The Effect of a Mental Task Versus Unilateral Physical Fatigue on Non-Local Muscle Fatigue in Recreationally Active Young Adults.

Non-local muscle fatigue (NLMF) has been attributed to both physical and mental fatigue. The purpose of this study was to investigate the effects of mental exertion versus unilateral physical fatigue on NLMF. Sixteen recreationally active participants completed a physical task (2-sets of 100-s unilateral knee extension (KE) maximal voluntary isometric contractions (MVIC) with the dominant leg with 40-s recovery between sets, mental task (4-minute Stroop task), and control condition. Before and after each condition, blood lactate was collected, and contralateral 5-s KE, flexion (KF) and bilateral lateral trunk flexors MVIC (measure of trunk stability strength) was performed. Following the post-test 5-s MVICs, participants performed 12 non-dominant KE MVICs with a work-to-rest ratio of 5/10-s. Electromyography was monitored during the MVICs. Neither the 4-minute Stroop test or the unilateral KE physical fatigue intervention adversely affected the non-dominant KE forces or EMG activity with a single MVIC or 12 repetition MVICs. Although the non-dominant KF fatigue index forces and hamstrings EMG were not impaired by the interventions, there was a significant interaction (p = 0.001) small magnitude (d = 0.42) decrease in the non-dominant KF single MVIC force following the contralateral fatigue intervention, albeit with no significant change in hamstrings EMG. This MVIC deficit may be related to the significant decrease in dominant (p = 0.046, d = 2.6) and non-dominant external obliques (p = 0.048, d = 0.57) activation adversely affecting trunk stability. In conclusion, a 4-minute Stroop test or unilateral KE physical fatigue intervention did not impair non-dominant KE single or repeated 12 repetition MVIC forces or EMG activity. The small magnitude deficit in the non-dominant KF single MVIC force following the contralateral fatigue intervention are in accord with the heterogenous findings common in the literature.

Lack of Evidence for Crossover Fatigue with Plantar Flexor Muscles.

The occurrence and mechanisms underlying non-local or crossover muscle fatigue is an ongoing issue. This study aimed to investigate crossover fatigue of the plantar flexor muscles. Sixteen recreationally active males (n = 6) and females (n = 10) visited the laboratory for four sessions and performed a single 5-s pre-test maximal voluntary isometric contraction (MVIC) with each plantar flexors muscle. Thereafter, the fatigue intervention involved two 100-s MVICs (60-s recovery) with their dominant plantar flexors or rested for 260-s (control). Subsequently, in two separate sessions, Hoffman reflexes (H-reflex) were evoked in the non-dominant, non-exercised, leg before and following the dominant leg fatigue or control intervention (Fatigue-Reflex and Control-Reflex conditions). MVIC forces and volitional (V)-waves were monitored in the non-dominant leg in the other two sessions (Fatigue-MVIC and Control-MVIC) before and after the intervention (fatigue or control) as well as during 12 repeated MVICs and immediately thereafter. Despite the force reduction in the dominant leg (42.4%, p = 0.002), no crossover force deficit with single (F(1,9) = 0.02, p = 0.88, pƞ2 = 0.003) or repeated (F(1,9) = 0.006, p = 0.93, pƞ2 = 0.001) MVIC testing were observed. The H-reflex did not change after the fatigue (F(1,7) = 0.51; p = 0.49; pƞ2 = 0.06) or repeated MVICs (F(1,8) = 0.27; p = 0.61; pƞ2 = 0.03). There were also no crossover effects of fatigue on the V-wave with single (F(1,8) = 3.71, p = 0.09, pƞ2 = 0.31) or repeated MVICs (F(1,6) = 1.45, p = 0.27, pƞ2 = 0.19). Crossover fatigue was not evident with the plantar flexors nor any significant changes in H-reflex and V-waves in the soleus muscle. This finding suggests that crossover fatigue may not necessarily occur in slow-twitch predominant muscle groups.

ABCC4/MRP4 contributes to the aggressiveness of Myc-associated epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a complex disease comprising discrete histological and molecular subtypes, for which survival rates remain unacceptably low. Tailored approaches for this deadly heterogeneous disease are urgently needed. Efflux pumps belonging to the ATP-binding cassette (ABC) family of transporters are known for roles in both drug resistance and cancer biology and are also highly targetable. Here we have investigated the association of ABCC4/MRP4 expression to clinical outcome and its biological function in endometrioid and serous tumors, common histological subtypes of EOC. We found high expression of ABCC4/MRP4, previously shown to be directly regulated by c-Myc/N-Myc, was associated with poor prognosis in endometrioid EOC (P = .001) as well as in a subset of serous EOC with a "high-MYCN" profile (C5/proliferative; P = .019). Transient siRNA-mediated suppression of MRP4 in EOC cells led to reduced growth, migration and invasion, with the effects being most pronounced in endometrioid and C5-like serous cells compared to non-C5 serous EOC cells. Sustained knockdown of MRP4 also sensitized endometrioid cells to MRP4 substrate drugs. Furthermore, suppression of MRP4 decreased the growth of patient-derived EOC cells in vivo. Together, our findings provide the first evidence that MRP4 plays an important role in the biology of Myc-associated ovarian tumors and highlight this transporter as a potential therapeutic target for EOC.

Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability.

To explore the genetic architecture of human overgrowth syndromes and human growth control, we performed experimental and bioinformatic analyses of 710 individuals with overgrowth (height and/or head circumference ≥+2 SD) and intellectual disability (OGID). We identified a causal mutation in 1 of 14 genes in 50% (353/710). This includes HIST1H1E, encoding histone H1.4, which has not been associated with a developmental disorder previously. The pathogenic HIST1H1E mutations are predicted to result in a product that is less effective in neutralizing negatively charged linker DNA because it has a reduced net charge, and in DNA binding and protein-protein interactions because key residues are truncated. Functional network analyses demonstrated that epigenetic regulation is a prominent biological process dysregulated in individuals with OGID. Mutations in six epigenetic regulation genes-NSD1, EZH2, DNMT3A, CHD8, HIST1H1E, and EED-accounted for 44% of individuals (311/710). There was significant overlap between the 14 genes involved in OGID and 611 genes in regions identified in GWASs to be associated with height (p = 6.84 × 10-8), suggesting that a common variation impacting function of genes involved in OGID influences height at a population level. Increased cellular growth is a hallmark of cancer and there was striking overlap between the genes involved in OGID and 260 somatically mutated cancer driver genes (p = 1.75 × 10-14). However, the mutation spectra of genes involved in OGID and cancer differ, suggesting complex genotype-phenotype relationships. These data reveal insights into the genetic control of human growth and demonstrate that exome sequencing in OGID has a high diagnostic yield.

Foam Rolling Prescription: A Clinical Commentary.

Behm, DG, Alizadeh, S, Hadjizadeh Anvar, S, Mahmoud, MMI, Ramsay, E, Hanlon, C, and Cheatham, S. Foam rolling prescription: a clinical commentary. J Strength Cond Res 34(11): 3301-3308, 2020-Although the foam rolling and roller massage literature generally reports acute increases in range of motion (ROM) with either trivial or small performance improvements, there is little information regarding appropriate rolling prescription. The objective of this literature review was to appraise the evidence and provide the best prescriptive recommendations for rolling to improve ROM and performance. The recommendations represent studies with the greatest magnitude effect size increases in ROM and performance. A systematic search of the rolling-related literature found in PubMed, ScienceDirect, Web of Science, and Google Scholar was conducted using related terms such as foam rolling, roller massage, ROM, flexibility, performance, and others. From the measures within articles that monitored ROM (25), strength (41), jump (41), fatigue (67), and sprint (62) variables; regression correlations and predictive quadratic equations were formulated for number of rolling sets, repetition frequency, set duration, and rolling intensity. The analysis revealed the following conclusions. To achieve the greatest ROM, the regression equations predicted rolling prescriptions involving 1-3 sets of 2-4-second repetition duration (time for a single roll in one direction over the length of a body part) with a total rolling duration of 30-120-second per set. Based on the fewer performance measures, there were generally trivial to small magnitude decreases in strength and jump measures. In addition, there was insufficient evidence to generalize on the effects of rolling on fatigue and sprint measures. In summary, relatively small volumes of rolling can improve ROM with generally trivial to small effects on strength and jump performance.

Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer.

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth.

Overgrowth syndromes comprise a group of heterogeneous disorders characterised by excessive growth parameters, often in association with intellectual disability. To identify new causes of human overgrowth, we have been undertaking trio-based exome sequencing studies in overgrowth patients and their unaffected parents. Prioritisation of functionally relevant genes with multiple unique de novo mutations revealed four mutations in protein phosphatase 2A (PP2A) regulatory subunit B family genes protein phosphatase 2, regulatory Subunit B', beta (PPP2R5B); protein phosphatase 2, regulatory Subunit B', gamma (PPP2R5C); and protein phosphatase 2, regulatory Subunit B', delta (PPP2R5D). This observation in 3 related genes in 111 individuals with a similar phenotype is greatly in excess of the expected number, as determined from gene-specific de novo mutation rates (P = 1.43 × 10(-10)). Analysis of exome-sequencing data from a follow-up series of overgrowth probands identified a further pathogenic mutation, bringing the total number of affected individuals to 5. Heterozygotes shared similar phenotypic features including increased height, increased head circumference and intellectual disability. The mutations clustered within a region of nine amino acid residues in the aligned protein sequences (P = 1.6 × 10(-5)). We mapped the mutations onto the crystal structure of the PP2A holoenzyme complex to predict their molecular and functional consequences. These studies suggest that the mutations may affect substrate binding, thus perturbing the ability of PP2A to dephosphorylate particular protein substrates. PP2A is a major negative regulator of v-akt murine thymoma viral oncogene homolog 1 (AKT). Thus, our data further expand the list of genes encoding components of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signalling cascade that are disrupted in human overgrowth conditions.

Multi-stage genome-wide association study identifies new susceptibility locus for testicular germ cell tumour on chromosome 3q25.

Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for >15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage experiment, involving 4098 cases and 18 972 controls. Stage 1 comprised previously published GWAS analysis of 307 291 SNPs in 986 cases and 4946 controls. In Stage 2, we used previously published customised Illumina iSelect genotyping array (iCOGs) data across 694 SNPs in 1064 cases and 10 082 controls. Here, we report new genotyping of eight SNPs showing some evidence of association in combined analysis of Stage 1 and Stage 2 in an additional 2048 cases of TGCT and 3944 controls (Stage 3). Through fixed-effects meta-analysis across three stages, we identified a novel locus at 3q25.31 (rs1510272) demonstrating association with TGCT [per-allele odds ratio (OR) = 1.16, 95% confidence interval (CI) = 1.06-1.27; P = 1.2 × 10(-9)].

Corticosteroids inhibit sphingosine 1-phosphate-induced interleukin-6 secretion from human airway smooth muscle via mitogen-activated protein kinase phosphatase 1-mediated repression of mitogen and stress-activated protein kinase 1.

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that plays an important proinflammatory role in asthmatic airways. Corticosteroids are first-line antiinflammatories in asthma; however, their repressive effects on S1P-induced cytokine secretion have not been investigated. To address this, our in vitro study reveals the molecular mechanisms by which corticosteroids inhibit S1P-induced IL-6 expression in the pivotal immunomodulatory cell type, airway smooth muscle (ASM). We first uncover the cellular signaling pathways responsible: S1P activates a cyclic adenosine monophosphate/cAMP response-element-binding protein (CREB)/CRE-dependent pathway to induce IL-6 transcription, concomitant with stimulation of the mitogen-activated protein kinase (MAPK) superfamily and downstream mitogen and stress-activated protein kinase 1 (MSK1) and histone H3 phosphorylation. In this way, S1P stimulates parallel signaling pathways to induce IL-6 secretion via CRE-driven transcription of the IL-6 gene promoter in a relaxed chromatin environment achieved through histone H3 phosphorylation. Second, we investigated how corticosteroids mediate their repressive effects. The corticosteroid dexamethasone inhibits S1P-induced IL-6 protein secretion and mRNA expression, but CREB/CRE transrepression, inhibition of IL-6 mRNA stability, or subcellular relocation of MSK1 were not responsible for the repressive effects of dexamethasone. Rather, we show that dexamethasone rapidly induces up-regulation of the MAPK deactivator MAPK phosphatase 1 (MKP-1) and that MKP-1 blocks the MAPK-driven activation of MSK1 and phosphorylation of histone H3. This was confirmed by treatment with triptolide, an inhibitor of MKP-1 up-regulation, where repressive effects of corticosteroids were reversed. Our study reveals the molecular mechanism underlying the antiinflammatory capacity of corticosteroids to repress proinflammatory functions induced by the potent bioactive sphingolipid S1P in the lung.

Employing pancreatic tumor γ-glutamyltransferase for therapeutic delivery.

γ-Glutamyltransferase (γGT) is a cell surface enzyme that catalyzes hydrolysis of the bond linking the glutamate and cysteine residues of glutathione and glutathione-S-conjugates. We have observed that human pancreatic tumor cells and tumor-associated stellate cells express high levels of this enzyme when compared to normal pancreatic epithelial and stellate cells. Detection of the protein in tumor sections correlated with γGT activity on the surface of the cultured tumor and stellate cells. We tested whether the tumor γGT could be employed to deliver a therapeutic to the tumor endothelial cells. GSAO is a glutathione-S-conjugate of a trivalent arsenical that is activated to enter endothelial cells by γGT cleavage of the γ-glutamyl residue. The arsenical moiety triggers proliferation arrest and death of the endothelial cells by targeting the mitochondria. Human pancreatic tumor and stellate cell γGT activated GSAO in culture and γGT activity positively correlated with GSAO-mediated proliferation arrest and death of endothelial cells in Transwell and coculture systems. A soluble form of γGT is found in blood, and we measured the rate of activation of GSAO by this enzyme. We calculated that systemically administered GSAO would circulate through the pancreatic blood supply several times before appreciable activation by normal blood levels of γGT. In support of this finding, tumor γGT activity positively correlated with GSAO-mediated inhibition of pancreatic tumor angiogenesis and tumor growth in mice. Our findings indicate that pancreatic tumor γGT can be used to deliver a therapeutic to the tumor.

Making it happen: Development of an interprofessional deprescribing education programme.

Deprescribing is the planned and supervised reduction or discontinuation of medications that may be causing harm or are no longer benefiting a patient. The need for deprescribing to be a routine part of patient care is essential with an aging population and the rising prevalence of polypharmacy, which has been associated with increased adverse outcomes such as falls, hospitalizations and mortality. Deprescribing is a complex intervention that requires collaboration between the patient, caregivers and healthcare providers to adequately support all involved, as well as to ensure medications are not restarted in error. The objective of this article is to describe the stepwise approach to planning and ongoing development of an online, interprofessional deprescribing education programme for healthcare providers and students with the goal of enhancing deprescribing practice. There were four main planning and development components: (1) a needs assessment to provide guidance on programme design, development and delivery; (2) a consultative programme planning process with an advisory group of stakeholders and patient partners to inform programme learning outcomes and content; (3) a core development team for the creation of programme content; and (4) planning for programme evaluation. Based on the stepwise and consultative process, programme outcomes were identified, and five modules were developed.

Psychometric properties of the Mini-Balance Evaluation Systems Test and physical function measures in patients with Ehlers-Danlos syndrome/hypermobility spectrum disorders.

PURPOSE: Ehlers-Danlos syndrome (EDS) and hypermobility spectrum disorders (HSD) are associated with impairments in balance and physical function. However, the psychometric properties of relevant outcome measures remain largely unexplored. The objectives of this study were to evaluate the construct validity of the Mini-Balance Evaluation Systems Test (Mini-BESTest) alongside the test-retest reliability of the Mini-BESTest, Six Minute Walk Test (6MWT), and Lower Extremity Functional Scale (LEFS) in patients with the hypermobility subtype of EDS (hEDS) and HSD. MATERIALS AND METHODS: Participants with hEDS/HSD (n = 20) attended two visits scheduled one to two weeks apart. The construct validity of the Mini-BESTest was determined through Pearson correlations between force plate balance measures, 6MWT, and LEFS. Test-retest reliability of the measures was evaluated through intraclass correlation coefficients (ICC). Minimal detectable change values with 95% confidence (MDC95) were also calculated. RESULTS: Mini-BESTest demonstrated significant correlations with force plate measures, 6MWT, and LEFS (r = -0.41 to 0.66). Test-retest reliability was excellent for the Mini-BESTest, 6MWT, and LEFS (ICC = 0.91 to 0.96). MDC95 was 4 for the Mini-BESTest, 77 m for the 6MWT, and 11 for the LEFS. CONCLUSION: The Mini-BESTest is valid and reliable for assessing balance and mobility in patients with hEDS/HSD.IMPLICATIONS FOR REHABILITATIONThe Mini Balance Evaluation Systems Test (Mini-BESTest) is valid in capturing aspects of balance and physical function in patients with hypermobile Ehlers-Danlos syndrome or hypermobility spectrum disorders.However, the Mini-BESTest may show a potential ceiling effect for high functioning patients in this population.The Mini-BESTest, 6 Minute Walk Test, and the Lower Extremity Functional Scale also show excellent test-retest reliability in this population.The Minimal Detectable Change with 95% confidence intervals is 4 for the Mini-BESTest, 77 m for the 6 Minute Walk Test, and 11 for the Lower Extremity Functional Scale in this population.

Spatio-temporal development of the urban heat island in a socioeconomically diverse tropical city.

Urban heat islands, where temperatures are elevated relative to non-urban surrounds, are near-ubiquitous in cities globally. Yet, the magnitude and form of urban heat islands in the tropics, where heat has a large morbidity and mortality burden, is not well understood, especially for those of urban informal settlements. We used 29 years of Landsat satellite-derived surface temperature, corroborated by in situ temperature measurements, to provide a detailed spatial and temporal assessment of urban heat islands in Makassar, Indonesia, a city that is representative of rapidly growing urban settlements across the tropics. Our analysis identified surface urban heat islands of up to 9.2 °C in long-urbanised parts of the city and 6.3 °C in informal settlements, the seasonal patterns of which were driven by change in non-urban areas rather than in urban areas themselves. In recently urbanised areas, the majority of urban heat island increase occurred before land became 50% urbanised, whereas the established heat island in long-urbanised areas remained stable in response to urban expansion. Green and blue space protected some informal settlements from the worst urban heat islands observed across the city and maintenance of such space will be essential to mitigate the growing heat burden from urban expansion and anthropogenic climate change. Settlements further than 4 km from the coast and with Normalised Difference Vegetation Index (NDVI) less than 0.2 had higher surface temperatures, with modelled effects of more than 5 °C. Surface temperature measurements were representative of in situ heat exposure, measured in a subset of 12 informal settlements, where mean indoor temperature had the strongest relationship with surface temperature (R2 = 0.413, P = 0.001). We advocate for green space to be prioritised in urban planning, redevelopment and informal settlement upgrading programs, with consideration of the unique environmental and socioeconomic context of tropical cities.

Proteasomal inhibition upregulates the endogenous MAPK deactivator MKP-1 in human airway smooth muscle: mechanism of action and effect on cytokine secretion.

Asthma is a chronic inflammatory condition. Inhibition of the ubiquitin-proteasome system offers promise as a anti-inflammatory strategy, being responsible for the degradation of key proteins involved in crucial cellular functions, including gene expression in inflammation (e.g. inhibitory IkappaB-alpha and the endogenous MAPK deactivator - MKP-1). As MKP-1 inhibits MAPK-mediated pro-remodeling functions in human airway smooth muscle (ASM; a pivotal immunomodulatory cell in asthma) in this study we investigate the effect of the proteasome inhibitor MG-132 on MKP-1 and evaluate the anti-inflammatory effect of MG-132 on cytokine secretion from ASM cells. Examining the time-course of induction of MKP-1 mRNA and protein by MG-132 (10microM) we show that MKP-1 mRNA was first detected at 30min, increased to significant levels by 4h, resulting in a 12.6+/-1.5-fold increase in MKP-1 mRNA expression by 24h (P<0.05). MKP-1 protein levels corroborate the mRNA results. Investigating the effect of MG-132 on secretion of the cytokine IL-6 we show that while short-term pretreatment with MG-132 (30min) partially reduced TNFalpha-induced IL-6 via inhibition of IkappaB-alpha degradation and the NF-kappaB pathway, longer-term proteasome inhibition (up to 24h) robustly upregulated MKP-1 and was temporally correlated with repression of p38-mediated IL-6 secretion from ASM cells. Moreover, utilizing a cytokine array we show that MG-132 represses the secretion of multiple cytokines implicated in asthma. Taken together, our results demonstrate that MG-132 upregulates MKP-1 and represses cytokine secretion from ASM and highlight the potential of the proteasome as a therapeutic target in asthma.

Mitochondrial metabolism inhibitors for cancer therapy.

Cancer cells catabolise nutrients in a different way than healthy cells. Healthy cells mainly rely on oxidative phosphorylation, while cancer cells employ aerobic glycolysis. Glucose is the main nutrient catabolised by healthy cells, while cancer cells often depend on catabolism of both glucose and glutamine. A key organelle involved in this altered metabolism is mitochondria. Mitochondria coordinate the catabolism of glucose and glutamine across the cancer cell. Targeting mitochondrial metabolism in cancer cells has potential for the treatment of this disease. Perhaps the most promising target is the hexokinase-voltage dependent anion channel-adenine nucleotide translocase complex that spans the outer- and inner-mitochondrial membranes. This complex links glycolysis, oxidative phosphorylation and mitochondrial-mediated apoptosis in cancer cells. This review discusses cancer cell mitochondrial metabolism and the small molecule inhibitors of this metabolism that are in pre-clinical or clinical development.

Non-local Muscle Fatigue Effects on Muscle Strength, Power, and Endurance in Healthy Individuals: A Systematic Review with Meta-analysis.

BACKGROUND: The fatigue of a muscle or muscle group can produce global responses to a variety of systems (i.e., cardiovascular, endocrine, and others). There are also reported strength and endurance impairments of non-exercised muscles following the fatigue of another muscle; however, the literature is inconsistent. OBJECTIVE: To examine whether non-local muscle fatigue (NLMF) occurs following the performance of a fatiguing bout of exercise of a different muscle(s). DESIGN: Systematic review and meta-analysis. SEARCH AND INCLUSION: A systematic literature search using a Boolean search strategy was conducted with PubMed, SPORTDiscus, Web of Science, and Google Scholar in April 2020, and was supplemented with additional 'snowballing' searches up to September 2020. To be included in our analysis, studies had to include at least one intentional performance measure (i.e., strength, endurance, or power), which if reduced could be considered evidence of muscle fatigue, and also had to include the implementation of a fatiguing protocol to a location (i.e., limb or limbs) that differed to those for which performance was measured. We excluded studies that measured only mechanistic variables such as electromyographic activity, or spinal/supraspinal excitability. After search and screening, 52 studies were eligible for inclusion including 57 groups of participants (median sample = 11) and a total of 303 participants. RESULTS: The main multilevel meta-analysis model including all effects sizes (278 across 50 clusters [median = 4, range = 1 to 18 effects per cluster) revealed a trivial point estimate with high precision for the interval estimate [- 0.02 (95% CIs = - 0.14 to 0.09)], yet with substantial heterogeneity (Q(277) = 642.3, p < 0.01), I2 = 67.4%). Subgroup and meta-regression analyses showed that NLMF effects were not moderated by study design (between vs. within-participant), homologous vs. heterologous effects, upper or lower body effects, participant training status, sex, age, the time of post-fatigue protocol measurement, or the severity of the fatigue protocol. However, there did appear to be an effect of type of outcome measure where both strength [0.11 (95% CIs = 0.01-0.21)] and power outcomes had trivial effects [- 0.01 (95% CIs = - 0.24 to 0.22)], whereas endurance outcomes showed moderate albeit imprecise effects [- 0.54 (95% CIs = - 0.95 to - 0.14)]. CONCLUSIONS: Overall, the findings do not support the existence of a general NLMF effect; however, when examining specific types of performance outcomes, there may be an effect specifically upon endurance-based outcomes (i.e., time to task failure). However, there are relatively fewer studies that have examined endurance effects or mechanisms explaining this possible effect, in addition to fewer studies including women or younger and older participants, and considering causal effects of prior training history through the use of longitudinal intervention study designs. Thus, it seems pertinent that future research on NLMF effects should be redirected towards these still relatively unexplored areas.

Chronic heat stress in tropical urban informal settlements.

The health and economic impacts of extreme heat on humans are especially pronounced in populations without the means to adapt. We deployed a sensor network across 12 informal settlements in Makassar, Indonesia to measure the thermal environment that people experience inside and outside their homes. We calculated two metrics to assess the magnitude and frequency of heat stress conditions, wet bulb temperature and wet bulb globe temperature, and compared our in situ data to that collected by weather stations. We found that informal settlement residents experience chronic heat stress conditions, which are underestimated by weather stations. Wet bulb temperatures approached the uppermost limits of human survivability, and wet bulb globe temperatures regularly exceeded recommended physical activity thresholds, both in houses and outdoors. Under a warming climate, a growing number of people living informally will face potentially severe impacts from heat stress that have likely been previously overlooked or underestimated.

A planetary health model for reducing exposure to faecal contamination in urban informal settlements: Baseline findings from Makassar, Indonesia.

BACKGROUND: The intense interactions between people, animals and environmental systems in urban informal settlements compromise human and environmental health. Inadequate water and sanitation services, compounded by exposure to flooding and climate change risks, expose inhabitants to environmental contamination causing poor health and wellbeing and degrading ecosystems. However, the exact nature and full scope of risks and exposure pathways between human health and the environment in informal settlements are uncertain. Existing models are limited to microbiological linkages related to faecal-oral exposures at the individual level, and do not account for a broader range of human-environmental variables and interactions that affect population health and wellbeing. METHODS: We undertook a 12-month health and environmental assessment in 12 flood-prone informal settlements in Makassar, Indonesia. We obtained caregiver-reported health data, anthropometric measurements, stool and blood samples from children < 5 years, and health and wellbeing data for children 5-14 years and adult respondents. We collected environmental data including temperature, mosquito and rat species abundance, and water and sediment samples. Demographic, built environment and household asset data were also collected. We combined our data with existing literature to generate a novel planetary health model of health and environment in informal settlements. RESULTS: Across the 12 settlements, 593 households and 2764 participants were enrolled. Two-thirds (64·1%) of all houses (26·3-82·7% per settlement) had formal land tenure documentation. Cough, fever and diarrhoea in the week prior to the survey were reported among an average of 34.3%, 26.9% and 9.7% of children aged < 5 years, respectively; although proportions varied over time, prevalence among these youngest children was consistently higher than among children 5-14 years or adult respondents. Among children < 5 years, 44·3% experienced stunting, 41·1% underweight, 12.4% wasting, and 26.5% were anaemic. There was self- or carer-reported poor mental health among 16.6% of children aged 5-14 years and 13.9% of adult respondents. Rates of potential risky exposures from swimming in waterways, eating uncooked produce, and eating soil or dirt were high, as were exposures to flooding and livestock. Just over one third of households (35.3%) had access to municipal water, and contamination of well water with E. coli and nitrogen species was common. Most (79·5%) houses had an in-house toilet, but no houses were connected to a piped sewer network or safe, properly constructed septic tank. Median monthly settlement outdoor temperatures ranged from 26·2 °C to 29.3 °C, and were on average, 1·1 °C warmer inside houses than outside. Mosquito density varied over time, with Culex quinquefasciatus accounting for 94·7% of species. Framed by a planetary health lens, our model includes four thematic domains: (1) the physical/built environment; (2) the ecological environment; (3) human health; and (4) socio-economic wellbeing, and is structured at individual, household, settlement, and city/beyond spatial scales. CONCLUSIONS: Our planetary health model includes key risk factors and faecal-oral exposure pathways but extends beyond conventional microbiological faecal-oral enteropathogen exposure pathways to comprehensively account for a wider range of variables affecting health in urban informal settlements. It includes broader ecological interconnections and planetary health-related variables at the household, settlement and city levels. It proposes a composite framework of markers to assess water and sanitation challenges and flood risks in urban informal settlements for optimal design and monitoring of interventions.