Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine and prevalence of molecular markers of anti-malarial drug resistance in children in Togo in 2021.

BACKGROUND: Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are the currently recommended first- and second-line therapies for uncomplicated Plasmodium falciparum infections in Togo. This study assessed the efficacy of these combinations, the proportion of Day3-positive patients (D3 +), the proportion of molecular markers associated with P. falciparum resistance to anti-malarial drugs, and the variable performance of HRP2-based malaria rapid diagnostic tests (RDTs). METHODS: A single arm prospective study evaluating the efficacy of AL and DP was conducted at two sites (Kouvé and Anié) from September 2021 to January 2022. Eligible children were enrolled, randomly assigned to treatment at each site and followed up for 42 days after treatment initiation. The primary endpoint was polymerase chain reaction (PCR) adjusted adequate clinical and parasitological response (ACPR). At day 0, samples were analysed for mutations in the Pfkelch13, Pfcrt, Pfmdr-1, dhfr, dhps, and deletions in the hrp2/hrp3 genes. RESULTS: A total of 179 and 178 children were included in the AL and DP groups, respectively. After PCR correction, cure rates of patients treated with AL were 97.5% (91.4-99.7) at day 28 in Kouvé and 98.6% (92.4-100) in Anié, whereas 96.4% (CI 95%: 89.1-98.8) and 97.3% (CI 95%: 89.5-99.3) were observed at day 42 in Kouvé and Anié, respectively. The cure rates of patients treated with DP at day 42 were 98.9% (CI 95%: 92.1-99.8) in Kouvé and 100% in Anié. The proportion of patients with parasites on day 3 (D3 +) was 8.5% in AL and 2.6% in DP groups in Anié and 4.3% in AL and 2.1% DP groups in Kouvé. Of the 357 day 0 samples, 99.2% carried the Pfkelch13 wild-type allele. Two isolates carried nonsynonymous mutations not known to be associated with artemisinin partial resistance (ART-R) (A578S and A557S). Most samples carried the Pfcrt wild-type allele (97.2%). The most common Pfmdr-1 allele was the single mutant 184F (75.6%). Among dhfr/dhps mutations, the quintuple mutant haplotype N51I/C59R/S108N + 437G/540E, which is responsible for SP treatment failure in adults and children, was not detected. Single deletions in hrp2 and hrp3 genes were detected in 1/357 (0.3%) and 1/357 (0.3%), respectively. Dual hrp2/hrp3 deletions, which could affect the performances of HRP2-based RDTs, were not observed. CONCLUSION: The results of this study confirm that the AL and DP treatments are highly effective. The absence of the validated Pfkelch13 mutants in the study areas suggests the absence of ART -R, although a significant proportion of D3 + cases were found. The absence of dhfr/dhps quintuple or sextuple mutants (quintuple + 581G) supports the continued use of SP for IPTp during pregnancy and in combination with amodiaquine for seasonal malaria chemoprevention. TRIAL REGISTRATION: ACTRN12623000344695.

Progress towards malaria elimination in the Greater Mekong Subregion: perspectives from the World Health Organization.

Malaria remains a global health challenge, disproportionately affecting vulnerable communities. Despite substantial progress, the emergence of anti-malarial drug resistance poses a constant threat. The Greater Mekong Subregion (GMS), which includes Cambodia, China's Yunnan province, Lao People's Democratic Republic, Myanmar, Thailand, and Viet Nam has been the epicentre for the emergence of resistance to successive generations of anti-malarial therapies. From the perspective of the World Health Organization (WHO), this article considers the collaborative efforts in the GMS, to contain Plasmodium falciparum artemisinin partial resistance and multi-drug resistance and to advance malaria elimination. The emergence of artemisinin partial resistance in the GMS necessitated urgent action and regional collaboration resulting in the Strategy for Malaria Elimination in the Greater Mekong Subregion (2015-2030), advocating for accelerated malaria elimination interventions tailored to country needs, co-ordinated and supported by the WHO Mekong malaria elimination programme. The strategy has delivered substantial reductions in malaria across all GMS countries, with a 77% reduction in malaria cases and a 97% reduction in malaria deaths across the GMS between 2012 and 2022. Notably, China was certified malaria-free by WHO in 2021. Countries' ownership and accountability have been pivotal, with each GMS country outlining its priorities in strategic and annual work plans. The development of strong networks for anti-malarial drug resistance surveillance and epidemiological surveillance was essential. Harmonization of policies and guidelines enhanced collaboration, ensuring that activities were driven by evidence. Challenges persist, particularly in Myanmar, where security concerns have limited recent progress, though an intensification and acceleration plan aims to regain momentum. Barriers to implementation can slow progress and continuing innovation is needed. Accessing mobile and migrant populations is key to addressing remaining transmission foci, requiring effective cross-border collaboration. In conclusion, the GMS has made significant progress towards malaria elimination, particularly in the east where several countries are close to P. falciparum elimination. New and persisting challenges require sustained efforts and continued close collaboration. The GMS countries have repeatedly risen to every obstacle presented, and now is the time to re-double efforts and achieve the 2030 goal of malaria elimination for the region.

The Npc2Gt(LST105)BygNya mouse signifies pathological changes comparable to human Niemann-Pick type C2 disease.

INTRODUCTION: Niemann-Pick type C2 disease (NP-C2) is a fatal neurovisceral disorder caused by defects in the lysosomal cholesterol transporter protein NPC2. Consequently, cholesterol and other lipids accumulate within the lysosomes, causing a heterogeneous spectrum of clinical manifestations. Murine models are essential for increasing the understanding of the complex pathology of NP-C2. This study, therefore, aims to describe the neurovisceral pathology in the NPC2-deficient mouse model to evaluate its correlation to human NP-C2. METHODS: Npc2-/- mice holding the LST105 mutation were used in the present study (Npc2Gt(LST105)BygNya). Body and organ weight and histopathological evaluations were carried out in six and 12-week-old Npc2-/- mice, with a special emphasis on neuropathology. The Purkinje cell (PC) marker calbindin, the astrocytic marker GFAP, and the microglia marker IBA1 were included to assess PC degeneration and neuroinflammation, respectively. In addition, the pathology of the liver, lungs, and spleen was assessed using hematoxylin and eosin staining. RESULTS: Six weeks old pre-symptomatic Npc2-/- mice showed splenomegaly and obvious neuropathological changes, especially in the cerebellum, where initial PC loss and neuroinflammation were evident. The Npc2-/- mice developed neurological symptoms at eight weeks of age, severely progressing until the end-stage of the disease at 12 weeks. At the end-stage of the disease, Npc2-/- mice were characterized by growth retardation, tremor, cerebellar ataxia, splenomegaly, foam cell accumulation in the lungs, liver, and spleen, brain atrophy, pronounced PC degeneration, and severe neuroinflammation. CONCLUSION: The Npc2Gt(LST105)BygNya mouse model resembles the pathology seen in NP-C2 patients and denotes a valuable model for increasing the understanding of the complex disease manifestation and is relevant for testing the efficacies of new treatment strategies.

Is patients' activities of daily living self-care score in Norwegian home care a proxy for workers standing at work?

BACKGROUND: Prolonged standing at work may contribute to increased risk of musculoskeletal pain in home care workers. Patients' activities of daily living (ADL) score may be a proxy for home care workers' standing time at work. The objective of the present study was to investigate the association between patients' ADL self-care score, and workers standing time. METHODS: This cross-sectional study measured time spent standing, sitting and in physical activity for seven days using thigh-worn accelerometers, among 14 home care workers. Patients' ADL self-care scores are routinely adjusted by home care nurses, and time intervals of home care visits are stored in home care services electronic patient journal. We collected ADL self-care scores and start and end time points of visits, and categorized ADL self-care scores as low (ADL ≤ 2.0), medium (ADL > 2.0 to 3.0) or high (ADL > 3.0). Physical behavior data were transformed to isometric log-ratios and a mixed-effect model was used to investigate differences in physical behavior between the three ADL self-care score categories. RESULTS: We analyzed 931 patient visits and found that high ADL self-care scores were associated with longer standing times relative to sitting and physical activity, compared to low ADL score (0.457, p = 0.001). However, no significant differences in time spent standing were found between high and medium ADL patient visits (0.259, p = 0.260), nor medium and low (0.204, p = 0.288). High ADL score patients made up 33.4% of the total care time, despite only making up 7.8% of the number of patients. CONCLUSION: Our findings suggest that caring for patients with high ADL self-care score requires workers to stand for longer durations and that this group of patients constitute a significant proportion of home care workers' total work time. The findings of this study can inform interventions to improve musculoskeletal health among home care workers by appropriate planning of patient visits.

A novel strategy for delivering Niemann-Pick type C2 proteins across the blood-brain barrier using the brain endothelial-specific AAV-BR1 virus.

Treating central nervous system (CNS) diseases is complicated by the incapability of numerous therapeutics to cross the blood-brain barrier (BBB), mainly composed of brain endothelial cells (BECs). Genetically modifying BECs into protein factories that supply the CNS with recombinant proteins is a promising approach to overcome this hindrance, especially in genetic diseases, like Niemann Pick disease type C2 (NPC2), where both CNS and peripheral cells are affected. Here, we investigated the potential of the BEC-specific adeno-associated viral vector (AAV-BR1) encoding NPC2 for expression and secretion from primary BECs cultured in an in vitro BBB model with mixed glial cells, and in healthy BALB/c mice. Transduced primary BECs had significantly increased NPC2 gene expression and secreted NPC2 after viral transduction, which significantly reversed cholesterol deposition in NPC2 deficient fibroblasts. Mice receiving an intravenous injection with AAV-BR1-NCP2-eGFP were sacrificed 8 weeks later and examined for its biodistribution and transgene expression of eGFP and NPC2. AAV-BR1-NPC2-eGFP was distributed mainly to the brain and lightly to the heart and lung, but did not label other organs including the liver. eGFP expression was primarily found in BECs throughout the brain but occasionally also in neurons suggesting transport of the vector across the BBB, a phenomenon also confirmed in vitro. NPC2 gene expression was up-regulated in the brain, and recombinant NPC2 protein expression was observed in both transduced brain capillaries and neurons. Our findings show that AAV-BR1 transduction of BECs is possible and that it may denote a promising strategy for future treatment of NPC2.

Antimalarial drug efficacy and resistance in malaria-endemic countries in HANMAT-PIAM_net countries of the Eastern Mediterranean Region 2016-2020: Clinical and genetic studies.

INTRODUCTION: The World Health Organization recommends regular monitoring of the efficacy of nationally recommended antimalarial drugs. We present the results of studies on the efficacy of recommended antimalarials and molecular markers of artemisinin and partner resistance in Afghanistan, Pakistan, Somalia, Sudan and Yemen. METHODS: Single-arm prospective studies were conducted to evaluate the efficacy of artesunate-sulfadoxine-pyrimethamine (ASSP) in Afghanistan and Pakistan, artemether-lumefantrine (AL) in all countries, or dihydroartemisinin-piperaquine (DP) in Sudan for the treatment of Plasmodium falciparum. The efficacy of chloroquine (CQ) and AL for the treatment of Plasmodium vivax was evaluated in Afghanistan and Somalia, respectively. Patients were treated and monitored for 28 (CQ, ASSP and AL) or 42 (DP) days. Polymerase chain reaction (PCR)-corrected cure rate and parasite positivity rate at Day 3 were estimated. Mutations in the P. falciparum kelch 13 (Pfk13) gene and amplifications of plasmepsin (Pfpm2) and multidrug resistance-1 (Pfmdr-1) genes were also studied. RESULTS: A total of 1680 (249 for ASSP, 1079 for AL and 352 for DP) falciparum cases were successfully assessed. A PCR-adjusted ASSP cure rate of 100% was observed in Afghanistan and Pakistan. For AL, the cure rate was 100% in all but four sites in Sudan, where cure rates ranged from 92.1% to 98.8%. All but one patient were parasite-free at Day 3. For P. vivax, cure rates were 98.2% for CQ and 100% for AL. None of the samples from Afghanistan, Pakistan and Yemen had a Pfk13 mutation known to be associated with artemisinin resistance. In Sudan, the validated Pfk13 R622I mutation accounted for 53.8% (14/26) of the detected non-synonymous Pfk13 mutations, most of which were repeatedly detected in Gadaref. A prevalence of 2.7% and 9.3% of Pfmdr1 amplification was observed in Pakistan and Yemen, respectively. CONCLUSION: High efficacy of ASSP, AL and DP in the treatment of uncomplicated falciparum infection and of CQ and AL in the treatment of P. vivax was observed in the respective countries. The repeated detection of a relatively high rate of Pfk13 R622I mutation in Sudan underscores the need for close monitoring of the efficacy of recommended ACTs, parasite clearance rates and Pfk13 mutations in Sudan and beyond. Registration numbers of the trials: ACTRN12622000944730 and ACTRN12622000873729 for Afghanistan, ACTRN12620000426987 and ACTRN12617001025325 for Pakistan, ACTRN12618001224213 for Somalia, ACTRN12617000276358, ACTRN12622000930785 and ACTRN12618001800213 for Sudan and ACTRN12617000283370 for Yemen.

Therapeutic efficacy of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Chad: clinical and genetic surveillance.

BACKGROUND: Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are the currently recommended first-and second-line therapies for uncomplicated Plasmodium falciparum infections in Chad. This study assessed the efficacy of these artemisinin-based combinations, proportion of day 3 positive patients, proportions of molecular markers associated with P. falciparum resistance to anti-malarial drugs and variable performance of HRP2-based malaria rapid diagnostic tests (RDTs). METHODS: A single-arm prospective study assessing the efficacy of AS-AQ and AL at three sites (Doba, Kelo and Koyom) was conducted between November 2020 to January 2021. Febrile children aged 6 to 59 months with confirmed uncomplicated P. falciparum infection were enrolled sequentially first to AS-AQ and then AL at each site and followed up for 28 days. The primary endpoint was PCR-adjusted adequate clinical and parasitological response (ACPR). Samples collected on day 0 were analysed for mutations in pfkelch13, pfcrt, pfmdr-1, pfdhfr, pfdhps genes and deletions in pfhrp2/pfhrp3 genes. RESULTS: By the end of 28-day follow-up, per-protocol PCR corrected ACPR of 97.8% (CI 95% 88.2-100) in Kelo and 100% in Doba and Kayoma were observed among AL treated patients. For ASAQ, 100% ACPR was found in all sites. All, but one patient, did not have parasites detected on day 3. Out of the 215 day 0 samples, 96.7% showed pfkelch13 wild type allele. Seven isolates carried nonsynonymous mutations not known to be associated artemisinin partial resistance (ART-R). Most of samples had a pfcrt wild type allele (79% to 89%). The most prevalent pfmdr-1 allele detected was the single mutant 184F (51.2%). For pfdhfr and pfdhps mutations, the quintuple mutant allele N51I/C59R/S108N + G437A/540E responsible for SP treatment failures in adults and children was not detected. Single deletion in the pfhrp2 and pfhrp3 gene were detected in 10/215 (4.7%) and 2/215 (0.9%), respectively. Dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, were observed in 5/215 (2.3%) isolates. CONCLUSION: The results of this study confirm that AS-AQ and AL treatments are highly efficacious in study areas in Chad. The absence of known pfkelch13 mutations in the study sites and the high parasite clearance rate at day 3 suggest the absence of ART-R. The absence of pfdhfr/pfdhps quintuple or sextuple (quintuple + 581G) mutant supports the continued use of SP for IPTp during pregnancy. The presence of parasites with dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, warrants the continued surveillance. Trial registration ACTRN12622001476729.

Objective Measurement of Posture and Movement in Young Children Using Wearable Sensors and Customised Mathematical Approaches: A Systematic Review.

Given the importance of young children's postures and movements to health and development, robust objective measures are required to provide high-quality evidence. This study aimed to systematically review the available evidence for objective measurement of young (0-5 years) children's posture and movement using machine learning and other algorithm methods on accelerometer data. From 1663 papers, a total of 20 papers reporting on 18 studies met the inclusion criteria. Papers were quality-assessed and data extracted and synthesised on sample, postures and movements identified, sensors used, model development, and accuracy. A common limitation of studies was a poor description of their sample data, yet over half scored adequate/good on their overall study design quality assessment. There was great diversity in all aspects examined, with evidence of increasing sophistication in approaches used over time. Model accuracy varied greatly, but for a range of postures and movements, models developed on a reasonable-sized (n > 25) sample were able to achieve an accuracy of >80%. Issues related to model development are discussed and implications for future research outlined. The current evidence suggests the rapidly developing field of machine learning has clear potential to enable the collection of high-quality evidence on the postures and movements of young children.

Blood-brain barrier transport using a high affinity, brain-selective VNAR antibody targeting transferrin receptor 1.

Transfer across the blood-brain barrier (BBB) remains a significant hurdle for the development of biopharmaceuticals with therapeutic effects within the central nervous system. We established a functional selection method to identify high affinity single domain antibodies to the transferrin receptor 1 (TfR1) with efficient biotherapeutic delivery across the BBB. A synthetic phage display library based on the variable domain of new antigen receptor (VNAR) was used for in vitro selection against recombinant human TfR1 ectodomain (rh-TfR1-ECD) followed by in vivo selection in mouse for brain parenchyma penetrating antibodies. TXB2 VNAR was identified as a high affinity, species cross-reactive VNAR antibody against TfR1-ECD that does not compete with transferrin or ferritin for receptor binding. IV dosing of TXB2 when fused to human Fc domain (TXB2-hFc) at 25 nmol/kg (1.875 mg/kg) in mice resulted in rapid binding to brain capillaries with subsequent transport into the brain parenchyma and specific uptake into TfR1-positive neurons. Likewise, IV dosing of TXB2-hFc fused with neurotensin (TXB2-hFc-NT) at 25 nmol/kg resulted in a rapid and reversible pharmacological response as measured by body temperature reduction. TXB2-hFc did not elicit any acute adverse reactions, bind, or deplete circulating reticulocytes or reduce BBB-expressed endogenous TfR1 in mice. There was no evidence of target-mediated clearance or accumulation in peripheral organs except lung. In conclusion, TXB2 is a high affinity, species cross-reactive, and brain-selective VNAR antibody to TfR1 that rapidly crosses the BBB and exhibits a favorable pharmacokinetic and safety profile and can be readily adapted to carry a wide variety of biotherapeutics from blood to brain.

Pain management in eldercare employees - the role of managers in addressing musculoskeletal pain and pain-related sickness absence.

PURPOSE: Managers' knowledge and behaviors in addressing musculoskeletal pain and sickness absence is not well understood. We investigated the association between managers' knowledge and behaviours in relation to employees' pain and their future risk of musculoskeletal pain and associated sickness absence. METHODS: The prospective study included 535 eldercare employees, and 42 managers from 20 nursing homes. Managers' self-reported knowledge and behaviors in relation to employees' pain were grouped using Principal Components Analysis. Eldercare employees reported pain-related sickness absence, and number of days with musculoskeletal pain repeatedly over 1 year. We investigated associations using mixed-effects regression models. RESULTS: We identified four types of managers' knowledge and behaviors: 1) Pain-prevention (actions for prevention of employee pain), 2) Pain-management (actions to assist employees manage pain), 3) Pain-entitlements (communicating entitlements to employees with pain), and 4) Pain-accommodations (ability to facilitate workplace accommodations for employees with pain). The employees of managers with higher scores on knowledge of pain-entitlements reported fewer days of pain-related sickness absence (ß = -0.62; 95%CI [-1.14; -0.10]). The employees of managers with higher scores on pain-management were more likely to report low back pain (ß = 0.57; 95%CI [0.02; 1.11]). We found several key associations between the knowledge and behaviors measures and pain-related sickness absence (interactions). CONCLUSION: Managers' knowledge and behaviors in relation to employees' pain were associated with employees' future musculoskeletal pain and sickness absence. The relationships are complex, suggesting that a multifaceted approach is needed to ensure that managers are adequately informed on how to manage and accommodate employees with musculoskeletal pain to reduce sickness absence.

Designing industrial work to be 'just right' to promote health - a study protocol for a goldilocks work intervention.

BACKGROUND: The Goldilocks Work Principle expresses that productive work should be designed to promote workers' health. We recently showed that it is feasible to develop and implement modifications to productive work that change physical behaviors (i.e. sitting, standing and being active) in a direction that may promote health among industrial workers. Therefore, the aim of the present study is to conduct a cluster randomised controlled trial investigating health effects of implementing the Goldilocks Work intervention among industrial workers. METHODS: Our implementation plan consists of educating work teams, organizing implementation meetings, and providing feedback to workers. Three meetings with a preselected local workplace group will be scheduled. The first meeting educates the group to use a planning tool by which work can be planned to have 'just right' physical behaviors. The second and third meetings will focus on supporting implementation of the tool in daily work. An expected 28 clusters of work teams across two participating production sites will be randomized to either intervention or control group. Data collection will consist of 1) questionnaires regarding work and musculoskeletal health, 2) wearable sensor measurements of the physical behavior, and 3) assessment of general health indicators, including BMI, blood pressure, and fat percentage. The primary outcome is musculoskeletal health, measured by low back pain intensity, and secondary outcomes are 1) physical behaviors at work, 2) accumulated time in long bouts of sitting, standing, and being active and 3) perceived fatigue and energy during work. Furthermore, implementation and cost of the intervention will be evaluated based on questionnaires and data from the planning tool completed by the workers. DISCUSSION: This study will evaluate the effectiveness and implementation of a 12 - weeks Goldilocks Work intervention with the aim of improving musculoskeletal health among industrial workers. The cluster randomized controlled study design and the evaluation of the implementation, results and costs of the intervention will make it capable of contributing with valuable evidence of how productive work may be designed to promote industrial workers' health. TRIAL REGISTRATION: Clinical trial registration was assigned 10-09-2021 (ISRCTN80969503). https://doi.org/10.1186/ISRCTN80969503.

Using Intervention Mapping to Develop a Decision Support System-Based Smartphone App (selfBACK) to Support Self-management of Nonspecific Low Back Pain: Development and Usability Study.

BACKGROUND: International guidelines consistently endorse the promotion of self-management for people with low back pain (LBP); however, implementation of these guidelines remains a challenge. Digital health interventions, such as those that can be provided by smartphone apps, have been proposed as a promising mode of supporting self-management in people with chronic conditions, including LBP. However, the evidence base for digital health interventions to support self-management of LBP is weak, and detailed descriptions and documentation of the interventions are lacking. Structured intervention mapping (IM) constitutes a 6-step process that can be used to guide the development of complex interventions. OBJECTIVE: The aim of this paper is to describe the IM process for designing and creating an app-based intervention designed to support self-management of nonspecific LBP to reduce pain-related disability. METHODS: The first 5 steps of the IM process were systematically applied. The core processes included literature reviews, brainstorming and group discussions, and the inclusion of stakeholders and representatives from the target population. Over a period of >2 years, the intervention content and the technical features of delivery were created, tested, and revised through user tests, feasibility studies, and a pilot study. RESULTS: A behavioral outcome was identified as a proxy for reaching the overall program goal, that is, increased use of evidence-based self-management strategies. Physical exercises, education, and physical activity were the main components of the self-management intervention and were designed and produced to be delivered via a smartphone app. All intervention content was theoretically underpinned by the behavior change theory and the normalization process theory. CONCLUSIONS: We describe a detailed example of the application of the IM approach for the development of a theory-driven, complex, and digital intervention designed to support self-management of LBP. This description provides transparency in the developmental process of the intervention and can be a possible blueprint for designing and creating future digital health interventions for self-management.

Physical Activity Advice for Prevention and Rehabilitation of Low Back Pain- Same or Different? A Study on Device-Measured Physical Activity and Register-Based Sickness Absence.

Purpose We lack knowledge on whether the advice of "being physically active" should be the same for prevention and rehabilitation of low back pain (LBP). Sickness absence is a key outcome for LBP prevention and rehabilitation. We investigated the associations between physical activity and long-term sickness absence (LTSA) among employees with and without LBP. Methods Between 2011 and 2013, 925 Danish employees wore a Actigraph GTX3 accelerometer for 1-5 workdays to measure physical activity and reported LBP in past 7 days. Employees were followed for 4 years to determine their first register-based LTSA event (≥ 6 consecutive weeks). Results Among employees with LBP, increasing moderate-to-vigorous-intensity physical activity at work by 20 min and decreasing the remaining behaviors at work (ie., sitting, standing and light-intensity activity) by 20 min was associated with 38% (95% CI 17%; 63%) higher LTSA risk. Increasing light-intensity activity at work by 20 min and decreasing 20 min from the remaining behaviors was associated with 18% (95% CI 4%; 30%) lower risk. During leisure, increasing moderate-to-vigorous-intensity activity by 20 min or standing by 40 min was associated with 26% (95% CI 3%; 43%) lower and 37% (95% CI 0%; 87%) higher risk, respectively. Among employees without LBP, we found no such associations. Conclusions The physical activity advice ought to be different for LBP prevention and rehabilitation to reduce LTSA risk, and specified by domain and activity intensity. At work, employees with LBP should be advised to spend time on light-intensity physical activity and limit their time on moderate-to-vigorous-intensity physical activity. During leisure, employees should spend time on moderate-to-vigorous-intensity physical activity.

Is there evidence of anti-malarial multidrug resistance in Burkina Faso?

Recently, Gansané and colleagues published an article on inadequate efficacy of two different forms of artemisinin-based combination therapy (ACT) in Burkina Faso. The development of Plasmodium falciparum resistance to different ACT partner drugs at levels that could affect the efficacy of two ACT would both be startling and a cause for great concern. In reviewing the available data collected since 2008 on ACT efficacy in Burkina Faso, the analysis shows that the reported efficacy of the tested ACT varies greatly. Most of the studies have considerable methodological deviations and challenges, especially in PCR correction done to distinguish between recrudescence and re-infection, and in the failure to omit re-infections in the calculation of efficacy rates. So far, there is no convincing evidence in the articles reviewed that multidrug resistance has emerged in Burkina Faso. However, the potential consequence of failing ACT means that the results published by Gansané et al. urgently need to be confirmed. Furthermore, articles reporting on efficacy data need to include an examination of the potential consequences of any methodological deviations.

The effect of leisure time physical activity and sedentary behaviour on the health of workers with different occupational physical activity demands: a systematic review.

BACKGROUND: Although it is generally accepted that physical activity reduces the risk for chronic non-communicable disease and mortality, accumulating evidence suggests that occupational physical activity (OPA) may not confer the same health benefits as leisure time physical activity (LTPA). It is also unclear if workers in high OPA jobs benefit from LTPA the same way as those in sedentary jobs. Our objective was to determine whether LTPA and leisure time sedentary behaviour (LTSB) confer the same health effects across occupations with different levels of OPA. METHODS: Searches were run in Medline, Embase, PsycINFO, ProQuest Public Health and Scopus from inception to June 9, 2020. Prospective or experimental studies which examined the effects of LTPA or LTSB on all-cause and cardiovascular mortality and cardiovascular disease, musculoskeletal pain, diabetes, metabolic syndrome, arrhythmias and depression among adult workers grouped by OPA (low OPA/sitters, standers, moderate OPA/intermittent movers, high OPA/heavy labourers) were eligible. Results were synthesized using narrative syntheses and harvest plots, and certainty of evidence assessed with GRADE. RESULTS: The review includes 38 papers. Across all outcomes, except cardiovascular mortality, metabolic syndrome and atrial fibrillation, greater LTPA was consistently protective among low OPA, but conferred less protection among moderate and high OPA. For cardiovascular mortality and metabolic syndrome, higher levels of LTPA were generally associated with similar risk reductions among all OPA groups. Few studies examined effects in standers and none examined effects of LTSB across OPA groups. CONCLUSIONS: Evidence suggests that LTPA is beneficial for all workers, but with larger risk reductions among those with low compared to high OPA jobs. This suggests that, in our attempts to improve the health of workers through LTPA, tailored interventions for different occupational groups may be required. More high-quality studies are needed to establish recommended levels of LTPA/LTSB for different OPA groups. PROTOCOL REGISTRATION: PROSPERO # CRD42020191708 .

Day-to-day pattern of work and leisure time physical behaviours: are low socioeconomic status adults couch potatoes or work warriors?

BACKGROUND: Most studies on day-to-day patterns of physical behaviours (i.e. physical activities and sedentary behaviour) are based on adults with high socioeconomic status (SES) and without differentiating between work and leisure time. Thus, we aimed to characterise the day-to-day leisure time physical behaviours patterns among low SES adults and investigate the influence of work physical behaviours. METHODS: This cross-sectional study included 963 adults from low SES occupations (e.g. manufacturing, cleaning and transportation). The participants wore accelerometers for 1-7 days to measure physical behaviours during work and leisure time, expressed as time-use compositions consisting of time spent sedentary, standing or being active (walking, running, stair climbing, or cycling). Compositional multivariate multilevel models were used to regress daily leisure time-use composition against work time-use compositions. Interaction between weekday and (1) type of day, (i.e., work/non-work) and (2) the work time-use composition were tested. Compositional isotemporal substitution was used to interpret the estimates from the models. RESULTS: Each weekday, workers consistently spent most leisure time being sedentary and most work time standing. Leisure time physical behaviours were associated with type of day (p < 0.005, more sedentary on workdays vs. non-workdays), weekday (p < 0.005, more sedentary on Friday, Saturday and Sunday), standing work (p < 0.005, more sedentary and less standing and active leisure time on Sunday), and active work (p < 0.005, less sedentary and more standing and active leisure time on Sunday). Sedentary leisure time increased by 18 min, while standing and active leisure time decreased by 11 and 7 min, respectively, when 30 min were reallocated to standing at work on Sunday. Conversely, sedentary leisure time decreased by 25 min, and standing and active leisure time increased by 15 and 10 min, respectively, when 30 min were reallocated to active time at work on Sunday. CONCLUSIONS: While low SES adults' leisure time was mostly sedentary, their work time was predominantly standing. Work physical behaviours differently influenced day-to-day leisure time behaviours. Thus, public health initiatives aiming to change leisure time behaviours among low SES adults should consider the influence of work physical behaviours.

Movement behavior profiles and obesity: a latent profile analysis of 24-h time-use composition among Danish workers.

BACKGROUND/OBJECTIVES: An element of obesity prevention is increasing total physical activity energy expenditure. However, this approach does not incorporate the balance of various movement behaviors-physical activity, sedentary behaviors and sleep-across domains of the day. We aimed to identify time-use profiles over work and leisure, termed 'movement behavior profiles' and to investigate their association with obesity. SUBJECTS/METHODS: Eight-hundred-and-seven workers completed (a) thigh accelerometry and diaries to determine their 24-h composition of behaviors (sedentary and standing, light physical activity and moderate-to-vigorous physical activity at work and leisure, and time in bed) and (b) obesity measurements. Movement behavior profiles were determined using latent profile analyses of isometric log-ratios of the 24-h composition, and labeled according to animal movement behavior traits. Linear models were applied to determine the association between profiles and obesity. RESULTS: Four profiles were identified, labeled as "Chimpanzees" (n = 226), "Lions" (n = 179), "Ants" (n = 244), and "Koalas" (n = 158). "Chimpanzees" work time was evenly distributed between behaviors while their leisure time was predominantly active. Compared to Chimpanzees, "Lions" were more active at work and sedentary during leisure and spent more time in bed; "Ants" were more active at work and during leisure; "Koalas" were more sedentary at work and leisure and spent similar time in bed. With "Chimpanzees" as reference, "Lions" had least favorable obesity indicators: +2.0 (95% confidence interval [CI] 0.6, 3.4) %body fat, +4.3 cm (1.4, 7.3) waist circumference and +1.0 (2.0, 0.0) Body Mass Index (BMI), followed by "Koalas" +2.0 (0.4, 3.7) %body fat, +3.1 cm (0.1, 6.0) waist circumference, and +0.8 (-0.30, 1.94) BMI. No significant differences were found between "Chimpanzees" and "Ants". CONCLUSIONS: Movement behavior profiles across work and leisure time-use compositions are associated with obesity. Achieving adequate balance between work and leisure movement behaviors should be further investigated as a potential obesity prevention strategy.

The physical activity paradox revisited: a prospective study on compositional accelerometer data and long-term sickness absence.

BACKGROUND: The 'physical activity paradox' advocates that leisure physical activity (PA) promotes health while high occupational PA impairs health. However, this paradox can be explained by methodological limitations of the previous studies-self-reported PA measures, insufficient adjustment for socioeconomic confounding or not addressing the compositional nature of PA. Therefore, this study investigated if we still observe the PA paradox in relation to long-term sick absence (LTSA) after adjusting for the abovementioned limitations. METHODS: Time spent on moderate-to-vigorous physical activity (MVPA) and remaining physical behaviors (sedentary behavior, standing, light PA and time in bed) at work and in leisure was measured for 929 workers using thigh accelerometry and expressed as isometric log-ratios (ilrs). LTSA was register-based first event of ≥6 consecutive weeks of sickness absence during 4-year follow-up. The association between ilrs and LTSA was analyzed using a Cox proportional hazards model adjusted for remaining physical behaviors and potential confounders, then separately adjusting for and stratifying by education and type of work. RESULTS: During the follow-up, 21% of the workers experienced LTSA. In leisure, more relative MVPA time was negatively associated with LTSA (20% lower risk with 20 min more MVPA, p = 0.02). At work, more relative MVPA time was positively associated with LTSA (15% higher risk with 20 min more MVPA, p = 0.02). Results remained unchanged when further adjusted for or stratified by education and type of work. CONCLUSION: These findings provide further support to the 'PA paradox'.

Zero problems with compositional data of physical behaviors: a comparison of three zero replacement methods.

BACKGROUND: Researchers applying compositional data analysis to time-use data (e.g., time spent in physical behaviors) often face the problem of zeros, that is, recordings of zero time spent in any of the studied behaviors. Zeros hinder the application of compositional data analysis because the analysis is based on log-ratios. One way to overcome this challenge is to replace the zeros with sensible small values. The aim of this study was to compare the performance of three existing replacement methods used within physical behavior time-use epidemiology: simple replacement, multiplicative replacement, and log-ratio expectation-maximization (lrEM) algorithm. Moreover, we assessed the consequence of choosing replacement values higher than the lowest observed value for a given behavior. METHOD: Using a complete dataset based on accelerometer data from 1310 Danish adults as reference, multiple datasets were simulated across six scenarios of zeros (5-30% zeros in 5% increments). Moreover, four examples were produced based on real data, in which, 10 and 20% zeros were imposed and replaced using a replacement value of 0.5 min, 65% of the observation threshold, or an estimated value below the observation threshold. For the simulation study and the examples, the zeros were replaced using the three replacement methods and the degree of distortion introduced was assessed by comparison with the complete dataset. RESULTS: The lrEM method outperformed the other replacement methods as it had the smallest influence on the structure of relative variation of the datasets. Both the simple and multiplicative replacements introduced higher distortion, particularly in scenarios with more than 10% zeros; although the latter, like the lrEM, does preserve the ratios between behaviors with no zeros. The examples revealed that replacing zeros with a value higher than the observation threshold severely affected the structure of relative variation. CONCLUSIONS: Given our findings, we encourage the use of replacement methods that preserve the relative structure of physical behavior data, as achieved by the multiplicative and lrEM replacements, and to avoid simple replacement. Moreover, we do not recommend replacing zeros with values higher than the lowest observed value for a behavior.

Light-intensity physical activity derived from count or activity types is differently associated with adiposity markers.

AIM: The aim of this study was to compare the association between count- and activity type-based definitions of light-intensity physical activity (LIPA) and adiposity markers. METHODS: A total of 516 Danish workers participated in 1-4 days of hip- and thigh-based accelerometer measurements. Three definitions of average daily time spent in LIPA were derived: LIPA (1) time spent between 100 and 2029 CPM, LIPA (2) time spent moving and slow walking, and LIPA (3) time spent moving, walking slow, and standing. Adiposity markers were body mass index (BMI), body fat percentage, and waist circumference. The cross-sectional association between the three LIPA definitions and adiposity markers was analyzed and interpreted using compositional regression models followed by reallocation of time between LIPA, moderate-to-vigorous physical activity (MVPA), and sedentary behavior (SB), respectively. RESULTS: The geometric means of daily time (min/day) spent in LIPA 1, LIPA 2, and LIPA 3 were 326, 102, and 274, respectively. We found the direction and strength of the association between the relative importance of daily time spent in LIPA and the adiposity markers to depend on the LIPA definition. For example, reallocating 30 minutes from MVPA to LIPA 1, LIPA 2 and LIPA 3 were associated with a 2.97 (95% CI: 0.68; 5.27), -0.71 (95% CI: -1.43; 0.02), and -0.45 (95% CI: -1.01; 0.11) difference in BMI, respectively. CONCLUSION: Our findings highlight the need for caution when comparing results from studies using different definitions of LIPA.