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Nanoparticles (NPs), as drug delivery systems, appear to be a promising tool for prolonged therapeutic strategies as they allow a controlled drug release over time. However, most of the studies found in the literature simply contemplate the use of a single or low number of dosages with low NPs concentrations. In the context of chronic diseases, like Alzheimer's disease, cancer or human immunodeficiency virus (HIV), where the therapeutic scheme is also chronic, studies with numerous repeated dosages are often neglected. We screened different NPs, polymeric and lipid-based, in a repeated-dose toxicity study, to evaluate the safety and tissue distribution of promising nanocarriers to be used in the treatment of long-lasting diseases. After administrating 24 high concentrated doses of the selected NPs intraperitoneally (i.p.) (3 times a week for 2 months), animals have presented NPs accumulation in different tissues. However, neither toxicity, bodyweight changes nor clinical signs of disease were observed. This work demonstrates no general adverse effects upon the studied NPs repeated-dose exposure, indicating the most promising NPs to be used in the different therapeutic circumstances, which may be useful in chronic diseases treatment.

Background ICON® Maxx (Syngenta) is an insecticide treatment kit of pyrethroid and binding agent for long-lasting treatment of mosquito nets. Interim recommendation for use on nets was granted by the World Health Organization (WHO) after successful evaluation in experimental huts following multiple washes. A full WHO recommendation is contingent upon demonstration of continued bio-efficacy after 3 years of use. Methods A household-randomized prospective study design was used to assess ICON Maxx-treated nets over 3 years in north-eastern Tanzania. Conventional treated nets (with lambda-cyhalothrin, but without binder) served as a positive control. At 6-monthly intervals, cross-sectional household surveys monitored net use and physical integrity, while cone and tunnel tests assessed insecticidal efficacy. Pyrethroid content was determined after 12 and 36 months. A parallel cohort of nets was monitored annually for evidence of net deterioration and attrition. Results After 12 months’ use, 97% of ICON Maxx-treated nets but only 67% of CTN passed the WHO efficacy threshold for insecticidal durability (> 80% mortality in cone or tunnel or 90% feeding inhibition in tunnel). After 24- and 36-months use, 67% and 26% of ICON Maxx treated nets met the cone criteria, respectively, and over 90% met the combined cone and tunnel criteria. Lambda-cyhalothrin content after 36 months was 17% (15.8 ± 4.3 mg/m 2 ) of initial content. ICON Maxx nets were used year-round and washed approximately 4 times per year. In cross-sectional survey after 36 months the average number of holes was 20 and hole index was 740 cm 2 per net. Cohort nets had fewer holes and smaller hole index than cross-sectional nets. However, only 15% (40/264) of cohort nets were not lost to follow-up or not worn out after 36 months. Conclusions Because more than 80% of nets met the WHO efficacy criteria after 36 months use, ICON Maxx was granted WHO full recommendation. Cross-sectional and cohort surveys were complementary and gave a fuller understanding of net durability. To improve net usage and retention, stronger incentives and health messaging should be introduced in WHO LLIN longitudinal trials. Untreated polyester nets may be made long-lastingly insecticidal in Africa through simple household treatment using ICON Maxx pyrethroid-binder kits.

Background After almost 70 years of using indoor residual spraying (IRS) as the primary intervention for malaria vector control, the Republic of Panama wanted to evaluate the operational feasibility and acceptability of distributing long-lasting insecticidal hammock nets (LLIHNs) and long-lasting insecticidal nets (LLINs) in the country. Methods A pilot study conducted in 2019 distributed LLINs and LLIHNs to cover all sleeping spaces in 15 high burden localities of the indigenous Comarca of Guna Yala and measured retention, coverage, use and physical deterioration, washing and drying practices, as well as people’s satisfaction with product characteristics post-distribution. Results Overall, 89.9% of enumerated sleeping spaces were covered during the campaign. Monitoring post-distribution showed that 82.7% of the population received messages about the campaign before it happened and 92.4% claimed to know the purpose of the net and how to care for and repair it. Mild adverse reactions, specifically skin irritation associated with the insecticide in LLINs and LLIHNs, were reported by 38.4% of households. Two years after distribution, 86.3% of the LLIHN/LLINs were retained. Use was very high right after distribution (85%) but decreased to 57% six months after distribution and to 38% two years after distribution. The main reason for not using the LLIHN/LLINs was the reported absence of mosquitoes. Two years post-distribution, LLIHN/LLINs were preserved in good physical condition (4% torn), very few were washed with insecticide-damaging products (chlorine or detergent) (9%) or dried under the sun (15%), and LLIHN/LLINs were washed on average less than once every two months. The average number of people per sleeping space was 1.34. Conclusion Although the distribution of LLIHN/LLINs was operationally feasible and LLIHN/LLINs were initially well-accepted and cared for by these communities, use decreased drastically over the two years of follow up after distribution. Hence, should there be future LLIHN/LLIN distributions in this area, sufficient resources and efforts need to be allocated to promoting LLIHN/LLIN use. Further investigation into the reasons for low LLIHN/LLIN use are needed to guide such efforts.

Background Pregnant women are particularly vulnerable to many health conditions, including infectious diseases, which place them at elevated risk of severe outcomes. In particular, malaria poses a significant burden during pregnancy, and as such there has long been a strong focus on delivering malaria prevention interventions to pregnant women during antenatal care (ANC), including long-lasting insecticide-treated nets (LLINs) and intermittent preventive treatment in pregnancy (IPTp). However, outreach to drive uptake of these interventions presents some distinct challenges. For example, pregnant women may not attend ANC or may not do it in public health facilities, where these interventions are freely available, precluding access. In this study, an implementation of routine annual indoor residual spraying (IRS) on Bioko Island, Equatorial Guinea was leveraged to identify pregnant women and conduct follow-up visits focused on awareness and uptake of LLINs and IPTp. Methods IRS campaign data was used to generate lists of households with pregnant women for follow-up visits, during which communication agents conducted an interview based on relevant sections of a malaria indicator survey to assess knowledge about malaria, LLINs and IPTp, and uptake of these interventions. Uptake was defined on an ordinal, three-category scale, and ordinal regression modeling was performed to assess the relationship between uptake and knowledge indicators. Results In total, 1,567 households were visited, and 589 pregnant women identified. There was a high awareness about LLINs (76.9% cited LLINs as a malaria prevention method), but low awareness of IPTp (34.5% could cite any benefit and 37.1% were aware of availability in public health facilities). In line with awareness levels, regular use of LLINs (54.8% reported using every night) was higher than IPTp uptake (35.2% on track for three doses). Ordinal regression modelling confirmed that LLIN use on some or all nights was associated with awareness that LLINs prevent malaria, and IPTp uptake was associated with awareness of the number of doses required. Conclusions This work demonstrated that complementary malaria control interventions can be leveraged to identify pregnant women for further outreach. The information collected provides a baseline to evaluate the impact of future activities on Bioko Island and suggests that increasing awareness of IPTp could improve coverage, while further increasing LLIN use will likely require identifying specific barriers to use.

Introduction Long-lasting pain in adolescents may affect education, social interactions, and is associated with mental health challenges. Current interventions are often suboptimal due to insufficient understanding of the challenges faced by adolescents with long-lasting pain and those who support them. Understanding the management challenges experienced by adolescents with long-lasting pain, along with those faced by their parents, education professionals, and healthcare professionals (HCPs), is crucial for informing person-centered interventions and improving care and outcomes. Objectives This study aimed to gather insights and visions from adolescents with long-lasting pain, along with their parents, HCPs, and teachers, to develop a person-centered intervention for managing pain. Methods We used a qualitative Action Research approach, employing three workshops with 1) adolescents with long-lasting pain, 2) HCPs and teachers, and 3) parents. Workshops incorporated case vignettes and design-card exercises to foster dialogue, knowledge construction and articulation of insights and visions to inform intervention design. Data were collected through audio recordings, participant artifacts, and field notes, then analyzed using Reflexive Thematic Analysis and matrix synthesis to create a conceptual model highlighting tension points for future interventions. Results In three separate workshops, 13 adolescents with long-lasting pain, 16 HCPs and teachers (four physiotherapists, four senior high school teachers, three psychologists, three school health nurses, and two General Practitioners), and four parents participated. Adolescents described pain’s pervasive impact on their education, social lives, and self-identity. Barriers to improvement included limited coordination between healthcare and school, as well as a lack of communication. The school setting and school health services were identified as an ideal setting for interventions. Key visions for interventions included early holistic assessments, enhanced interdisciplinary collaboration with dedicated coordination roles, specialized adolescent-focused expertise, and the use of digital tools for personalized management. Conclusion This study brought new insights into the development of a person-centered intervention for adolescents with long-lasting pain, highlighting the impact of pain on those affected and barriers to optimal care. It emphasized the need for including education professionals and school health services in interdisciplinary collaboration, holistic assessments, and improved expertise in adolescent pain management.

Background Conflicting results exist on the added benefit of combining long-lasting insecticidal nets (LLINs) with indoor residual spraying (IRS) to control malaria infection. The main study objective was to evaluate whether the combined use of LLINs and IRS with propoxur provides additional protection against Plasmodium falciparum and/or Plasmodium vivax among all age groups compared to LLINs or IRS alone. Methods This cluster-randomized, controlled trial was conducted in the Rift Valley area of Ethiopia from September 2014 to January 2017 (121 weeks); 44 villages were allocated to each of four study arms: LLIN + IRS, IRS, LLIN, and control. Each week, 6071 households with 34,548 persons were surveyed by active and passive case detection for clinical malaria. Primary endpoints were the incidence of clinical malaria and anaemia prevalence. Results During the study, 1183 malaria episodes were identified, of which 55.1% were P. falciparum and 25.3% were P. vivax , and 19.6% were mixed infections of P. falciparum and P. vivax . The overall malaria incidence was 16.5 per 1000 person-years of observation time (PYO), and similar in the four arms with 17.2 per 1000 PYO in the LLIN + IRS arm, 16.1 in LLIN, 17.0 in IRS, and 15.6 in the control arm. There was no significant difference in risk of anaemia among the trial arms. Conclusions The clinical malaria incidence and anaemia prevalence were similar in the four study groups. In areas with low malaria incidence, using LLINs and IRS in combination or alone may not eliminate malaria. Complementary interventions that reduce residual malaria transmission should be explored in addition to LLINs and IRS to further reduce malaria transmission in such settings. Trial registration PACTR201411000882128 (08 September 2014)

Background Quality assurance (QA) of insecticide-treated nets (ITNs) delivered to malaria-endemic countries is conducted by measuring physiochemical parameters, but not bioefficacy against malaria mosquitoes. This study explored utility of cone bioassays for pre-delivery QA of pyrethroid ITNs to test the assumption that cone bioassays are consistent across locations, mosquito strains, and laboratories. Methods Double-blinded bioassays were conducted on twenty unused pyrethroid ITNs of 4 brands (100 nets, 5 subsamples per net) that had been delivered for mass distribution in Papua New Guinea (PNG) having passed predelivery inspections. Cone bioassays were performed on the same net pieces following World Health Organization (WHO) guidelines at the PNG Institute of Medical Research (PNGIMR) using pyrethroid susceptible Anopheles farauti sensu stricto ( s.s .) and at Ifakara Health Institute (IHI), Tanzania using pyrethroid susceptible Anopheles gambiae s.s . Additionally, WHO tunnel tests were conducted at IHI on ITNs that did not meet cone bioefficacy thresholds. Results from IHI and PNGIMR were compared using Spearman’s Rank correlation, Bland–Altman (BA) analysis and analysis of agreement. Literature review on the use of cone bioassays for unused pyrethroid ITNs testing was conducted. Results In cone bioassays, 13/20 nets (65%) at IHI and 8/20 (40%) at PNGIMR met WHO bioefficacy criteria. All nets met WHO bioefficacy criteria on combined cone/tunnel tests at IHI. Results from IHI and PNGIMR correlated on 60-min knockdown (KD60) (r s  = 0.6, p  = 0.002,n = 20) and 24-h mortality (M24) (r s  = 0.9, p  < 0.0001,n = 20) but BA showed systematic bias between the results. Of the 5 nets with discrepant result between IHI and PNGIMR, three had confidence intervals overlapping the 80% mortality threshold, with averages within 1–3% of the threshold. Including these as a pass, the agreement between the results to predict ITN failure was good with kappa = 0.79 (0.53–1.00) and 90% accuracy. Conclusions Based on these study findings, the WHO cone bioassay is a reproducible bioassay for ITNs with > 80% M24, and for all ITNs provided inherent stochastic variation and systematic bias are accounted for. The literature review confirms that WHO cone bioassay bioefficacy criteria have been previously achieved by all pyrethroid ITNs (unwashed), without the need for additional tunnel tests. The 80% M24 threshold remains the most reliable indicator of pyrethroid ITN quality using pyrethroid susceptible mosquitoes. In the absence of alternative tests, cone bioassays could be used as part of pre-delivery QA.

Background A key goal of malaria control is to achieve universal access to, and use of, long-lasting insecticidal nets (LLINs) among people at risk for malaria. Quantifying the number of LLINs needed to achieve and maintain universal coverage requires knowing when nets need replacement. Longitudinal studies have observed physical deterioration in LLINs well before the assumed net lifespan of 3 years. The objective of this study was to describe attrition, physical integrity and insecticide persistence of LLINs over time to assist with better quantification of nets needing replacement. Methods 999 LLINs distributed in 2011 in two highly endemic provinces in Zambia were randomly selected, and were enrolled at 12 months old. LLINs were followed every 6 months up to 30 months of age. Holes were counted and measured (finger, fist, and head method) and a proportional hole index (pHI) was calculated. Households were surveyed about net care and repair and if applicable, reasons for attrition. Functional survival was defined as nets with a pHI <643 and present for follow-up. At 12 and 24 months of age, 74 LLINs were randomly selected for examination of insecticidal activity and content using bioassay and chemical analysis methods previously described by the World Health Organization (WHO). Results A total of 999 LLINs were enrolled; 505 deltamethrin-treated polyester nets and 494 permethrin-treated polyethylene nets. With 74 used to examine insecticide activity, 925 were available for full follow-up. At 30 months, 325 (33 %) LLINs remained. Net attrition was primarily due to disposal (29 %). Presence of repairs and use over a reed mat were significantly associated with larger pHIs. By 30 months, only 56 % of remaining nets met criteria for functional survival. A shorter functional survival was associated with having been washed. At 24 months, nets had reduced insecticidal activity (57 % met WHO minimal criteria) and content (5 % met WHO target insecticide content). Conclusions The median functional survival time for LLINs observed the study was 2.5–3 years and insecticide activity and content were markedly decreased by 2 years. A better measure of net survival incorporating insecticidal field effectiveness, net physical integrity, and attrition is needed.

Background Malaria presents a disproportionate threat to pregnant women, making access to malaria prevention tools crucial for controlling the disease in this vulnerable population. Methods This prospective descriptive study targeted women of reproductive age (13–49 years old) living in the Mopeia district, a high malaria endemic area in Zambezia province, Mozambique. As part of the BOHEMIA cluster randomized trial, the study included a simplified and full census to collect data on socio-demographic, socio-economic and household factors, health status, and malaria prevention tools from the target population. Results Data from 7,099 women of reproductive age living in the BOHEMIA clinical trial study area was collected, including 497 (7.0%) self-referred as pregnant. Access to malaria vector control tools was high, with 89.9% of women self-referred as pregnant, 87.9% of women self-referred as not- pregnant living in a household with at least one long-lasting insecticidal net and 69.6% of women self-referred as pregnant and 73.4% of women self-referred as not-pregnant living in household that received indoor residual spraying in the past 12 months. Intermittent preventive treatment coverage was moderate-low, with 53.1% of women self-reported as pregnant having taken at least one dose. Conclusions This study found that women of reproductive age in the highly-endemic Mopeia district have good access to malaria vector control tools. However, intermittent preventive treatment coverage remains below World Health Organization-recommended levels. Focused efforts are needed to improve this coverage, and continuous monitoring along with tailored interventions are essential for achieving optimal prevention outcomes among vulnerable populations.

Background Long-lasting insecticidal nets (LLINs) are the principal tool for malaria control in Africa and are presently treated with a single class of insecticide; however, increasing levels of insecticide resistance threaten their success. In response to this threat nets have been developed that incorporate the synergist, piperonyl butoxide (PBO), which inhibits the activity of cytochrome P450s which is one main mechanisms of insecticide resistance, allowing resistance to pyrethroids to be reversed. However, data on the value and cost effectiveness of these nets is lacking. A large-scale cluster randomised trial of conventional LLINs and PBO-LLINs was conducted in Uganda in 104 health sub-districts (HSDs) in 2017–2019. Prior to the mass distribution of LLINs, a baseline entomological survey was carried out, the results of which are reported herein. Ten households from each HSD were randomly selected for entomological surveillance at baseline which included household mosquito collections. Results Prior to LLIN distribution entomological collections were carried out in 1029 houses across the 104 HSDs. Anopheles gambiae ( s.l. ) was the principal vector in all but 9 of the 71 HSDs that yielded vector species. Molecular analysis found An. gambiae ( s.s. ) to be the predominant vector collected. Plasmodium falciparum was detected in 5.5% of An. gambiae ( s.s. ) and in 4.0% of An. funestus ( s.s. ) examined. Infection rates of other plasmodium species ( P. vivax , P. ovale and P. malariae ) were lower with infection rates of 1.2% and 1.7% for An. gambiae ( s.s. ) and An. funestus ( s.s. ), respectively. The knockdown resistance ( kdr) mutation Vgsc -L1014S was found at very high frequency in An. gambiae ( s.s. ) with the Vgsc -L1014F mutation at low frequency and the wild-type allele virtually absent. In An. arabiensis the wild-type allele was predominant. The resistance-associated alleles, Cyp4j5 -L43F and Coeae1d were found at moderate frequencies which varied across the study site. Vgsc -N1575Y mutation was not found in any samples examined. Conclusions No significant differences between planned intervention arms was observed in vector densities, sporozoite infection rate or insecticide resistance marker frequency across the study site prior to the distribution of LLINs. Very high levels of kdr resistance were observed in all areas; however, the resistance-associated markers Cyp4j5 -L43F and Coeae1d were found at varying frequencies across the study site which may have implications for the effectiveness of standard LLINs. Trial registration This study is registered with ISRCTN, ISRCTN17516395. Registered 14 February 2017, http://www.isrctn.com/ISRCTN17516395