Germ line ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition.

ABSTRACT: The genomics era has facilitated the discovery of new genes that predispose individuals to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ETS-related gene (ERG), a novel, autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor that is critical for definitive hematopoiesis, stem cell function, and platelet maintenance. ERG colocalizes with other transcription factors, including RUNX family transcription factor 1 (RUNX1) and GATA binding protein 2 (GATA2), on promoters or enhancers of genes that orchestrate hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 individuals with thrombocytopenia from 1 family and 14 additional ERG variants in unrelated individuals with BMF/HM, including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germ line ERG variants included cytopenias (thrombocytopenia, neutropenia, and pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense and 1 truncating), including 3 missense population variants, were functionally characterized. Thirteen potentially pathogenic erythroblast transformation specific (ETS) domain missense variants displayed loss-of-function (LOF) characteristics, thereby disrupting transcriptional transactivation, DNA binding, and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture and to promote acute erythroleukemia when transplanted into mice, concordant with these being LOF variants. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germ line ERG variants has clinical implications for patient and family diagnoses, counseling, surveillance, and treatment strategies, including selection of bone marrow donors and cell or gene therapy.

Impact of hindlimb length variation on jumping dynamics in the Longshanks mouse.

Distantly related mammals (e.g. jerboa, tarsiers, kangaroos) have convergently evolved elongated hindlimbs relative to body size. Limb elongation is hypothesized to make these species more effective jumpers by increasing their kinetic energy output (through greater forces or acceleration distances), thereby increasing take-off velocity and jump distance. This hypothesis, however, has rarely been tested at the population level, where natural selection operates. We examined the relationship between limb length, muscular traits and dynamics using Longshanks mice, which were selectively bred over 22 generations for longer tibiae. Longshanks mice have approximately 15% longer tibiae and 10% longer femora compared with random-bred Control mice from the same genetic background. We collected in vivo measures of locomotor kinematics and force production, in combination with behavioral data and muscle morphology, to examine how changes in bone and muscle structure observed in Longshanks mice affect their hindlimb dynamics during jumping and clambering. Longshanks mice achieved higher mean and maximum lunge-jump heights than Control mice. When jumping to a standardized height (14 cm), Longshanks mice had lower maximum ground reaction forces, prolonged contact times and greater impulses, without significant differences in average force, power or whole-body velocity. While Longshanks mice have longer plantarflexor muscle bodies and tendons than Control mice, there were no consistent differences in muscular cross-sectional area or overall muscle volume; improved lunge-jumping performance in Longshanks mice is not accomplished by simply possessing larger muscles. Independent of other morphological or behavioral changes, our results point to the benefit of longer hindlimbs for performing dynamic locomotion.

A review of selective indoor residual spraying for malaria control.

BACKGROUND: Indoor residual spraying (IRS) is one of the most effective malaria control tools. However, its application has become limited to specific contexts due to the increased costs of IRS products and implementation programmes. Selective spraying-selective spray targeted to particular areas/surfaces of dwellings-has been proposed to maintain the malaria control and resistance-management benefits of IRS while decreasing the costs of the intervention. METHODS: A literature search was conducted to find (1) studies that assessed the resting behaviour of Anopheles mosquitoes and (2) studies that evaluated the impact of selective spraying on entomological and malaria outcomes. Additional articles were identified through hand searches of all references cited in articles identified through the initial search. A cost model was developed from PMI VectorLink IRS country programmes, and comparative cost analysis reports to describe the overall cost benefits of selective IRS. RESULTS: In some studies, there appeared to be a clear resting preference for certain Anopheles species in terms of the height at which they rested. However, for other species, and particularly the major African malaria vectors, a clear resting pattern was not detected. Furthermore, resting behaviour was not measured in a standardized way. For the selective spray studies that were assessed, there was a wide range of spray configurations, which complicates the comparison of methods. Many of these spray techniques were effective and resulted in reported 25-68% cost savings and reduced use of insecticide. The reported cost savings in the literature do not always consider all of the IRS implementation costs. Using the IRS cost model, these savings ranged from 17 to 29% for programs that targeted Anopheles spp. and 18-41% for programmes that targeted Aedes aegypti. CONCLUSIONS: Resting behaviour is generally measured in a simplistic way; noting the resting spot of mosquitoes in the morning. This is likely an oversimplification, and there is a need for better monitoring of resting mosquitoes. This may improve the target surface for selective spray techniques, which could reduce the cost of IRS while maintaining its effectiveness. Reporting of cost savings should be calculated considering the entire implementation costs, and a cost model was provided for future calculations.

The non-inferiority of piperonyl-butoxide Yorkool® G3 insecticide-treated nets compared to Olyset®Plus measured by Anopheles arabiensis mortality in experimental huts in Tanzania.

BACKGROUND: Non-inferiority trials are recommended by the World Health Organization (WHO) to demonstrate that health products show comparable efficacy to that of existing standard of care. As part of the WHO Global Malaria Programme (GMP) process of assessment of malaria vector control products, a second-in-class insecticide-treated net (ITN) must be shown to be non-inferior to a first-in-class product based on mosquito mortality. The public health impact of the first-in-class pyrethroid-piperonyl butoxide (PBO) ITN, Olyset® Plus, has been demonstrated in epidemiological trials in areas with insecticide-resistant mosquitoes, but there is a need to determine the efficacy of other pyrethroid-PBO nets to ensure timely market availability of nets in order to increase access to ITNs. The non-inferiority of a deltamethrin-PBO ITN Yorkool® G3 was evaluated entomologically against Olyset® Plus in experimental huts in Tanzania, following WHO guidelines for non-inferiority trials. METHODS: The trial of the two pyrethroid-PBO ITNs was conducted in experimental huts in Lupiro, Tanzania, using a randomized 7 × 7 Latin square block design. The study ran for 49 nights in 14 huts assessing the mosquito mortality and blood-feeding of wild, free-flying, pyrethroid-resistant Anopheles arabiensis. Using the non-inferiority approach, the comparative efficacy (primary endpoint was mosquito mortality at 24 h and secondary endpoint was blood-feeding) of unwashed and 20 times field-washed pyrethroid-PBO Yorkool® G3 ITNs, were compared with the first-in-class product Olyset® Plus and against a pyrethroid-only ITN, PermaNet® 2.0 ITNs, as a standard comparator. RESULTS: The experimental hut trial demonstrated non-inferiority and superiority of Yorkool® G3 to Olyset® Plus based on mosquito mortality [51% vs. 39%, OR 1.68 (95% CI 1.50-1.88)], given that lower 95% CI exceeded 0.74 (delta of 39%) and the margin of no difference (1). Blood-feeding inhibition was high for all treated ITNs (> 90%) and Yorkool® G3 was non-inferior to Olyset® Plus [4% vs. 2%, OR 1.81 (95% CI 1.46-2.39)], given that upper 95% CI was less than 4.85 (delta of 4%). The pyrethroid-PBO ITNs were superior to the pyrethroid-only net, PermaNet® 2.0, as determined by both the proportion of mortality and blood-feeding of mosquitoes (p-value < 0.05). CONCLUSION: Yorkool® G3 ITNs demonstrated non-inferiority to the first-in-class Olyset® Plus and superiority over the standard pyrethroid-only ITN, PermaNet® 2.0 as measured by mortality and blood-feeding inhibition of wild pyrethroid-resistant An. arabiensis mosquitoes. Yorkool® G3 ITNs are potential tools for the control of metabolic insecticide-resistant malaria vectors, and their market availability will contribute to the cost-effective selection of ITNs by malaria control programmes to improve population access to ITNs.

Screening of malaria infections in human blood samples with varying parasite densities and anaemic conditions using AI-Powered mid-infrared spectroscopy.

BACKGROUND: Effective testing for malaria, including the detection of infections at very low densities, is vital for the successful elimination of the disease. Unfortunately, existing methods are either inexpensive but poorly sensitive or sensitive but costly. Recent studies have shown that mid-infrared spectroscopy coupled with machine learning (MIRs-ML) has potential for rapidly detecting malaria infections but requires further evaluation on diverse samples representative of natural infections in endemic areas. The aim of this study was, therefore, to demonstrate a simple AI-powered, reagent-free, and user-friendly approach that uses mid-infrared spectra from dried blood spots to accurately detect malaria infections across varying parasite densities and anaemic conditions. METHODS: Plasmodium falciparum strains NF54 and FCR3 were cultured and mixed with blood from 70 malaria-free individuals to create various malaria parasitaemia and anaemic conditions. Blood dilutions produced three haematocrit ratios (50%, 25%, 12.5%) and five parasitaemia levels (6%, 0.1%, 0.002%, 0.00003%, 0%). Dried blood spots were prepared on Whatman™ filter papers and scanned using attenuated total reflection-Fourier Transform Infrared (ATR-FTIR) for machine-learning analysis. Three classifiers were trained on an 80%/20% split of 4655 spectra: (I) high contrast (6% parasitaemia vs. negative), (II) low contrast (0.00003% vs. negative) and (III) all concentrations (all positive levels vs. negative). The classifiers were validated with unseen datasets to detect malaria at various parasitaemia levels and anaemic conditions. Additionally, these classifiers were tested on samples from a population survey in malaria-endemic villages of southeastern Tanzania. RESULTS: The AI classifiers attained over 90% accuracy in detecting malaria infections as low as one parasite per microlitre of blood, a sensitivity unattainable by conventional RDTs and microscopy. These laboratory-developed classifiers seamlessly transitioned to field applicability, achieving over 80% accuracy in predicting natural P. falciparum infections in blood samples collected during the field survey. Crucially, the performance remained unaffected by various levels of anaemia, a common complication in malaria patients. CONCLUSION: These findings suggest that the AI-driven mid-infrared spectroscopy approach holds promise as a simplified, sensitive and cost-effective method for malaria screening, consistently performing well despite variations in parasite densities and anaemic conditions. The technique simply involves scanning dried blood spots with a desktop mid-infrared scanner and analysing the spectra using pre-trained AI classifiers, making it readily adaptable to field conditions in low-resource settings. In this study, the approach was successfully adapted to field use, effectively predicting natural malaria infections in blood samples from a population-level survey in Tanzania. With additional field trials and validation, this technique could significantly enhance malaria surveillance and contribute to accelerating malaria elimination efforts.

Database Integration Correlates Street Crossing Design Strategies With Pedestrian Injury.

INTRODUCTION: Transportation databases have limited data regarding injury severity of pedestrian versus automobile patients. To identify opportunities to reduce injury severity, transportation and trauma databases were integrated to examine the differences in pedestrian injury severity at street crossings that were signalized crossings (SCs) versus nonsignalized crossings (NSCs). It was hypothesized that trauma database integration would enhance safety analysis and pedestrians struck at NSC would have greater injury severity. METHODS: Single-center retrospective review of all pedestrian versus automobile patients treated at a level 1 trauma center from 2014 to 2018 was performed. Patients were matched to the transportation database by name, gender, and crash date. Google Earth Pro satellite imagery was used to identify SC versus NSC. Injury severity of pedestrians struck at SC was compared to NSC. RESULTS: A total of 512 patients were matched (median age = 41 y [Q1 = 26, Q3 = 55], 74% male). Pedestrians struck at SC (n = 206) had a lower injury severity score (ISS) (median = 9 [4, 14] versus 17 [9, 26], P < 0.001), hospital length of stay (median = 3 [0, 7] versus 6 [1, 15] days, P < 0.001), and mortality (21 [10%] versus 52 [17%], P = 0.04), as compared to those struck at NSC (n = 306). The transportation database had a sensitivity of 63.4% (55.8%-70.4%) and specificity of 63.4% (57.7%-68.9%) for classifying severe injuries (ISS >15). CONCLUSIONS: Pedestrians struck at SC were correlated with a lower ISS and mortality compared to those at NSC. Linkage with the trauma database could increase the transportation database's accuracy of injury severity assessment for nonfatal injuries. Database integration can be used for evidence-based action plans to reduce pedestrian morbidity, such as increasing the number of SC.

Cross-sectional and longitudinal associations between the 24-hour movement behaviours, including muscle and bone strengthening activity, with bone and lean mass from childhood to adolescence.

BACKGROUND: This study aimed to assess whether moderate-to-vigorous physical activity (MVPA), sport and exercise as a proxy measure of muscle and bone strengthening activity, sedentary behaviour, and sleep were associated with total-body-less-head (TBLH) bone mineral content (BMC) and TBLH lean mass cross-sectionally and longitudinally from age 6 to 9 years and age 9 to 11 years to age 15 to 17 years. METHODS: We used longitudinal data from a population sample of Finnish children from the Physical Activity and Nutrition in Children study (age 6 to 9 years: n = 478, 229 females; age 9 to 11 years: n = 384, 197 females; age 15 to 17 years: n = 222, 103 females). Linear regression analysed the cross-sectional and longitudinal associations between accelerometer-assessed MVPA, sedentary time and sleep, and questionnaire-assessed sport and exercise participation and screen time with dual-energy X-ray absorptiometry-assessed TBLH BMC and lean mass. RESULTS: In females, MVPA at age 6 to 9 years was positively associated with TBLH BMC at age 15 to 17 years (ß = 0.008, p = 0.010). Sport and exercise at age 9 to 11 years was positively associated with TBLH BMC (ß = 0.020, p = 0.002) and lean mass (ß = 0.343, p = 0.040) at age 15 to 17 years. MVPA at age 9 to 11 years was positively associated with TBLH lean mass (ß = 0.272, p = 0.004) at age 15 to 17 years. In males, sleep at age 6 to 9 years was positively associated with TBLH lean mass (ß = 0.382, p = 0.003) at age 15 to 17 years. Sport and exercise at age 9 to 11 years was positively associated with TBLH BMC (ß = 0.027, p = 0.012) and lean mass (ß = 0.721, p < 0.001) at age 15 to 17 years. CONCLUSIONS: Promoting engagement in the 24-hour movement behaviours in childhood, particularly sport and exercise to strengthen muscle and bone, is important in supporting bone and lean mass development in adolescence. TRIAL REGISTRATION: NCT01803776; first trial registration date: 04/03/2013.

Risk of Cesarean Delivery Among People With Inflammatory Bowel Disease According to Disease Characteristics: A Population-Based Study.

OBJECTIVES: It is unclear if use of cesarean delivery in people with inflammatory bowel disease (IBD) is guideline-concordant. We compared the odds of cesarean delivery among primiparous individuals with IBD versus without, overall, and by disease characteristics, as well as time to subsequent delivery. METHODS: Retrospective matched population-based cohort study between 1 April 1994 and 31 March 2020. Primiparous individuals aged 15-55 years with IBD were matched to those without IBD on age, year, hospital, and number of newborns delivered. Primary outcome was cesarean delivery versus vaginal delivery. Multivariable conditional logistic regression analyses were performed to estimate the odds of cesarean delivery among individuals with and without IBD as a binary exposure, and a categorical exposure based on IBD-related indications for cesarean delivery. Time to subsequent delivery was evaluated using a Cox proportional hazard model. RESULTS: We matched 7472 individuals with IBD to 37 360 individuals without (99.02% match rate). Individuals with IBD were categorised as having perianal (PA) disease (IBD-PA, n = 764, 10.2%), prior ileal pouch-anal anastomosis (n = 212, 2.8%), or IBD-Other (n = 6496, 86.9%). Cesarean delivery rates were 35.4% in the IBD group versus 30.4% in their controls (adjusted odds ratio 1.27; 95% CI 1.20-1.34). IBD-ileal pouch-anal anastomosis had a cesarean delivery rate of 66.5%, compared to 49.9% in IBD-PA and 32.7% in IBD-Other. There was no significant difference in the rate of subsequent delivery in those with and without IBD (adjusted hazard ratio 1.03; 95% CI 1-1.07). CONCLUSIONS: The higher risk of cesarean delivery in people with IBD reflects guideline-concordant use. Individuals with and without IBD were equally likely to have a subsequent delivery with similar timing.

A photoaging smartphone application to promote sun safety behaviors among youth in late childhood and adolescence.

BACKGROUND: Ultraviolet (UV)-exposure behaviors can directly impact an individual's skin cancer risk, with many habits formed during childhood and adolescence. We explored the utility of a photoaging smartphone application to motivate youth to improve sun safety practices. METHODS: Participants completed a preintervention survey to gather baseline sun safety perceptions and behaviors. Participants then used a photoaging mobile application to view the projected effects of chronic UV exposure on participants' self-face image over time, followed by a postintervention survey to assess motivation to engage in future sun safety practices. RESULTS: The study sample included 87 participants (median [interquartile (IQR)] age, 14 [11-16] years). Most participants were White (50.6%) and reported skin type that burns a little and tans easily (42.5%). Preintervention sun exposure behaviors among participants revealed that 33 (37.9%) mostly or always used sunscreen on a sunny day, 48 (55.2%) experienced at least one sunburn over the past year, 26 (30.6%) engaged in outdoor sunbathing at least once during the past year, and zero (0%) used indoor tanning beds. Non-skin of color (18 [41.9%], p = .02) and older (24 [41.4%], p = .007) participants more often agreed they felt better with a tan. Most participants agreed the intervention increased their motivation to practice sun-protective behaviors (wear sunscreen, 74 [85.1%]; wear hats, 64 [74.4%]; avoid indoor tanning, 73 [83.9%]; avoid outdoor tanning, 68 [79%]). CONCLUSION: The findings of this cross-sectional study suggest that a photoaging smartphone application may serve as a useful tool to promote sun safety behaviors from a young age.

Technology-Based Interventions in Tobacco Use Treatment Among People Who Identify as African American/Black, Hispanic/Latina/o, and American Indian/Alaska Native: Scoping Review.

BACKGROUND: Although tobacco use has significantly declined in the general population, traditional tobacco use treatment uptake and success rates remain disproportionately low among people who identify as African American/Black, Hispanic/Latina/o, and American Indian/Alaska Native. Technology-based interventions (TBIs) for tobacco use are promising alternatives to traditional tobacco use treatments. OBJECTIVE: This scoping review aims to investigate the extent to which the use of digital TBIs in tobacco use treatment research promotes health equity among people who identify as African American/Black, Hispanic/Latina/o, and American Indian/Alaska Native. METHODS: This scoping review identifies US-based studies (between January 2000 and March 2021) that enlist TBIs for tobacco use treatment and include people who identify as African American/Black, Hispanic/Latina/o, and American Indian/Alaska Native at ≥50% of the sample when combined; features studies that are also race and ethnicity conscious; and highlights health equity-promoting insights from included studies. RESULTS: In 85% (22/26) of the studies, the largest proportion of the sample was African American/Black, most participants had low socioeconomic status, and recruitment was most commonly from medical settings. In total, 58% (15/26) of the studies were race and ethnicity conscious, and 67% (10/15) of these studies sought to partner with potential end users. An array of TBIs were represented; however, SMS text messaging was most prevalent. Most TBIs were combined with other evidence-based intervention components (eg, nicotine replacement therapy). Approximately one-third of the studies (8/26, 31%) required participants to have their own device or internet access. The majority were underpowered to detect substantial differences. CONCLUSIONS: The modest number of studies, particularly for persons who identify as Hispanic/Latina/o and American Indian/Alaska Native, demonstrates the limited application of TBIs for tobacco use and that additional research is needed to determine the extent to which TBIs for tobacco use promote health equity among these populations. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/34508.

Enzymatically amplified linear dbDNATM as a rapid and scalable solution to industrial lentiviral vector manufacturing.

Traditional bacterial fermentation techniques used to manufacture plasmid are time-consuming, expensive, and inherently unstable. The production of sufficient GMP grade material thus imposes a major bottleneck on industrial-scale manufacturing of lentiviral vectors (LVV). Touchlight's linear doggybone DNA (dbDNATM) is an enzymatically amplified DNA vector produced with exceptional speed through an in vitro dual enzyme process, enabling industrial-scale manufacturing of GMP material in a fraction of the time required for plasmid. We have previously shown that dbDNATM can be used to produce functional LVV; however, obtaining high LVV titres remained a challenge. Here, we aimed to demonstrate that dbDNATM could be optimised for the manufacture of high titre LVV. We found that dbDNATM displayed a unique transfection and expression profile in the context of LVV production, which necessitated the optimisation of DNA input and construct ratios. Furthermore, we demonstrate that efficient 3' end processing of viral genomic RNA (vgRNA) derived from linear dbDNATM transfer vectors required the addition of a strong 3' termination signal and downstream spacer sequence to enable efficient vgRNA packaging. Using these improved vector architectures along with optimised transfection conditions, we were able to produce a CAR19h28z LVV with equivalent infectious titres as achieved using plasmid, demonstrating that dbDNATM technology can provide a highly effective solution to the plasmid bottleneck.

Addenda to ISCN 2020.

Since the publication of ISCN 2020, the ISCN Standing Committee have noted some clarification of the text and additional examples were needed. These addenda have already been published online (https://iscn.karger.com/) and this short report summarises the ISCN 2020 addenda for the benefit of participants. These addenda will be included in the release of the next version of ISCN.

Genome Mapping Nomenclature.

Background Genome Mapping Technologies (optical and electronic) uses ultra high-molecular weight DNA to detect structural variation and has an application in constitutional genetic disorders, haematological neoplasms and solid tumours. Genome mapping can detect balanced and unbalanced structural variation, copy number changes and haplotypes. The technique is analogous to chromosomal microarray analysis although genome mapping has the added benefit of being able to detect and ascertain the nature of more abnormalities than array, karyotyping or FISH. Key Messages This paper describes a specific nomenclature for genome mapping that can be used by diagnostic and research centres to accurately report their findings. An international nomenclature is essential for patient results to be understood by different healthcare providers as well as clear communication in publications and consistency in databases. Summary Genome mapping can detect aneuploidy, balanced and unbalanced structural variation as well as copy number changes. The Standing Committee for the International System for Human Cytogenomic Nomenclature (ISCN), recognised there was a need for a specific nomenclature for genome mapping that encompasses the range of abnormalities detected by this technique. This paper explains the general principles of the nomenclature as well as giving specific ISCN examples for the different types of numerical and structural rearrangements.

Non-targeted LC-MS/MS metabolomic profiling of human plasma uncovers a novel Mediterranean diet biomarker panel.

INTRODUCTION: Consumption of a Mediterranean diet (MD) has established health benefits, and the identification of novel biomarkers could enable objective monitoring of dietary pattern adherence. OBJECTIVES: The present investigation performed untargeted metabolomics on blood plasma from a controlled study of MD adherence, to identify novel blood-based metabolite biomarkers associated with the MD pattern, and to build a logistic regression model that could be used to characterise MD adherence. METHODS: A hundred and thirty-five plasma samples from n = 58 patients collected at different time points were available. Using a 14-point scale MD Score (MDS) subjects were divided into 'high' or 'low' MDS adherence groups and liquid chromatography-mass spectrometry (LC-MS/MS) was applied for analysis. RESULTS: The strongest association with MDS was pectenotoxin 2 seco acid (r = 0.53; ROC = 0.78), a non-toxic marine xenobiotic metabolite. Several lipids were useful biomarkers including eicosapentaenoic acid, the structurally related lysophospholipid (20:5(5Z,8Z,11Z,14Z,17Z)/0:0), a phosphatidylcholine (P-18:1(9Z)/16:0) and also xi-8-hydroxyhexadecanedioic acid. Two metabolites negatively correlated with MDS, these were the monoacylglycerides (0:0/16:1(9Z)/0:0) and (0:0/20:3(5Z,8Z,11Z)/0:0). By stepwise elimination we selected a panel of 3 highly discriminatory metabolites and developed a linear regression model which identified 'high MDS' individuals with high sensitivity and specificity [AUC (95% CI) 0.83 (0.76-0.97)]. CONCLUSION: Our study highlights the utility of metabolomics as an approach for developing novel panels of dietary biomarkers. Quantitative profiling of these metabolites is required to validate their utility for evaluating dietary adherence.

A semi-field evaluation in Thailand of the use of human landing catches (HLC) versus human-baited double net trap (HDN) for assessing the impact of a volatile pyrethroid spatial repellent and pyrethroid-treated clothing on Anopheles minimus landing.

BACKGROUND: The mosquito landing rate measured by human landing catches (HLC) is the conventional endpoint used to evaluate the impact of vector control interventions on human-vector exposure. Non-exposure based alternatives to the HLC are desirable to minimize the risk of accidental mosquito bites. One such alternative is the human-baited double net trap (HDN), but the estimated personal protection of interventions using the HDN has not been compared to the efficacy estimated using HLC. This semi-field study in Sai Yok District, Kanchanaburi Province, Thailand, evaluates the performance of the HLC and the HDN for estimating the effect on Anopheles minimus landing rates of two intervention types characterized by contrasting modes of action, a volatile pyrethroid spatial repellent (VSPR) and insecticide-treated clothing (ITC). METHODS: Two experiments to evaluate the protective efficacy of (1) a VPSR and (2) ITC, were performed. A block randomized cross-over design over 32 nights was carried out with both the HLC or HDN. Eight replicates per combination of collection method and intervention or control arm were conducted. For each replicate, 100 An. minimus were released and were collected for 6 h. The odds ratio (OR) of the released An. minimus mosquitoes landing in the intervention compared to the control arm was estimated using logistic regression, including collection method, treatment, and experimental day as fixed effects. RESULTS: For the VPSR, the protective efficacy was similar for the two methods: 99.3%, 95% CI (99.5-99.0) when measured by HLC, and 100% (100, Inf) when measured by HDN where no mosquitoes were caught (interaction test p = 0.99). For the ITC, the protective efficacy was 70% (60-77%) measured by HLC but there was no evidence of protection when measured by HDN [4% increase (15-27%)] (interaction test p < 0.001). CONCLUSIONS: Interactions between mosquitoes, bite prevention tools and the sampling method may impact the estimated intervention protective efficacy. Consequently, the sampling method must be considered when evaluating these interventions. The HDN is a valid alternative trapping method (relative to the HLC) for evaluating the impact of bite prevention methods that affect mosquito behaviour at a distance (e.g. VPSR), but not for interventions that operate through tarsal contact (e.g., ITC).

Multi-country evaluation of the durability of pyrethroid plus piperonyl-butoxide insecticide-treated nets: study protocol.

BACKGROUND: Mass distributions of long-lasting insecticidal nets (LLINs) have contributed to large reductions in the malaria burden. However, this success is in jeopardy due in part to the increasing pyrethroid-resistant mosquito population as well as low LLINs coverage in various areas because the lifespan of LLINs is often shorter than the interval between replenishment campaigns. New insecticide-treated nets (ITNs) containing pyrethroid and piperonyl-butoxide (PBO) have shown a greater reduction in the incidence of malaria than pyrethroid LLINs in areas with pyrethroid-resistant mosquitoes. However, the durability (attrition, bio-efficacy, physical integrity and chemical retainment) of pyrethroid-PBO ITNs under operational settings has not been fully characterized. This study will measure the durability of pyrethroid-PBO ITNs to assess whether they meet the World Health Organization (WHO) three years of operational performance criteria required to be categorized as "long-lasting". METHODS: A prospective household randomized controlled trial will be conducted simultaneously in Tanzania, India and Côte d'Ivoire to estimate the field durability of three pyrethroid-PBO ITNs (Veeralin®, Tsara® Boost, and Olyset® Plus) compared to a pyrethroid LLIN: MAGNet®. Durability monitoring will be conducted up to 36 months post-distribution and median survival in months will be calculated. The proportion of ITNs: (1) lost (attrition), (2) physical integrity, (3) resistance to damage score, (4) meeting WHO bio-efficacy (≥ 95% knockdown after 1 h or ≥ 80% mortality after 24 h for WHO cone bioassay, or ≥ 90% blood-feeding inhibition or ≥ 80% mortality after 24 h for WHO Tunnel tests) criteria against laboratory-reared resistant and susceptible mosquitoes, and insecticidal persistence over time will be estimated. The non-inferiority of Veeralin® and Tsara® Boost to the first-in-class, Olyset® Plus will additionally be assessed for mortality, and the equivalence of 20 times washed ITNs compared to field aged ITNs will be assessed for mortality and blood-feeding inhibition endpoints in the Ifakara Ambient Chamber Test, Tanzania. CONCLUSION: This will be the first large-scale prospective household randomized controlled trial of pyrethroid-PBO ITNs in three different countries in East Africa, West Africa and South Asia, simultaneously. The study will generate information on the replenishment intervals for PBO nets.

Efficacy of the spatial repellent product Mosquito Shield™ against wild pyrethroid-resistant Anopheles arabiensis in south-eastern Tanzania.

BACKGROUND: Spatial repellents that create airborne concentrations of an active ingredient (AI) within a space offer a scalable solution to further reduce transmission of malaria, by disrupting mosquito behaviours in ways that ultimately lead to reduced human-vector contact. Passive emanator spatial repellents can protect multiple people within the treated space and can last for multiple weeks without the need for daily user touchpoints, making them less intrusive interventions. They may be particularly advantageous in certain use cases where implementation of core tools may be constrained, such as in humanitarian emergencies and among mobile at-risk populations. The purpose of this study was to assess the efficacy of Mosquito Shield™ deployed in experimental huts against wild, free-flying, pyrethroid-resistant Anopheles arabiensis mosquitoes in Tanzania over 1 month. METHODS: The efficacy of Mosquito Shield™ transfluthrin spatial repellent in reducing mosquito lands and blood-feeding was evaluated using 24 huts: sixteen huts were allocated to Human Landing Catch (HLC) collections and eight huts to estimating blood-feeding. In both experiments, half of the huts received no intervention (control) while the remaining received the intervention randomly allocated to huts and remained fixed for the study duration. Outcomes measured were mosquito landings, blood-fed, resting and dead mosquitoes. Data were analysed by multilevel mixed effects regression with appropriate dispersion and link function accounting for volunteer, hut and day. RESULTS: Landing inhibition was estimated to be 70% (57-78%) [IRR 0.30 (95% CI 0.22-0.43); p < 0.0001] and blood-feeding inhibition was estimated to be 69% (56-79%) [IRR 0.31 (95% CI 0.21-0.44; p < 0.0001] There was no difference in the protective efficacy estimates of landing and blood-feeding inhibition [IRR 0.98 (95% CI 0.53-1.82; p = 0.958]. CONCLUSIONS: This study demonstrated that Mosquito Shield™ was efficacious against a wild pyrethroid-resistant strain of An. arabiensis mosquitoes in Tanzania for up to 1 month and could be used as a complementary or stand-alone tool where gaps in protection offered by core malaria vector control tools exist. HLC is a suitable technique for estimating bite reductions conferred by spatial repellents especially where direct blood-feeding measurements are not practical or are ethically limited.

CDC light traps underestimate the protective efficacy of an indoor spatial repellent against bites from wild Anopheles arabiensis mosquitoes in Tanzania.

BACKGROUND: Methods for evaluating efficacy of core malaria interventions in experimental and operational settings are well established but gaps exist for spatial repellents (SR). The objective of this study was to compare three different techniques: (1) collection of blood-fed mosquitoes (feeding), (2) human landing catch (HLC), and (3) CDC light trap (CDC-LT) collections for measuring the indoor protective efficacy (PE) of the volatile pyrethroid SR product Mosquito Shield™ METHODS: The PE of Mosquito Shield™ against a wild population of pyrethroid-resistant Anopheles arabiensis mosquitoes was determined via feeding, HLC, or CDC-LT using four simultaneous 3 by 3 Latin squares (LS) run using 12 experimental huts in Tanzania. On any given night each technique was assigned to two huts with control and two huts with treatment. The LS were run twice over 18 nights to give a sample size of 72 replicates for each technique. Data were analysed by negative binomial regression. RESULTS: The PE of Mosquito Shield™ measured as feeding inhibition was 84% (95% confidence interval (CI) 58-94% [Incidence Rate Ratio (IRR) 0.16 (0.06-0.42), p < 0.001]; landing inhibition 77% [64-86%, (IRR 0.23 (0.14-0.36) p < 0.001]; and reduction in numbers collected by CDC-LT 30% (0-56%) [IRR 0.70 (0.44-1.0) p = 0.160]. Analysis of the agreement of the PE measured by each technique relative to HLC indicated no statistical difference in PE measured by feeding inhibition and landing inhibition [IRR 0.73 (0.25-2.12) p = 0.568], but a significant difference in PE measured by CDC-LT and landing inhibition [IRR 3.13 (1.57-6.26) p = 0.001]. CONCLUSION: HLC gave a similar estimate of PE of Mosquito Shield™ against An. arabiensis mosquitoes when compared to measuring blood-feeding directly, while CDC-LT underestimated PE relative to the other techniques. The results of this study indicate that CDC-LT could not effectively estimate PE of the indoor spatial repellent in this setting. It is critical to first evaluate the use of CDC-LT (and other tools) in local settings prior to their use in entomological studies when evaluating the impact of indoor SR to ensure that they reflect the true PE of the intervention.

Measuring severe obesity in pediatrics using body mass index-derived metrics from the Centers for Disease Control and Prevention and World Health Organization: a secondary analysis of CANadian Pediatric Weight management Registry (CANPWR) data.

To examine the (i) relationships between various body mass index (BMI)-derived metrics for measuring severe obesity (SO) over time based the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) references and (ii) ability of these metrics to discriminate children and adolescents based on the presence of cardiometabolic risk factors. In this cohort study completed from 2013 to 2021, we examined data from 3- to 18-year-olds enrolled in the CANadian Pediatric Weight management Registry. Anthropometric data were used to create nine BMI-derived metrics based on the CDC and WHO references. Cardiometabolic risk factors were examined, including dysglycemia, dyslipidemia, and elevated blood pressure. Analyses included Pearson correlations, intraclass correlation coefficients (ICC), and receiver operator characteristic area-under-the-curve (ROC AUC). Our sample included 1,288 participants (n = 666 [52%] girls; n = 874 [68%] white). The prevalence of SO varied from 60-67%, depending on the definition. Most BMI-derived metrics were positively and significantly related to one another (r = 0.45-1.00); ICCs revealed high tracking (0.90-0.94). ROC AUC analyses showed CDC and WHO metrics had a modest ability to discriminate the presence of cardiometabolic risk factors, which improved slightly with increasing numbers of risk factors. Overall, most BMI-derived metrics rated poorly in identifying presence of cardiometabolic risk factors.    Conclusion: CDC BMI percent of the 95th percentile and WHO BMIz performed similarly as measures of SO, although neither showed particularly impressive discrimination. They appear to be interchangeable in clinical care and research in pediatrics, but there is a need for a universal standard. WHO BMIz may be useful for clinicians and researchers from countries that recommend using the WHO growth reference. What is Known: • Severe obesity in pediatrics is a global health issue. • Few reports have evaluated body mass index (BMI)-derived metrics based on the World Health Organization growth reference. What is New: • Our analyses showed that the Centers for Disease Control and Prevention BMI percent of the 95th percentile and World Health Organization (WHO) BMI z-score (BMIz) performed similarly as measures of severe obesity in pediatrics. • WHO BMIz should be a useful metric to measure severe obesity for clinicians and researchers from countries that recommend using the WHO growth reference.

Home-based versus centre-based cardiac rehabilitation.

BACKGROUND: Cardiovascular disease is the most common cause of death globally. Traditionally, centre-based cardiac rehabilitation programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based and technology-supported cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation, especially during the SARS-CoV-2 pandemic. This is an update of a review previously published in 2009, 2015, and 2017. OBJECTIVES: To compare the effect of home-based (which may include digital/telehealth interventions) and supervised centre-based cardiac rehabilitation on mortality and morbidity, exercise-capacity, health-related quality of life, and modifiable cardiac risk factors in patients with heart disease SEARCH METHODS: We updated searches from the previous Cochrane Review by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) on 16 September 2022. We also searched two clinical trials registers as well as previous systematic reviews and reference lists of included studies. No language restrictions were applied. SELECTION CRITERIA: We included randomised controlled trials that compared centre-based cardiac rehabilitation (e.g. hospital, sports/community centre) with home-based programmes (± digital/telehealth platforms) in adults with myocardial infarction, angina, heart failure, or who had undergone revascularisation. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all identified references for inclusion based on predefined inclusion criteria. Disagreements were resolved through discussion or by involving a third review author. Two authors independently extracted outcome data and study characteristics and assessed risk of bias. Certainty of evidence was assessed using GRADE. MAIN RESULTS: We included three new trials in this update, bringing a total of 24 trials that have randomised a total of 3046 participants undergoing cardiac rehabilitation. A further nine studies were identified and are awaiting classification. Manual searching of trial registers until 16 September 2022 revealed a further 14 clinical trial registrations - these are ongoing. Participants had a history of acute myocardial infarction, revascularisation, or heart failure. Although there was little evidence of high risk of bias, a number of studies provided insufficient detail to enable assessment of potential risk of bias; in particular, details of generation and concealment of random allocation sequencing and blinding of outcome assessment were poorly reported. No evidence of a difference was seen between home- and centre-based cardiac rehabilitation in our primary outcomes up to 12 months of follow-up: total mortality (risk ratio [RR] = 1.19, 95% confidence interval [CI] 0.65 to 2.16; participants = 1647; studies = 12/comparisons = 14; low-certainty evidence) or exercise capacity (standardised mean difference (SMD) = -0.10, 95% CI -0.24 to 0.04; participants = 2343; studies = 24/comparisons = 28; low-certainty evidence). The majority of evidence (N=71 / 77 comparisons of either total or domain scores) showed no significant difference in health-related quality of life up to 24 months follow-up between home- and centre-based cardiac rehabilitation. Trials were generally of short duration, with only three studies reporting outcomes beyond 12 months (exercise capacity: SMD 0.11, 95% CI -0.01 to 0.23; participants = 1074; studies = 3; moderate-certainty evidence). There was a similar level of trial completion (RR 1.03, 95% CI 0.99 to 1.08; participants = 2638; studies = 22/comparisons = 26; low-certainty evidence) between home-based and centre-based participants. The cost per patient of centre- and home-based programmes was similar. AUTHORS' CONCLUSIONS: This update supports previous conclusions that home- (± digital/telehealth platforms) and centre-based forms of cardiac rehabilitation formally supported by healthcare staff seem to be similarly effective in improving clinical and health-related quality of life outcomes in patients after myocardial infarction, or revascularisation, or with heart failure. This finding supports the continued expansion of healthcare professional supervised home-based cardiac rehabilitation programmes (± digital/telehealth platforms), especially important in the context of the ongoing global SARS-CoV-2 pandemic that has much limited patients in face-to-face access of hospital and community health services. Where settings are able to provide both supervised centre- and home-based programmes, consideration of the preference of the individual patient would seem appropriate. Although not included in the scope of this review, there is an increasing evidence base supporting the use of hybrid models that combine elements of both centre-based and home-based cardiac rehabilitation delivery. Further data are needed to determine: (1) whether the short-term effects of home/digital-telehealth and centre-based cardiac rehabilitation models of delivery can be confirmed in the longer term; (2) the relative clinical effectiveness and safety of home-based programmes for other heart patients, e.g. post-valve surgery and atrial fibrillation.