Cost Optimisation of Individual-Based Institutional Reward Incentives for Promoting Cooperation in Finite Populations.

In this paper, we study the problem of cost optimisation of individual-based institutional incentives (reward, punishment, and hybrid) for guaranteeing a certain minimal level of cooperative behaviour in a well-mixed, finite population. In this scheme, the individuals in the population interact via cooperation dilemmas (Donation Game or Public Goods Game) in which institutional reward is carried out only if cooperation is not abundant enough (i.e., the number of cooperators is below a threshold 1 ≤ t ≤ N - 1 , where N is the population size); and similarly, institutional punishment is carried out only when defection is too abundant. We study analytically the cases t = 1 for the reward incentive under the small mutation limit assumption and two different initial states, showing that the cost function is always non-decreasing. We derive the neutral drift and strong selection limits when the intensity of selection tends to zero and infinity, respectively. We numerically investigate the problem for other values of t and for population dynamics with arbitrary mutation rates.

Cost optimisation of hybrid institutional incentives for promoting cooperation in finite populations.

In this paper, we rigorously study the problem of cost optimisation of hybrid (mixed) institutional incentives, which are a plan of actions involving the use of reward and punishment by an external decision-maker, for maximising the level (or guaranteeing at least a certain level) of cooperative behaviour in a well-mixed, finite population of self-regarding individuals who interact via cooperation dilemmas (Donation Game or Public Goods Game). We show that a mixed incentive scheme can offer a more cost-efficient approach for providing incentives while ensuring the same level or standard of cooperation in the long-run. We establish the asymptotic behaviour (namely neutral drift, strong selection, and infinite-population limits). We prove the existence of a phase transition, obtaining the critical threshold of the strength of selection at which the monotonicity of the cost function changes and providing an algorithm for finding the optimal value of the individual incentive cost. Our analytical results are illustrated with numerical investigations. Overall, our analysis provides novel theoretical insights into the design of cost-efficient institutional incentive mechanisms for promoting the evolution of cooperation in stochastic systems.

The cost-effectiveness of bevacizumab for the treatment of advanced ovarian cancer in Canada.

BACKGROUND: The overall survival (os) analysis of the icon7 trial demonstrated that frontline ovarian cancer patients with a high risk of progression (stage iii suboptimally debulked, and stage iii or iv with unresectable disease) benefited from the addition of bevacizumab to standard chemotherapy compared with standard chemotherapy alone. The objective of the present study was to investigate the cost-effectiveness, from a Canadian publicly funded perspective, of adding bevacizumab to frontline treatment of ovarian cancer at high risk of progression. METHODS: An area-under-the-curve, Markov-structured model was used to estimate the cost-effectiveness of the treatments. Long-term progression-free survival (pfs) and os were extracted from the icon7 trial (subgroup at high risk of relapse) and extrapolated by parametric time-to-event functions over a time horizon of 10 years. Canadian pfs health state utility values were obtained from the EQ-5D (EuroQoL Group, Rotterdam, Netherlands) questionnaires in the icon7 high-risk patient population. Canadian post-progression utility values were consistent with those for other gynecologic cancers. Cost inputs were informed by public sources. An annual 5% efficacy and cost discount rate was applied. A probabilistic sensitivity analysis and one-way sensitivity analyses were conducted. RESULTS: Ovarian cancer patients at high risk of progression receiving bevacizumab plus standard chemotherapy experienced a mean incremental quality-adjusted life year (qaly) gain of 0.374 years. At an additional cost of $35,901.54, the incremental cost-effectiveness ratio (icer) for the addition of bevacizumab to standard chemotherapy, relative to standard chemotherapy alone, was $95,942 per qaly. CONCLUSIONS: No formal health technology assessment willingness-to-pay threshold exists in Canada. However, at a threshold of $100,000 per qaly, bevacizumab in addition to chemotherapy is a cost-effective alternative for ovarian cancer patients who are at high risk of progression (stage iii suboptimally debulked, and stage iii or iv with unresectable disease). Using the $100,000 per qaly threshold in a probabilistic sensitivity analysis, it was determined that, compared with standard chemotherapy, the addition of bevacizumab to chemotherapy is cost-effective in 56% of tested scenarios.

Effect of Facilitation of Local Maternal-and-Newborn Stakeholder Groups on Neonatal Mortality: Cluster-Randomized Controlled Trial.

BACKGROUND: Facilitation of local women's groups may reportedly reduce neonatal mortality. It is not known whether facilitation of groups composed of local health care staff and politicians can improve perinatal outcomes. We hypothesised that facilitation of local stakeholder groups would reduce neonatal mortality (primary outcome) and improve maternal, delivery, and newborn care indicators (secondary outcomes) in Quang Ninh province, Vietnam. METHODS AND FINDINGS: In a cluster-randomized design 44 communes were allocated to intervention and 46 to control. Laywomen facilitated monthly meetings during 3 years in groups composed of health care staff and key persons in the communes. A problem-solving approach was employed. Births and neonatal deaths were monitored, and interviews were performed in households of neonatal deaths and of randomly selected surviving infants. A latent period before effect is expected in this type of intervention, but this timeframe was not pre-specified. Neonatal mortality rate (NMR) from July 2008 to June 2011 was 16.5/1,000 (195 deaths per 11,818 live births) in the intervention communes and 18.4/1,000 (194 per 10,559 live births) in control communes (adjusted odds ratio [OR] 0.96 [95% CI 0.73-1.25]). There was a significant downward time trend of NMR in intervention communes (p = 0.003) but not in control communes (p = 0.184). No significant difference in NMR was observed during the first two years (July 2008 to June 2010) while the third year (July 2010 to June 2011) had significantly lower NMR in intervention arm: adjusted OR 0.51 (95% CI 0.30-0.89). Women in intervention communes more frequently attended antenatal care (adjusted OR 2.27 [95% CI 1.07-4.8]). CONCLUSIONS: A randomized facilitation intervention with local stakeholder groups composed of primary care staff and local politicians working for three years with a perinatal problem-solving approach resulted in increased attendance to antenatal care and reduced neonatal mortality after a latent period.

Lessons learned from stakeholders in a facilitation intervention targeting neonatal health in Quang Ninh province, Vietnam.

BACKGROUND: In northern Vietnam the Neonatal health - Knowledge Into Practice (NeoKIP, Current Controlled Trials ISRCTN44599712) trial has evaluated facilitation as a knowledge translation intervention to improve neonatal survival. The results demonstrated that intervention sites, each having an assigned group including local stakeholders supported by a facilitator, lowered the neonatal mortality rate by 50% during the last intervention year compared with control sites. This process evaluation was conducted to identify and describe mechanisms of the NeoKIP intervention based on experiences of facilitators and intervention group members. METHODS: Four focus group discussions (FGDs) were conducted with all facilitators at different occasions and 12 FGDs with 6 intervention groups at 2 occasions. Fifteen FGDs were audio recorded, transcribed verbatim, translated into English, and analysed using thematic analysis. RESULTS: Four themes and 17 sub-themes emerged from the 3 FGDs with facilitators, and 5 themes and 18 sub-themes were identified from the 12 FGDs with the intervention groups mirroring the process of, and the barriers to, the intervention. Facilitators and intervention group members concurred that having groups representing various organisations was beneficial. Facilitators were considered important in assembling the groups. The facilitators functioned best if coming from the same geographical area as the groups and if they were able to come to terms with the chair of the groups. However, the facilitators' lack of health knowledge was regarded as a deficit for assisting the groups' assignments. FGD participants experienced the NeoKIP intervention to have impact on the knowledge and behaviour of both intervention group members and the general public, however, they found that the intervention was a slow and time-consuming process. Perceived facilitation barriers were lack of money, inadequate support, and the function of the intervention groups. CONCLUSIONS: This qualitative process evaluation contributes to explain the improved neonatal survival and why this occurred after a latent period in the NeoKIP project. The used knowledge translation intervention, where facilitators supported multi-stakeholder coalitions with the mandate to impact upon attitudes and behaviour in the communes, has low costs and potential for being scaled-up within existing healthcare systems.

Characteristics and outcomes in patients with a prior myocardial infarction treated with extended dual antiplatelet therapy with ticagrelor 60 mg: findings from ALETHEIA, a multi-country observational study.

BACKGROUND: Guidelines recommend extended dual antiplatelet therapy, including ticagrelor 60 mg twice daily, in high-risk post-myocardial infarction (MI) patients who have tolerated 12 months and are not at high bleeding risk. The real-world utilization and bleeding and ischaemic outcomes associated with long-term ticagrelor 60 mg in routine clinical practice have not been well described. METHODS: Register and claims data from the USA (Optum Clinformatics, IBM MarketScan, and Medicare) and Europe (Sweden, Italy, UK, and Germany) were extracted. Patients initiating ticagrelor 60 mg ≥12 months after MI, meeting eligibility criteria for the PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin - Thrombolysis in Myocardial Infarction 45) 54 trial, were included. The cumulative incidence of the composite of MI, stroke, or all-cause mortality and that of bleeding requiring hospitalization were calculated. Meta-analyses were performed to combine estimates from each source. RESULTS: A total of 7035 patients treated with ticagrelor 60 mg met eligibility criteria. Median age was 67 years and 29% were females; 12% had a history of multiple MIs. The majority (95%) had been treated with ticagrelor 90 mg prior to initiating ticagrelor 60 mg. At 12 months from initiation of ticagrelor 60 mg, the cumulative incidence [95% confidence interval (CI)] of MI, stroke, or mortality was 3.33% (2.73-4.04) and was approximately three-fold the risk of bleeding (0.96%; 0.69-1.33). CONCLUSIONS: This study provides insights into the use of ticagrelor 60 mg in patients with prior MI in clinical practice. Observed event rates for ischaemic events and bleeding generally align with those in the pivotal trials, support the established safety profile of ticagrelor, and highlight the significant residual ischaemic risk in this population.Clinical Trials.gov Registration NCT04568083.

Histological and molecular biology diagnosis of neurocysticercosis in a patient without history of travel to endemic areas: case report.

BACKGROUND: in endemic areas, neurocysticercosis appears mainly as a single, large, spherical and non-enhancing intracranial cyst. CASE PRESENTATION: an atypical case of neurocysticercosis (NCC) in a French Caucasian, without history of travel to endemic areas, was confirmed by histology and molecular speciation. Imaging was atypical, showing several hook-bearing scolices visible in the cyst, while the serology employed was non-contributary. CONCLUSIONS: NCC should be considered when multiple taeniid scolices are observed within the same cystic lesion.

A Cadaveric Study of the Carpal Tunnel and Anatomical Variations of the Median Nerve in Vietnamese Adults: Implications for Single Portal Endoscopic Carpal Tunnel Release.

Introduction: Single-portal endoscopic carpal tunnel release using modified Agee technique is widely used in Vietnam. Yet information on the anatomy of the target space of Vietnamese people regarding this technique is scarce. We aimed to characterise the anatomical landmarks and variations of the carpal tunnel to propose a safer surgery. Materials and methods: All twenty hands of ten fresh frozen, unembalmed cadavers of Vietnamese adults were included. Dissection was performed after the vertical line, Kaplan's cardinal line and the distal wrist crease were drawn. The transverse carpal ligament (TCL), ulnar neurovascular bundle and superficial palmar arch were exposed. Measurements were made using Mitutoyo calliper. The variants of the median nerve and in the course of the thenar motor branch were recorded. Results: The median distances from the TCL distal margin to the distal wrist crease and superficial palmar arch were 31.2mm and 12.7mm, respectively. The ulnar neurovascular bundle was located 5.7mm and 4.4mm ulnar to the vertical line at the level of the TCL proximal margin and at the level of the TCL distal margin, respectively. The thenar motor branch of the median nerve was extra-ligamentous in 19 hands and preligamentous in 1 hand. Conclusion: If endoscopic portal is made along the distal wrist crease, blade assembly should not be inserted beyond the 35mm mark on its scale. Instruments should be aimed toward the radial border of the patient's ring finger. Surgeons should be aware of the preligamentous course of the thenar motor branch although this variant type is rare.

Prevalence of depression among heart failure inpatients and its associated socio-demographic factors: implications for personal-and family-based treatment management in health facilities in Vietnam.

OBJECTIVE: Our objective is to identify the prevalence of depression among inpatients with heart failure (HF), and to ascertain the factors associated with the depression from a wide spectrum of sociodemographic variables. MATERIALS AND METHODS: We conducted a hospital-based cross-sectional survey of prospectively collected data in inpatients with a diagnosis of HF at Vietnam National Heart Institute, Bach Mai Hospital (Hanoi, Vietnam) from July 2020 to July 2021. A sample size of 128 inpatients with HF was finally included. Primary outcome variable was depression ICD-10. RESULTS: The mean age was 62.34 (SD = 14.76). The sex ratio was 66 males to 62 females. The overall prevalence of depression ICD-10 was 46.88% among HF inpatients. The proportion of the depressed patients fluctuated between 37.21% and 83.33% by NYHA heart failure classification. Compared to the depressive prevalence among patients with NYHA class II, the odds were 8.43 times higher for those with NYHA class IV (OR univariate 8.43; 95% CI 1.63-43.46). Patient's age was significantly associated with increased prevalence of depression (OR multivariate 1.07; 95% CI 1.003-1.14). It was significantly higher odds of depression in HF patients who felt sadness after a diagnosis of an illness (OR multivariate 18.02, 95% CI: 4.21-77.08). Individuals with higher household economic status were less likely to be diagnosed with depression compared to those with lower household economic status (OR multivariate 0.15, 95% CI: 0.02-0.92). The odds of depression were significantly higher in HF patients who reported family conflict (OR multivariate 23.45, 95% CI: 1.29-423.55), and in those having the loss of a close family member (OR multivariate 38.62, 95% CI: 1.41-1055.98). CONCLUSIONS:   The prevalence of depression by ICD-10 was relatively high. Age of patient, sadness after a diagnosis of an illness, household economic status, family conflict and loss of a close family member were significantly associated with the depression among HF inpatients. Present results suggest a need for a disease management program addressing both psychological and HF aspects with the aim of improving health outcomes for the inpatients in Vietnam health facilities.

Effect of temperature on sporulation and spore development of giant kelp (Macrocystis pyrifera).

Rising ocean temperature is a major driver of kelp forest decline worldwide and one that threatens to intensify over the coming decades. What is not particularly well understood are the mechanisms that drive loss and how they operate at differing life stages. This study aimed to establish an understanding of the effects of increasing temperature on the early developmental stages of the giant kelp, Macrocystis pyrifera. Sporulation was carried out across 10 temperature treatments from 9.5 to 26.2°C ± 0.2°C at approximately 2°C intervals. Spores were then incubated at these temperatures under a 20.3±1.7 µmol photons m-2 s-1, 16L:8D photoperiod for 5 days. Results indicate that spore release was positively correlated with increasing temperature, whereas an inverse trend was observed between temperature and the growth of germ-tube. The thermal threshold for spore and germling development was determined to be between 21.7°C and 23.8°C. Spore settlement was the most drastically effected developmental phase by increasing temperature. This study highlights the vulnerability of early life stages of M. pyrifera development to rising ocean temperature and has implications for modelling future distribution of this valuable ecosystem engineer in a changing ocean.

Implementing knowledge into practice for improved neonatal survival; a cluster-randomised, community-based trial in Quang Ninh province, Vietnam.

BACKGROUND: Globally, almost 4 million newborns die during the first 4 weeks of life every year. By increased use of evidence-based knowledge in the healthcare system a large proportion of these neonatal deaths could be prevented. But there is a severe lack of knowledge on effective methods for successful implementation of evidence into practice, particularly in low- and middle-income countries. Recent studies have demonstrated promising results with increased survival among both mothers and newborns using community-based approaches. In Vietnam evidence-based guidelines on reproductive health were launched in 2003 and revised in 2009. The overall objective of the current project is to evaluate if a facilitation intervention on the community level, with a problem-solving approach involving local representatives if the healthcare system and the community, results in improvements of neonatal health and survival. METHODS/DESIGN: The study, which has been given the acronym NeoKIP (Neonatal Health - Knowledge Into Practice), took place in 8 districts composed by 90 communes in a province in northern Vietnam, where neonatal mortality rate was 24/1000 in 2005. A cluster randomised design was used, allocating clusters, as defined as a commune and its correponding Commune Health Center (CHC) to either intervention or control arm. The facilitation intervention targeted staff at healthcare centres and key persons in the communes. The facilitator role was performed by lay women (Women's Union representatives) using quality improvement techniques to initiate and sustain improvement processes targeting identified problem areas. The intervention has been running over 3 years and data were collected on the facilitation process, healthcare staff knowledge in neonatal care and their behaviour in clinical practice, and reproductive and perinatal health indicators. Primary outcome is neonatal mortality. DISCUSSION: The intervention is participatory and dynamic, focused on developing a learning process and a problem-solving cycle. The study recognises the vital role of the local community as actors in improving their own and their newborns' health, and applies a bottom-up approach where change will be accomplished by an increasing awareness at and demand from grass root level. By utilising the existing healthcare structure this intervention may, if proven successful, be well suited for scaling up. TRIAL REGISTRATION: Current Controlled Trials ISRCTN44599712.

Is there a need to widely prescribe antibiotics in patients hospitalized with COVID-19?

BACKGROUND: Debate continues regarding the usefulness and benefits of wide prescription of antibiotics in patients hospitalized with coronavirus disease 2019 (COVID-19). METHODS: All patients hospitalized in the Infectious Diseases Department, Dijon University Hospital, Dijon, France between 27 February and 30 April 2020 with confirmed COVID-19 were included in this study. Clinical, biological and radiological data were collected, as well as treatment and outcome data. An unfavourable outcome was defined as death or transfer to the intensive care unit. Patient characteristics and outcomes were compared between patients who did and did not receive antibiotic therapy using propensity score matching. FINDINGS: Among the 222 patients included, 174 (78%) received antibiotic therapy. The univariate analysis showed that patients who received antibiotic therapy were significantly older, frailer and had more severe presentation at admission compared with patients who did not receive antibiotic therapy. Unfavourable outcomes were more common in patients who received antibiotic therapy [hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.07-8.11; P = 0.04]. Multi-variate analysis and propensity score matching indicated that antibiotic therapy was not significantly associated with outcome (HR 1.612, 95% CI 0.562-4.629; P = 0.37). CONCLUSION: Antibiotics were frequently prescribed in this study and this was associated with more severe presentation at admission. However, antibiotic therapy was not associated with outcome, even after adjustment. In line with recent publications, such data support the need to streamline antibiotic therapy in patients with COVID-19.

Iterative Development of Clinician Guides to Support Deprescribing Decisions and Communication for Older Patients in Hospital: A Novel Methodology.

BACKGROUND/OBJECTIVES: Medication review is an important component of the management of older hospital patients. Deprescribing (supervised withdrawal of inappropriate medicines) is one outcome of review. This study aimed to iteratively develop and test the usability of deprescribing guides, which support multidisciplinary clinicians to reduce inappropriate polypharmacy in older inpatients. METHODS: Deprescribing guides for hospital clinicians were developed using a novel mixed-methods, ten-step process. Iterative development and usability testing were applied. This included content development through review of the literature; expert consensus through five rounds of feedback using a modified Delphi approach; and usability testing by 16 multidisciplinary hospital clinicians on hypothetical clinical scenarios involving observations, semi-structured interviews, and administration of the System Usability Scale. RESULTS: This novel process was used to develop deprescribing guides that facilitate implementation of evidence on deprescribing in routine hospital care. The guides present evidence-based information in a format that aligns with workflows of multidisciplinary hospital clinicians. The guides were adapted for various clinical roles to navigate efficiently to suit differing workflow needs. Guides include unique communication support in the form of "preferred language". Clinicians can use the "preferred language" to apply the evidence to the individual patient and relay decisions between health providers and with patients/carers. The total System Usability Scale score was 80.6 ± 2.0 (mean ± standard error of the mean), indicating excellent usability. Guides have been developed using consistent format for nine medication classes that are common targets for deprescribing and are publicly available. CONCLUSION: This study demonstrates a novel approach to the development and implementation of evidence-based recommendations that support deprescribing in routine hospital care.

Social Media Research Strategy to Understand Clinician and Public Perception of Health Care Messages.

INTRODUCTION: Despite the potential of social media to influence public health and generate insights, the process of monitoring and analyzing the dissemination of health care messages on social media has been described as difficult and in need of improvement. OBJECTIVES: The objective of this study was to describe and demonstrate a reproducible methodology for cataloging and analyzing health care-related social media comments and provide insight into how clinicians and members of the general public respond to health care messaging on social media. METHODS: We collected social media comments related to the American Dental Association's 2016 "Evidence-Based Clinical Practice Guideline for the Use of Pit-and-Fissure Sealants" between April 10, 2017, and October 31, 2017, from Facebook, Twitter, LinkedIn, Reddit, and online message boards for the New York Times, FiveThirtyEight, and Dentaltown. Using data provided in the comments, we conducted engagement analysis as well as content, network, and sentiment analysis across 8 categories. RESULTS: We collected 671 comments. Among our findings, Facebook (472 of 671) was the most popular platform among commentators; almost half of all comments (335 of 671) aligned with the recommendations of the 2016 American Dental Association sealants guideline; clinicians were more likely than the general public to like a comment that suggested an improvement to the guideline; and >75% of comments (521 of 671) were supported by anecdotal evidence. CONCLUSION: As the prevalence of anecdotes on social media suggests, the likelihood of falsehoods spreading on social media is high. Insights gleaned from the methodology described in this research could help combat the spread of such misinformation by providing disseminators of health care messaging with insight into their target audiences. Armed with this knowledge, disseminators can craft health care messages that more effectively engage clinicians and the general public. KNOWLEDGE TRANSFER STATEMENT: The methodology used in this research provides a reproducible strategy for tracking social media engagement with health care messages. Engagement results can assist future delivery of health care messages to key stakeholders and ensure better implementation and adoption of these communications.

Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib.

BACKGROUND: The existence of a cross-talk between peritumoral adipocytes and cancer cells has been increasingly investigated. Several studies have shown that these adipocytes protect tumor cells from the effect of anticancer agents. METHODS: To investigate a potential protective effect of adipocyte-conditioned medium on HER2 positive breast cancer cells exposed to tyrosine kinase inhibitors (TKI) such as lapatinib, we analyzed the sensitivity of HER2 positive breast cancer models in vitro and in vivo on SCID mice in the presence or absence of adipocytes or adipocyte-conditioned medium. RESULTS: Conditioned medium from differentiated adipocytes reduced the in vitro sensitivity of the HER2+ cell lines BT474 and SKBR3 to TKI. Particularly, conditioned medium abrogated P27 induction in tumor cells by lapatinib but this was observed only when conditioned medium was present during exposure to lapatinib. In addition, resistance was induced with adipocytes derived from murine NIH3T3 or human hMAD cells but not with fibroblasts or preadipocytes. In vivo studies demonstrated that the contact of the tumors with adipose tissue reduced sensitivity to lapatinib. Soluble factors involved in this resistance were found to be thermolabile. Pharmacological modulation of lipolysis in adipocytes during preparation of conditioned media showed that various lipolysis inhibitors abolished the protective effect of conditioned media on tumor cells, suggesting a role for adipocyte lipolysis in the induction of resistance of tumor cells to TKI. CONCLUSIONS: Overall, our results suggest that contact of tumor cells with proximal adipose tissue induces resistance to anti HER2 small molecule inhibitors through the production of soluble thermolabile factors, and that this effect can be abrogated using lipolysis inhibitors.

High rate of early virological failure with the once-daily tenofovir/lamivudine/nevirapine combination in naive HIV-1-infected patients.

BACKGROUND: The combination of one non-nucleoside reverse transcriptase inhibitor (NNRTI) with two nucleoside reverse transcriptase inhibitors is a validated first-line antiretroviral (ARV) therapy. The once-daily combination of lamivudine, tenofovirDF and nevirapine has not been evaluated in a clinical trial. METHODS: Randomized, open-label, multicentre, non-inferiority trial comparing lamivudine, tenofovirDF and nevirapine once daily (Group 2) with zidovudine/lamivudine and nevirapine twice daily (Group 1), in naive HIV-1-infected patients with a CD4 count <350/mm(3). We planned to enroll 250 patients. RESULTS: As of May 2006, 71 patients had been enrolled (35 in Group 1 and 36 in Group 2) and an unplanned interim analysis was done. The groups were comparable at baseline: median CD4 count was 195 and 191/mm(3) and median plasma viral load was 4.9 log(10) and 5.01 log(10), respectively, in Groups 1 and 2. Eight early non-responses (22.2%) were observed, all in Group 2, while two later viral rebounds occurred. Resistance genotypes for the nine Group 2 failing patients showed the mutations M184V/I (n = 3), K65R (n = 6), one or more NNRTI resistance mutations in all cases. At baseline, the nine Group 2 patients who failed had higher median plasma viral load (5.4 log(10)) and lower median CD4 count (110/mm(3)) than the other Group 2 patients (4.7 log(10), P = 0.002 and 223/mm(3), P = 0.004). Nevirapine trough concentrations were not different between the two groups, nor between patients with full viral suppression or those who failed in Group 2. Due to slow recruitment, and those results, the steering committee decided to stop the trial at 12 months. CONCLUSIONS: In ARV-naive HIV-1-infected patients, the once-daily lamivudine, tenofovirDF and nevirapine regimen resulted in a high rate of early virological failures. The reasons for the failures remain unclear.

Convolutional Neural Network for Automated FLAIR Lesion Segmentation on Clinical Brain MR Imaging.

BACKGROUND AND PURPOSE: Most brain lesions are characterized by hyperintense signal on FLAIR. We sought to develop an automated deep learning-based method for segmentation of abnormalities on FLAIR and volumetric quantification on clinical brain MRIs across many pathologic entities and scanning parameters. We evaluated the performance of the algorithm compared with manual segmentation and existing automated methods. MATERIALS AND METHODS: We adapted a U-Net convolutional neural network architecture for brain MRIs using 3D volumes. This network was retrospectively trained on 295 brain MRIs to perform automated FLAIR lesion segmentation. Performance was evaluated on 92 validation cases using Dice scores and voxelwise sensitivity and specificity, compared with radiologists' manual segmentations. The algorithm was also evaluated on measuring total lesion volume. RESULTS: Our model demonstrated accurate FLAIR lesion segmentation performance (median Dice score, 0.79) on the validation dataset across a large range of lesion characteristics. Across 19 neurologic diseases, performance was significantly higher than existing methods (Dice, 0.56 and 0.41) and approached human performance (Dice, 0.81). There was a strong correlation between the predictions of lesion volume of the algorithm compared with true lesion volume (ρ = 0.99). Lesion segmentations were accurate across a large range of image-acquisition parameters on >30 different MR imaging scanners. CONCLUSIONS: A 3D convolutional neural network adapted from a U-Net architecture can achieve high automated FLAIR segmentation performance on clinical brain MR imaging across a variety of underlying pathologies and image acquisition parameters. The method provides accurate volumetric lesion data that can be incorporated into assessments of disease burden or into radiologic reports.

Pesticides and antibiotics in permanent rice, alternating rice-shrimp and permanent shrimp systems of the coastal Mekong Delta, Vietnam.

BACKGROUND: Salinity intrusion into coastal regions is an increasing threat to agricultural production of salt sensitive crops like paddy rice. In the coastal Mekong Delta, farmers respond by shifting to more salinity tolerant agricultural production systems such as alternating rice-shrimp and permanent shrimp. While shrimps are sensitive to pesticide residues used on rice, the use of antibiotics in shrimp farming can cause contamination in rice crops. These patterns of cross-contamination are not well documented empirically in the rapidly changing agricultural landscape. OBJECTIVE AND METHODS: Our objective was to understand changing pollution patterns induced by shifts in agricultural land use system. We addressed this by i) documenting pesticide and antibiotic use in three different agriculture land use systems (permanent rice, alternating rice-shrimp and permanent shrimp), and by ii) determining residues of pesticides and antibiotics in top soil layers of these three land use systems. Samples were taken in Sóc Trang and Ben Tre province in the Mekong Delta, Vietnam. Chemical analyses comprised 12 of the most commonly used pesticides in rice paddies and six common antibiotics used in shrimp production. RESULTS: Results showed that residues of pesticides were present in all agricultural land use systems, including shrimp aquaculture. Active ingredients were mostly fungicides with a maximum concentration of 67 µg kg-1 found for isoprothiolane in permanent rice systems, followed by alternating rice-shrimp and permanent shrimp systems. Furthermore, antibiotics were present ubiquitously, with fluoroquinolones accumulating to larger amounts than sulfonamides and diaminopyrimidines. All concentrations were below critical lethal threshold values. CONCLUSION: Overall, farmers were most conscious of agrochemical use in alternating rice-shrimp systems to prevent harm to shrimps, which was reflected in overall lower concentrations of agrochemicals when compared to rice systems. Thus, alternating rice-shrimp systems present a low risk option in terms of food safety, which may bring additional benefits to this so far rather low-input system in brackish water transition zone.

The effect of IVX-0142, a heparin-derived hypersulfated disaccharide, on the allergic airway responses in asthma.

BACKGROUND: IVX-0142 is a heparin-derived hypersulfated disaccharide devoid of anticoagulant activity while possessing anti-allergic and anti-inflammatory activity in preclinical studies. In a proof-of-concept study, the allergen inhalation challenge model was used to investigate the effect of IVX-0142 in mild atopic asthma. METHODS: Nineteen subjects, not on controller medications, were randomized to an evaluator-blind, placebo-controlled, cross-over study. The effect of a single nebulized dose of IVX-0142 (80 mg) or placebo administered 30 min prior to allergen inhalation was evaluated on the allergic airway responses, airway responsiveness, and airway inflammation. RESULTS: When compared with placebo, 14 and 13 subjects experienced a relatively smaller maximum fall in forced expiratory volume in 1 s (maxFEV(1)%) for the early airway response (EAR) and late airway response (LAR) with IVX-0142, respectively (P < 0.01). The degree of attenuation in the EAR [maxFEV(1)% (mean +/- SE) 26.5 +/- 2.8%vs placebo 31.0 +/- 2.8%, P = 0.059] and LAR (15.6 +/- 2.9%vs placebo 19.0 +/- 2.9%, P = 0.24) with IVX-0142, however, was small and did not reach statistical significance compared with placebo. Similarly, a trend in the attenuation of allergen-induced increase in the absolute sputum cell counts was also observed. No difference in the allergen-induced increase in airway hyper-responsiveness and exhaled nitric oxide was noticed. CONCLUSIONS: The majority of mild atopic asthmatics demonstrated a reduction in the EAR and LAR to IVX-0142. However, the treatment effect observed with a single prechallenge dose of IVX-0142 was small and heterogeneous. The potential anti-allergic and anti-inflammatory effects using multiple higher doses need to be evaluated.

Secular trend, seasonality and effects of a community-based intervention on neonatal mortality: follow-up of a cluster-randomised trial in Quang Ninh province, Vietnam.

BACKGROUND: Little is know about whether the effects of community engagement interventions for child survival in low-income and middle-income settings are sustained. Seasonal variation and secular trend may blur the data. Neonatal mortality was reduced in a cluster-randomised trial in Vietnam where laywomen facilitated groups composed of local stakeholders employing a problem-solving approach for 3 years. In this analysis, we aim at disentangling the secular trend, the seasonal variation and the effect of the intervention on neonatal mortality during and after the trial. METHODS: In Quang Ninh province, 44 communes were allocated to intervention and 46 to control. Births and neonatal deaths were assessed in a baseline survey in 2005, monitored during the trial in 2008-2011 and followed up by a survey in 2014. Time series analyses were performed on monthly neonatal mortality data. RESULTS: There were 30 187 live births and 480 neonatal deaths. The intervention reduced the neonatal mortality from 19.1 to 11.6 per 1000 live births. The reduction was sustained 3 years after the trial. The control areas reached a similar level at the time of follow-up. Time series decomposition analysis revealed a downward trend in the intervention areas during the trial that was not found in the control areas. Neonatal mortality peaked in the hot and wet summers. CONCLUSIONS: A community engagement intervention resulted in a lower neonatal mortality rate that was sustained but not further reduced after the end of the trial. When decomposing time series of neonatal mortality, a clear downward trend was demonstrated in intervention but not in control areas. TRIAL REGISTRATION NUMBER: ISRCTN44599712, Post-results.