stress, and anxiety. Psychological counseling should always be offered especially during this difficult period.

Improving patient self-reporting of antihypertensive adverse drug events in primary care: a stepped wedge cluster randomised trial.

BACKGROUND: About 25% of patients experience adverse drug events (ADE) in primary care, but few events are reported by the patients themselves. One solution to improve the detection and management of ADEs in primary care is for patients to report them to their general practitioner. The study aimed to assess the effect of a booklet designed to improve communication and interaction between patients treated with anti-hypertensive drugs and general practitioners on the reporting of ADEs. METHODS: A cluster randomized controlled cross-sectional stepped wedge open trial (five periods of 3 months) was conducted. A cluster was a group of general practitioners working in ambulatory offices in France. Adults consulting their general practitioner to initiate, modify, or renew an antihypertensive prescription were included. A booklet including information on cardiovascular risks, antihypertensive treatments, and ADE report forms was delivered by the general practitioner to the patient in the intervention group. The primary outcome was the reporting of at least one ADE by the patient to his general practitioner during the three-month period after enrolment. Two clusters were randomised by sequence for a total of 8 to receive the intervention. An intention-to-treat analysis was conducted. A logistic mixed model with random intercept was used. RESULTS: Sixty general practitioners included 1095 patients (median: 14 per general practitioner; range: 1-103). More patients reported at least one ADE to their general practitioner in the intervention condition compared to the control condition (aOR = 3.5, IC95 [1.2-10.1], p = 0.02). The modification and initiation of an antihypertensive treatment were also significantly associated with the reporting of ADEs (aOR = 4.4, CI95 [1.9-10.0], p <  0.001 and aOR = 11.0, CI95 [4.6-26.4], p <  0.001, respectively). The booklet delivery also improved patient satisfaction on general practitioner communication and high blood pressure management. CONCLUSION: A booklet can improve patient self-reporting of ADEs to their general practitioners. Future research should assess whether it can improve general practitioner management of ADEs and patient's health status. TRIAL REGISTRATION: Trial registry identifier NCT01610817 (2012/05/30).

Measuring the effectiveness of integrated vector management with targeted outdoor residual spraying and autodissemination devices on the incidence of dengue in urban Malaysia in the iDEM trial (intervention for Dengue Epidemiology in Malaysia): study protocol for a cluster randomized controlled trial.

BACKGROUND: In common with many South East Asian countries, Malaysia is endemic for dengue. Dengue control in Malaysia is currently based on reactive vector management within 24 h of a dengue case being reported. Preventive rather than reactive vector control approaches, with combined interventions, are expected to improve the cost-effectiveness of dengue control programs. The principal objective of this cluster randomized controlled trial is to quantify the effectiveness of a preventive integrated vector management (IVM) strategy on the incidence of dengue as compared to routine vector control efforts. METHODS: The trial is conducted in randomly allocated clusters of low- and medium-cost housing located in the Federal Territory of Kuala Lumpur and Putrajaya. The IVM approach combines: targeted outdoor residual spraying with K-Othrine Polyzone, deployment of mosquito traps as auto-dissemination devices, and community engagement activities. The trial includes 300 clusters randomly allocated in a 1:1 ratio. The clusters receive either the preventive IVM in addition to the routine vector control activities or the routine vector control activities only. Epidemiological data from monthly confirmed dengue cases during the study period will be obtained from the Vector Borne Disease Sector, Malaysian Ministry of Health e-Dengue surveillance system. Entomological surveillance data will be collected in 12 clusters randomly selected from each arm. To measure the effectiveness of the IVM approach on dengue incidence, a negative binomial regression model will be used to compare the incidence between control and intervention clusters. To quantify the effect of the interventions on the main entomological outcome, ovitrap index, a modified ordinary least squares regression model using a robust standard error estimator will be used. DISCUSSION: Considering the ongoing expansion of dengue burden in Malaysia, setting up proactive control strategies is critical. Despite some limitations of the trial such as the use of passive surveillance to identify cases, the results will be informative for a better understanding of effectiveness of proactive IVM approach in the control of dengue. Evidence from this trial may help justify investment in preventive IVM approaches as preferred to reactive case management strategies. TRIAL REGISTRATION: ISRCTN ISRCTN81915073 . Retrospectively registered on 17 April 2020.

Evaluation of High-Throughput SARS-CoV-2 Serological Assays in a Longitudinal Cohort of Patients with Mild COVID-19: Clinical Sensitivity, Specificity, and Association with Virus Neutralization Test.

BACKGROUND: The association between SARS-CoV-2 commercial serological assays and virus neutralization test (VNT) has been poorly explored in mild patients with COVID-19. METHODS: 439 serum specimens were longitudinally collected from 76 healthcare workers with RT-PCR-confirmed COVID-19. The clinical sensitivity (determined weekly) of 9 commercial serological assays were evaluated. Clinical specificity was assessed using 69 pre-pandemic sera. Correlation, agreement, and concordance with the VNT were also assessed on a subset of 170 samples. Area under the ROC curve (AUC) was estimated at 2 neutralizing antibody titers. RESULTS: The Wantai Total Ab assay targeting the receptor binding domain (RBD) within the S protein presented the best sensitivity at different times during the course of disease. The clinical specificity was greater than 95% for all tests except for the Euroimmun IgA assay. The overall agreement with the presence of neutralizing antibodies ranged from 62.2% (95%CI; 56.0-68.1) for bioMérieux IgM to 91.2% (87.0-94.2) for Siemens. The lowest negative percent agreement (NPA) was found with the Wantai Total Ab assay (NPA 33% (21.1-48.3)). The NPA for other total Ab or IgG assays targeting the S or the RBD was 80.7% (66.7-89.7), 90.3% (78.1-96.1), and 96.8% (86.8-99.3) for Siemens, bioMérieux IgG, and DiaSorin, respectively. None of the commercial assays have sufficient performance to detect a neutralizing titer of 80 (AUC < 0.76). CONCLUSIONS: Although some assays show a better agreement with VNT than others, the present findings emphasize that commercialized serological tests, including those targeting the RBD, cannot substitute a VNT for the assessment of functional antibody response.

Avelumab in Patients With Gestational Trophoblastic Tumors With Resistance to Single-Agent Chemotherapy: Cohort A of the TROPHIMMUN Phase II Trial.

PURPOSE: Women with gestational trophoblastic tumors (GTT) resistant to single-agent chemotherapy receive alternative chemotherapy regimens, which, although effective, cause considerable toxicity. All GTT subtypes express programmed death-ligand 1 (PD-L1), and natural killer (NK) cells are involved in trophoblast immunosurveillance. Avelumab (anti-PD-L1) induces NK cell-mediated cytotoxicity. The TROPHIMMUN trial assessed avelumab in women with chemotherapy-resistant GTT. METHODS: In this phase II multicenter trial (ClinicalTrials.gov identifier: NCT03135769), women with GTT who experienced disease progression after single-agent chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. Rate of hCG normalization was the primary endpoint (2-step Simon design). RESULTS: Between December 2016 and September 2018, 15 patients were treated. Median age was 34 years; disease stage was I or III in 53.3% and 46.7% of women, respectively; and International Federation of Gynecology and Obstetrics (FIGO) score was 0-4 in 33.3%, 5-6 in 46.7%, and ≥ 7 in 20% of patients. Prior treatment included methotrexate (100%) and actinomycin D (7%). Median follow-up was 25 months, and median number of avelumab cycles was 8 (range, 2-11). Grade 1-2 treatment-related adverse events occurred in 93% of patients, most commonly (≥ 25%) fatigue (33.3%), nausea/vomiting (33.3%), and infusion-related reaction (26.7%). One patient had grade 3 uterine bleeding (treatment unrelated). Eight patients (53.3%) had hCG normalization after a median of 9 avelumab cycles; none subsequently relapsed. Probability of normalization was not associated with disease stage, FIGO score, or baseline hCG. One patient subsequently had a healthy pregnancy. In avelumab-resistant patients (46.7%), hCG was normalized with actinomycin D (42.3%) or combination chemotherapy/surgery (57.1%). CONCLUSION: In patients with single-agent chemotherapy-resistant GTT, avelumab had a favorable safety profile and cured approximately 50% of patients. Avelumab could be a new therapeutic option, particularly in patients who would otherwise receive combination chemotherapy.

Targeted outdoor residual spraying, autodissemination devices and their combination against Aedes mosquitoes: field implementation in a Malaysian urban setting.

Currently, dengue control relies largely on reactive vector control programmes. Proactive vector-control using a rational, well-balanced integrated vector management approach may prove more successful for dengue control. As part of the development of a cluster randomized controlled epidemiological trial, a study was conducted in Johor Bahru, Malaysia. The study included one control site (three buildings) and three intervention sites which were treated as follows: targeted outdoor residual spraying only (TORS site, two buildings); deployment of autodissemination devices only (ADD site, four buildings); and the previous two treatments combined (TORS + ADD site, three buildings). The primary entomological measurement was per cent of positive ovitraps-ovitrap index (OI). The effect of each intervention on OI was analyzed by a modified ordinary least squares regression model. Relative to the control site, the TORS and ADD sites showed a reduction in the Aedes OI (-6.5%, P = 0.04 and -8.3%, P = 0.10, respectively). Analysis by species showed that, relative to control, the Ae. aegypti OI was lower in ADD (-8.9%, P = 0.03) and in TORS (-10.4%, P = 0.02). No such effect was evident in the TORS + ADD site. The present study provides insights into the methods to be used for the main trial. The combination of multiple insecticides with different modes of action in one package is innovative, although we could not demonstrate the additive effect of TORS + ADD. Further work is required to strengthen our understanding of how these interventions impact dengue vector populations and dengue transmission.