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.

The emergence of artemisinin partial resistance in Africa: how do we respond?

Malaria remains one of the most important infectious diseases in the world, with the greatest burden in sub-Saharan Africa, primarily from Plasmodium falciparum infection. The treatment and control of malaria is challenged by resistance to most available drugs, but partial resistance to artemisinins (ART-R), the most important class for the treatment of malaria, was until recently confined to southeast Asia. This situation has changed, with the emergence of ART-R in multiple countries in eastern Africa. ART-R is mediated primarily by single point mutations in the P falciparum kelch13 protein, with several mutations present in African parasites that are now validated resistance mediators based on clinical and laboratory criteria. Major priorities at present are the expansion of genomic surveillance for ART-R mutations across the continent, more frequent testing of the efficacies of artemisinin-based regimens against uncomplicated and severe malaria in trials, more regular assessment of ex-vivo antimalarial drug susceptibilities, consideration of changes in treatment policy to deter the spread of ART-R, and accelerated development of new antimalarial regimens to overcome the impacts of ART-R. The emergence of ART-R in Africa is an urgent concern, and it is essential that we increase efforts to characterise its spread and mitigate its impact.

Effectiveness of a Goldilocks Work intervention in childcare workers - A cluster-randomized controlled trial.

OBJECTIVE: Poor cardiorespiratory fitness and health is common among childcare workers. We designed the `Goldilocks-games` according to the Goldilocks Work principle to provide high-intensity physical activity for childcare workers. We investigated the effectiveness of this Goldilocks Work intervention in increasing occupational high-intensity physical activity and improving work-related health. METHODS: In a two-arm cluster randomized trial, 16 childcare institutions with 142 workers were randomly allocated to either an 8-week Goldilocks Work intervention or a control group. The primary outcome was occupational time in high-intensity physical activity. Secondary outcomes were occupational time in active physical behaviors, heart rate during sleep, pain, physical exhaustion, energy at work, work productivity, and need for recovery. RESULTS: The intervention was successfully delivered and received. Both groups had a low amount of occupational high-intensity physical activity at baseline, and the intervention group reported playing the games 3.1 [standard deviation (SD) 1.5] times/week for a duration of 112.2 (SD 175.0) min/week. However, the intervention did not increase high-intensity physical activity or the secondary outcomes, except for energy at work, measured on a scale from 0-10, increasing 0.65 [95% confidence interval (CI) 0.08-1.21], and need for recovery, measured on a scale from 1-5, decreasing -0.32 (95% CI, -0.54- -0.09). CONCLUSION: The intervention was successfully delivered and received, but did not increase high-intensity physical activity. The intervention group increased their energy at work and decreased their need for recovery, but not the other health-related outcomes. Further research on how to design and implement health-promoting work environment interventions in childcare is needed.

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.

Evidence of artemisinin partial resistance in North-western Tanzania: clinical and drug resistance markers study.

Background: Artemisinin-based combination therapies (ACTs) are the recommended antimalarial drugs for the treatment of uncomplicated malaria. The recent emergence of artemisinin partial resistance (ART-R) in Rwanda, Uganda and Eritrea is of great concern. In Tanzania, a nationwide molecular malaria surveillance in 2021 showed a high prevalence of the Kelch13 (K13) 561H mutation in Plasmodium falciparum from the north-western region, close to the border with Rwanda and Uganda. This study was conducted in 2022 to evaluate the efficacy of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) for the treatment of uncomplicated falciparum malaria and to confirm the presence of ART-R in Tanzania. Methods: This single-arm study evaluated the efficacy of AL and ASAQ in eligible children aged six months to 10 years at Bukangara Dispensary in Karagwe District, Kagera Region. Clinical and parasitological responses were monitored for 28 days according to standard WHO protocol. Mutations in K13 gene and extended haplotypes with these mutations were analysed using Sanger and whole genome sequencing data, respectively. Findings: 176 children (88 in each AL and ASAQ group) were enrolled and all achieved the defined outcomes. PCR-corrected adequate clinical and parasitological response (ACPR) was 98.3% (95% CI: 90.8-100) and 100.0% (95% CI: 95.8-100) for AL and ASAQ, respectively. Parasitaemia on day 3 was observed in 11/88 (12.5%) and 17/88 (19.3%) in the AL and ASAQ groups, respectively. The half-life of parasitaemia was significantly higher (>6.5 hrs) in patients with parasitaemia on day 3 and/or mutations in K13 gene at enrolment. Most patients with parasitaemia on day 3 (8/11 = 72.7% in the AL group and 10/17 = 58.8% in the ASAQ group) had 561H mutation at enrolment. The parasites with K13 mutations were not similar to those from south-east Asia and Rwanda, but had the same core haplotype of a new 561H haplotype reported in Kagera in 2021. Interpretation: These findings confirm the presence of ART-R in Tanzania. A context-specific strategy to respond to artemisinin partial resistance is urgently needed. Although both AL and ASAQ showed high efficacy, increased vigilance for reduced efficacy of these ACTs and detection of ART-R in other parts of the country is critical.

Risks, solutions and implementation of a participatory ergonomic intervention in 16 day nurseries: A process evaluation of the TOY wait-list cluster-randomized controlled trial.

More evidence-based initiatives to reduce physical work demands during childcare work to prevent ill health and promote the ability to care for the children among childcare workers are needed. In a process evaluation performed alongside a two-arm, cluster-randomized study with a waiting-list control among 16 day nurseries lasting 20-weeks that significantly reduced musculoskeletal pain-related sickness absence we investigated 1) risk factors and solutions perceived by the childcare workers, and 2) implementation of the intervention. Most of the perceived risk factors were categorized as physical (70 %) with most of the suggested solutions also being categorized as physical (61 %). The remaining risk factors were categorized as organizational risk factors (16 %) and psychosocial risk factors (13 %). The remaining solutions were distributed almost equally between the organizational (20 %) and psychosocial categories (19 %). About half (51 %) of the action plans showed high implementation success. Of 16 workshops, 100 % were delivered with a fidelity of 83 %. Average participation, exposure, responsiveness and implementation were 68 %, 56 %, 83 % and 47 %. The implementation score differed for timing of intervention but not for nursery characteristics. This study showed that complex and diverse participatory ergonomic interventions should focus on physical, organizational and psychosocial factors to have a positive effect.

Physical activity dose for generalized anxiety disorder & worry: Results from the Irish longitudinal study on ageing.

The lowest moderate-to-vigorous physical activity (MVPA) dose that conveys protection for Generalized Anxiety Disorder (GAD) and worry is unknown. This study quantified associations of weekly accumulated MVPA doses with GAD and worry across 10 years using data from The Irish Longitudinal Study on Ageing (TILDA). Continuous MVPA (metabolic equivalent of task [MET] minutes per week [MET.min.week-1]; e.g., moderate-intensity brisk walking = 4METs), three-dose and, more precise, five-dose MVPA categories were examined. Worry symptoms and GAD status were measured using the Penn State Worry Questionnaire-Abbreviated and the Composite International Diagnostic Interview. Multivariable negative random effect binomial regression and logistic models adjusted for relevant covariates quantified associations across time. Among the 7,650 participants, compared to no MVPA (0 MET.min.week-1), 18 % (OR: 0.82; 95 %CI: [0.69-0.98]), 22 % (OR: 0.78; [ 0.64-0.95]) and 31 % (OR: 0.69; [0.59-0.79]) lower odds of GAD were found for the doses of 1-<600, 600-<1,200 and ≥2,400 MET.min.week-1 respectively. Post-hoc analysis demonstrated 47 % lower odds (OR: 0.53; (0.36-0.78) of GAD for 1-<200 MET.min.week1 compared to inactivity. Compared to no activity, engaging in even minimal physical activity equivalent of 10 min/day for five days/week of moderate-intensity activity (e.g., brisk walking), may lower the risk of GAD over time among older adults.

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.

The Goldilocks Day for healthy adiposity measures among children and adolescents.

Background: The optimal balance of time spent on daily movement behaviors ("The Goldilocks Day") associated with childhood obesity remains unknown. Objective: To estimate the optimal durations of sleep, sedentary behavior (SB), light physical activity (LPA), and moderate-to-vigorous physical activity (MPVA) associated with excess adiposity in a paediatric population. Methods: Accelerometer-measured 24-h movement behaviors were obtained from 659 Czech children and adolescents (8-18-year-olds). Adiposity indicators were body mass index z-score, fat mass percentage, fat-free mass index, and visceral adipose tissue. Excess adiposity was defined as exceeding the 85th percentile for an adiposity indicator. Compositional regression analyses were used investigate the associations between movement behaviors and adiposity indicators and estimating "The Goldilocks Day." Results: The movement behavior composition was associated with visceral adipose tissue (Fdf1 = 3,df2 = 317 = 3.672, p = 0.013) and fat mass percentage (Fdf1 = 3,df2 = 289 = 2.733, p = 0.044) among children and adolescents. The Goldilocks Day consisted of 8.5 h of sleep, 10.8 h of SB, 3.9 h of LPA, and 0.8 h of MVPA among children and 7.5 h of sleep, 12.4 h of SB, 3.6 h of LPA, and 0.5 h of MVPA among adolescents. Conclusion: Optimizing the time spent sleeping, and in sedentary and physical activities appears to be important in the prevention of excess adiposity.

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.

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.

Physical Activity Dose and Depression in a Cohort of Older Adults in The Irish Longitudinal Study on Ageing.

Importance: Among older adults (aged ≥50 years), depression is associated with an increased risk of physical, social, and cognitive dysfunction. Regular moderate to vigorous physical activity (MVPA) has been associated with lower odds of depression. However, the lowest dose for protection against depression and the extent to which exceeding this level conveys additional protection are unknown. Objective: To evaluate different MVPA doses, depressive symptoms, and major depression status in a large cohort of older adults with and without chronic disease. Design, Setting, and Participants: A longitudinal cohort study of the same 4016 individuals at each of 5 time points (ie, waves) from The Irish Longitudinal Study on Ageing was conducted. Data were collected from October 2009 to December 2018, and data were analyzed from June 15 to August 8, 2022. Exposures: Continuous MVPA (metabolic equivalent of task [MET]-minutes per week [MET-min/wk]), 3 dose categories, and 5 dose categories measured with the International Physical Activity Questionnaire. Main Outcomes and Measures: Depressive symptoms and major depression status were measured using the short form of the Centre for Epidemiological Studies Depression scale along with the Composite International Diagnostic Interview for diagnosis of a major depressive episode during the past 12 months. Multivariable negative random-effects binomial regression models, adjusted for relevant covariates, quantified associations across time. Results: Among the 4016 participants at each wave of the study (2205 women [54.9%]; mean [SD] age, 61.0 [8.1] years) during 10.0 years of follow-up, depression rates increased from a mean of 8.2% (95% CI, 7.4%-9.1%) to 12.2% (95% CI, 11.2%-13.2%). Bonferroni-corrected post hoc analysis indicated that participants performing 400 to less than 600 MET-min/wk had a 16% lower rate of depressive symptoms (adjusted incidence rate ratio [AIRR], 0.84; 95% CI, 0.81-0.86) and 43% lower odds of depression (adjusted odds ratio [AOR], 0.57; 95% CI, 0.49-0.66) compared with 0 MET-min/wk. Those with chronic disease performing 600 to less than 1200 MET-min/wk had an 8% (AIRR, 0.92; 95% CI, 0.86-0.98) lower rate of depressive symptoms and 44% (AOR, 0.56; 95% CI, 0.42-0.74) lower odds of depression compared with 0 MET-min/wk. Those without disease required more than 2400 MET-min/wk for similar protection for depressive symptoms (AIRR, 0.81; 95% CI, 0.73-0.90). Conclusions and relevance: In this cohort study of older adults, significant antidepressant benefits were noted for MVPA doses below current recommendations for overall health, although greater doses were associated with larger AIRR reductions. It may be useful for public health interventions to investigate the achievability of lower physical activity thresholds among older adults with and without chronic illness to reduce the risk of depression.

Physical activity for depression among the chronically Ill: Results from older diabetics in the Irish longitudinal study on ageing.

Among chronically-ill older adults, the benefits of moderate-to-vigorous physical activity (MVPA) are established. Comorbid depressive symptoms and Major Depression are prevalent among the chronically-ill, but how different doses of MVPA may protect against depression remains understudied. Thus, using 10 years of data from The Irish Longitudinal Study on Ageing, we quantified longitudinal associations between MVPA doses and depressive symptoms and Major Depression among chronically-ill older adults living with type 2 diabetes (T2DM). Continuous MVPA (MET.min.week-1), three dose and five dose MVPA categories were examined. Depressive symptoms and Major Depression were measured using the center for Epidemiological Studies Depression and the Composite International Diagnostic Interview for Major Depressive Episode. Negative binomial regression and logistic models, adjusted for covariates, quantified associations across time. Among the 2,262 participants, those adhering to the WHO guidelines of 600-<1,200 MET.min.week-1 had 28% lower odds of Major Depression compared to those not achieving the guidelines (OR: 0.72; 95%CI: 0.53-0.98). For depressive symptoms, a higher MVPA dose was required with a 13% (IRR: 0.87; 95%CI: 0.82-0.93) lower rate of symptoms among those exceeding recommendations (1200-<2,400 MET.min.week-1). Interventions should focus on enhancing achievability of and compliance with these MVPA doses among the chronically-ill, including T2DM, to protect against depression.

CDR3 Variants of the TXB2 Shuttle with Increased TfR1 Association Rate and Enhanced Brain Penetration.

Since the delivery of biologic drugs to the brain is greatly hampered by the existence of the blood-brain barrier (BBB), brain shuttles are being developed to enhance therapeutic efficacy. As we have previously shown, efficient and selective brain delivery was achieved with TXB2, a cross-species reactive, anti-TfR1 VNAR antibody. To further explore the limits of brain penetration, we conducted restricted randomization of the CDR3 loop, followed by phage display to identify improved TXB2 variants. The variants were screened for brain penetration in mice using a 25 nmol/kg (1.875 mg/kg) dose and a single 18 h timepoint. A higher kinetic association rate to TfR1 correlated with improved brain penetration in vivo. The most potent variant, TXB4, showed a 3.6-fold improvement over TXB2, which had on average 14-fold higher brain levels when compared to an isotype control. Like TXB2, TXB4 retained brain specificity with parenchymal penetration and no accumulation in other organs. When fused with a neurotensin (NT) payload, it led to a rapid drop in body temperature upon transport across the BBB. We also showed that fusion of TXB4 to four therapeutic antibodies (anti-CD20, anti-EGFRvIII, anti-PD-L1 and anti-BACE1) improved their brain exposure between 14- to 30-fold. In summary, we enhanced the potency of parental TXB2 brain shuttle and gained a critical mechanistic understanding of brain delivery mediated by the VNAR anti-TfR1 antibody.

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.

One size does not fit all: Participants' experiences of the selfBACK app to support self-management of low back pain-a qualitative interview study.

BACKGROUND: Low back pain (LBP) is one of the most common reasons for disability globally. Digital interventions are a promising means of supporting people to self-manage LBP, but implementation of digital interventions has been suboptimal. An artificial intelligence-driven app, selfBACK, was developed to support self-management of LBP as an adjunct to usual care. To better understand the process of implementation from a participant perspective, we qualitatively explored factors influencing embedding, integrating, and sustaining engagement with the selfBACK app, and the self-perceived effects, acceptability, and satisfaction with the selfBACK app. METHODS: Using a qualitative interview study and an analytic framework approach underpinned by Normalization Process Theory (NPT), we investigated the experiences of patients who participated in the selfBACK randomized controlled trial (RCT). Interviews focused on the motivation to participate in the RCT, experiences of using the selfBACK app, and views about future intended use and potential of using digital health interventions for self-management of LBP. Participants were purposively sampled to represent diversity in age, sex, and implementation reflected by a proxy measure of number of app-generated self-management plans during the first three months of RCT participation. RESULTS: Twenty-six participants aged 21-78, eleven females and fifteen men, with two to fourteen self-management plans, were interviewed between August 2019 and April 2020. A broad range of factors influencing implementation of selfBACK within all constructs of NPT were identified. Key facilitating factors were preferences and beliefs favoring self-management, a friendly, motivational, and reassuring supporter, tailoring and personalization, convenience and ease of use, trustworthiness, perceiving benefits, and tracking achievements. Key impeding factors were preferences and beliefs not favoring self-management, functionality issues, suboptimal tailoring and personalization, insufficient time or conflicting life circumstances, not perceiving benefits, and insufficient involvement of health care practitioners. Self-perceived effects on pain and health, behavior/attitude, and gaining useful knowledge varied by participant. CONCLUSIONS: The high prevalence of LBP globally coupled with the advantages of providing help through an app offers opportunities to help countless people. A range of factors should be considered to facilitate implementation of self-management of LBP or similar pain conditions using digital health tools.

Your best day: An interactive app to translate how time reallocations within a 24-hour day are associated with health measures.

Reallocations of time between daily activities such as sleep, sedentary behavior and physical activity are differentially associated with markers of physical, mental and social health. An individual's most desirable allocation of time may differ depending on which outcomes they value most, with these outcomes potentially competing with each other for reallocations. We aimed to develop an interactive app that translates how self-selected time reallocations are associated with multiple health measures. We used data from the Australian Child Health CheckPoint study (n = 1685, 48% female, 11-12 y), with time spent in daily activities derived from a validated 24-h recall instrument, %body fat from bioelectric impedance, psychosocial health from the Pediatric Quality of Life Inventory and academic performance (writing) from national standardized tests. We created a user-interface to the compositional isotemporal substitution model with interactive sliders that can be manipulated to self-select time reallocations between activities. The time-use composition was significantly associated with body fat percentage (F = 2.66, P < .001), psychosocial health (F = 4.02, P < .001), and academic performance (F = 2.76, P < .001). Dragging the sliders on the app shows how self-selected time reallocations are associated with the health measures. For example, reallocating 60 minutes from screen time to physical activity was associated with -0.8 [95% CI -1.0 to -0.5] %body fat, +1.9 [1.4 to 2.5] psychosocial score and +4.5 [1.8 to 7.2] academic performance. Our app allows the health associations of time reallocations to be compared against each other. Interactive interfaces provide flexibility in selecting which time reallocations to investigate, and may transform how research findings are disseminated.

A Simple Resident Need-for-Physical-Assistance Scale in Eldercare: Validation Using 4716 Observation Sequences of Caring Activities.

Accurate and simple measures for classifying nursing home residents according to their care needs would be valuable for planning eldercare work. Our aim was to validate a developed classification scale of residents' need for physical assistance. Eldercare workers and managers in 20 Danish nursing homes classified 1456 residents into four categories (from light to complete need for physical assistance). We validated the resident need-for-assistance scale against 4716 workplace observation sequences of caring activities performed by eldercare workers. We found a strong correlation between the resident need-for-assistance scale and observed number of resident handlings (r = 0.71) and a moderate correlation for observed duration of care (r = 0.57). The discriminative ability of the scale was good for both number of resident handlings (ROC-AUC = 0.81) and for duration of care (ROC-AUC = 0.76). Our findings indicate that this simple scale is valid and feasible for classifying residents according to their physical assistance needs.

The Use of Time Flow Analysis to Describe Changes in Physical Ergonomic Work Behaviours Following a Cluster-Randomized Controlled Participatory Ergonomic Intervention.

AIM: Evaluations of participatory ergonomic interventions are often challenging as these types of interventions are tailored to the context and need of the workplace in which they are implemented. We aimed to describe how time flow analysis can be used to describe changes in work behaviours following a participatory ergonomic intervention. METHOD: This study was based on data from a two-arm cluster-randomized controlled trial with 29 childcare institutions and 116 workers (intervention: n = 60, control: n = 56). Physical behaviours at work were technically measured at baseline and 4-month follow-up. Physical behaviours were expressed in terms of relative work time spent forward bending of the back ≥30°, kneeling, active (i.e. walking, stair climbing and running) and sedentary. Average time flow from baseline to follow-up were calculated for both groups to investigate if work time was allocated differently at follow-up. RESULTS: A total of 116 workers (60 in the intervention and 56 in the control group) had valid accelerometer at baseline and follow-up. The largest group difference in time flowing from baseline to follow-up was observed for forward bending of the back and time spent kneeling. Compared to the control, the intervention group had less time flowing from forward bending of the back to kneeling (intervention: +11 min day, control: +16 min day) and more time flowing from kneeling to sedentary behaviours (intervention: +15 min day, control: +10 min day). CONCLUSION: The results of this study showed that time flow analysis can be used to reveal changes in work time-use following a participatory ergonomic intervention. For example, the analysis revealed that the intervention group had replaced more work time spent kneeling with sedentary behaviours compared to the control group. This type of information on group differences in time reallocations would not have been possible to obtain by comparing group differences in work time-use following the intervention, supporting the usefulness of time flow analysis as a tool to evaluate complex, context-specific interventions.