Influencing factors of sedentary behaviour in people with chronic obstructive pulmonary disease: a systematic review.

BACKGROUND: People with chronic obstructive pulmonary disease (COPD) are more likely to adopt a sedentary lifestyle. Increased sedentary behaviour is associated with adverse health consequences and reduced life expectancy. AIM: This mixed-methods systematic review aimed to report the factors contributing to sedentary behaviour in people with COPD. METHODS: A systematic search of electronic databases (Medline, CINAHL, PsycINFO and Cochrane Library) was conducted and supported by a clinician librarian in March 2023. Papers were identified and screened by two independent researchers against the inclusion and exclusion criteria, followed by data extraction and analysis of quality. Quantitative and qualitative data synthesis was performed. RESULTS: 1037 records were identified, 29 studies were included (26 quantitative and 3 qualitative studies) and most studies were conducted in high-income countries. The most common influencers of sedentary behaviour were associated with disease severity, dyspnoea, comorbidities, exercise capacity, use of supplemental oxygen and walking aids, and environmental factors. In-depth findings from qualitative studies included a lack of knowledge, self-perception and motivation. However, sedentarism in some was also a conscious approach, enabling enjoyment when participating in hobbies or activities. CONCLUSIONS: Influencers of sedentary behaviour in people living with COPD are multifactorial. Identifying and understanding these factors should inform the design of future interventions and guidelines. A tailored, multimodal approach could have the potential to address sedentary behaviour. PROSPERO REGISTRATION NUMBER: CRD42023387335.

Deciphering the Molecular Mechanisms behind Drug Resistance in Ovarian Cancer to Unlock Efficient Treatment Options.

Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets.

Differential structure and function of phosphorus-mineralizing microbial communities in organic and upper mineral soil horizons across a temperate rainforest chronosequence.

Microbial community structure and function were assessed in the organic and upper mineral soil across a ~4000-year dune-based chronosequence at Big Bay, New Zealand, where total P declined and the proportional contribution of organic soil in the profile increased with time. We hypothesized that the organic and mineral soils would show divergent community evolution over time with a greater dependency on the functionality of phosphatase genes in the organic soil layer as it developed. The structure of bacterial, fungal, and phosphatase-harbouring communities was examined in both horizons across 3 dunes using amplicon sequencing, network analysis, and qPCR. The soils showed a decline in pH and total phosphorus (P) over time with an increase in phosphatase activity. The organic horizon had a wider diversity of Class A (phoN/phoC) and phoD-harbouring communities and a more complex microbiome, with hub taxa that correlated with P. Bacterial diversity declined in both horizons over time, with enrichment of Planctomycetes and Acidobacteria. More complex fungal communities were evident in the youngest dune, transitioning to a dominance of Ascomycota in both soil horizons. Higher phosphatase activity in older dunes was driven by less diverse P-mineralizing communities, especially in the organic horizon.

Ivermectin Augments the Anti-Cancer Activity of Pitavastatin in Ovarian Cancer Cells.

We have previously shown that pitavastatin has the potential to be used to treat ovarian cancer, although relatively high doses are likely to be necessary. One solution to this problem is to identify drugs that are synergistic with pitavastatin, thereby reducing the dose that is necessary to have a therapeutic effect. Here, we tested combinations of pitavastatin with the anti-parasitic drug ivermectin in six ovarian cancer cell lines. When tested on its own, ivermectin inhibited the growth of the cells but only with modest potency (IC50 = 10-20 µM). When the drugs were combined and assessed in cell growth assays, ivermectin showed synergy with pitavastatin in 3 cell lines and this was most evident in COV-318 cells (combination index ~ 0.6). Ivermectin potentiated the reduction in COV-318 cell viability caused by pitavastatin by 20-25% as well as potentiating apoptosis induced by pitavastatin, assessed by activation of caspase-3/7 (2-4 fold) and annexin-labelling (3-5 fold). These data suggest that ivermectin may be useful in the treatment of ovarian cancer when combined with pitavastatin, but methods to achieve an adequate ivermectin concentration in tumour tissue will be necessary.

Surviving severe COVID-19: Interviews with patients, informal carers and health professionals.

BACKGROUND: The COVID-19 pandemic has been associated with an unprecedented number of critical care survivors. Their experiences through illness and recovery are likely to be complex, but little is known about how best to support them. AIM: This study aimed to explore experiences of illness and recovery from the perspective of survivors, their relatives and professionals involved in their care. STUDY DESIGN: In-depth qualitative interviews were conducted with three stakeholder groups during the first wave of the pandemic. A total of 23 participants (12 professionals, 6 survivors and 5 relatives) were recruited from 5 acute hospitals in England and interviewed by telephone or video call. Data analysis followed the principles of Reflexive Thematic Analysis. FINDINGS: Three themes were generated from their interview data: (1) Deteriorating fast-a downhill journey from symptom onset to critical care; (2) Facing a new virus in a hospital-a remote place; and (3) Returning home as a survivor, maintaining normality and recovering slowly. CONCLUSIONS: Our findings highlight challenges in accessing care and communication between patients, hospital staff and relatives. Following hospital discharge, patients adopted a reframed 'survivor identity' to cope with their experience of illness and slow recovery process. The concept of survivorship in this patient group may be beneficial to promote and explore further. RELEVANCE TO CLINICAL PRACTICE: All efforts should be made to continue to improve communication between patients, relatives and health professionals during critical care admissions, particularly while hospital visits are restricted. Adapting to life after critical illness may be more challenging while health services are restricted by the impacts of the pandemic. It may be beneficial to promote the concept of survivorship, following admission to critical care due to severe COVID-19.

Marathon running and cell-cycle arrest biomarkers of acute kidney injury.

OBJECTIVES: Endurance exercise is known to cause a rise in serum creatinine. It is not known to what extent this rise reflects renal stress and a potential acute kidney injury (AKI). Increases in Insulin Like Growth Factor Binding Protein 7 (IGFBP7) and Tissue Inhibitor of Metalloprotinases-2 (TIMP-2), urinary biomarkers of cell cycle arrest and renal stress, are associated with the development of AKI in clinical populations. DESIGN: Repeated measures study. METHODS: Runners were recruited at the 2019 Brighton Marathon (UK) and provided urine and blood samples at baseline, immediately post-race and 24 h post-race. Serum creatinine, urinary creatinine and urinary IGFBP7 and TIMP-2 were analysed from the samples. RESULTS: Seventy nine participants (23 females, 56 males), aged 43 ±â€¯10 yrs. (mean ±â€¯SD), finish time 243 ±â€¯40mins were included for analysis. Serum creatinine increased over the race by 40 ±â€¯26% (p < 0.001), TIMP-2 increased by 555 ±â€¯697% (p < 0.001) and IGFBP7 increased by 1094 ±â€¯1491% (p < 0.001) over the race. A subset of twenty-two participants supplied samples 24 h post-race, reporting values similar to baseline for all variables. CONCLUSIONS: This study is the first to report large rises in IGFBP7 and TIMP-2 following marathon running. This suggests that rises in creatinine are not fully explained by changes in production and clearance and marathon running induces a state of kidney stress and potential injury.

Inhibition of branched-chain alpha-keto acid dehydrogenase kinase augments the sensitivity of ovarian and breast cancer cells to paclitaxel.

CONTEXT: Many cancer patients who initially respond to chemotherapy eventually develop chemoresistance, and to address this, we previously conducted a RNAi screen to identify genes contributing to resistance. One of the hits from the screen was branched-chain α-keto acid dehydrogenase kinase (BCKDK). BCKDK controls the metabolism of branched-chain amino acids (BCAAs) through phosphorylation and inactivation of the branched-chain α-keto acid dehydrogenase complex (BCKDH), thereby inhibiting catabolism of BCAAs. METHODS: We measured the impact on paclitaxel sensitivity of inhibiting BCKDK in ovarian and breast cancer cell lines. RESULTS: Inhibition of BCKDK using siRNA or two chemical inhibitors (BCKDKi) was synergistic with paclitaxel in both breast and ovarian cancer cells. BCKDKi reduced levels of BCAA and the addition of exogenous BCAA suppressed this synergy. BCKDKi inactivated the mTORC1-Aurora pathway, allowing cells to overcame M-phase arrest induced by paclitaxel. In some cases, cells almost completed cytokinesis, then reverted to a single cell, resulting in multinucleate cells. CONCLUSION: BCKDK is an attractive target to augment the sensitivity of cancer cells to paclitaxel.

Inflammatory and psychological consequences of chronic high exposure firefighting.

OBJECTIVES: This study aimed to examine the impact of extreme heat exposure frequency on inflammation and well-being in UK Fire Service personnel. METHODS: 136 Fire personnel and 14 controls (CON) were recruited [92 Firefighters (FF), 44 Breathing Apparatus Instructors (BAI)]. BAI were split into low (LBAI; ≤15 exposures per month) and high (HBAI; ≥20 exposures per month) categories. Measures of inflammation, mood and fatigue were collected at 0, 3 and 6 month times points. These variables were analysed for differences between groups and association with frequency of exposure. RESULTS: HBAI exhibited raised IL-1ß, IL-6, IL-10, IgE and lower IgM (p < 0.05). In addition, IL-1ß, IL-6, IL-10 and IgM were associated with monthly exposure number, with exposures accounting for 15.4% of the variance in IL-6, 11.8% of IL-1ß and 25.2% of IL-10. No differences in mood or fatigue were reported (p > 0.05). CONCLUSION: High exposure firefighting consistently causes systemic inflammation without perceptual recognition of potential health risks.

Using Smartwatches to Observe Changes in Activity During Recovery From Critical Illness Following COVID-19 Critical Care Admission: 1-Year, Multicenter Observational Study.

BACKGROUND: As a sequela of the COVID-19 pandemic, a large cohort of critical illness survivors have had to recover in the context of ongoing societal restrictions. OBJECTIVE: We aimed to use smartwatches (Fitbit Charge 3; Fitbit LLC) to assess changes in the step counts and heart rates of critical care survivors following hospital admission with COVID-19, use these devices within a remote multidisciplinary team (MDT) setting to support patient recovery, and report on our experiences with this. METHODS: We conducted a prospective, multicenter observational trial in 8 UK critical care units. A total of 50 participants with moderate or severe lung injury resulting from confirmed COVID-19 were recruited at discharge from critical care and given a smartwatch (Fitbit Charge 3) between April and June 2020. The data collected included step counts and daily resting heart rates. A subgroup of the overall cohort at one site-the MDT site (n=19)-had their smartwatch data used to inform a regular MDT meeting. A patient feedback questionnaire and direct feedback from the MDT were used to report our experience. Participants who did not upload smartwatch data were excluded from analysis. RESULTS: Of the 50 participants recruited, 35 (70%) used and uploaded data from their smartwatch during the 1-year period. At the MDT site, 74% (14/19) of smartwatch users uploaded smartwatch data, whereas 68% (21/31) of smartwatch users at the control sites uploaded smartwatch data. For the overall cohort, we recorded an increase in mean step count from 4359 (SD 3488) steps per day in the first month following discharge to 7914 (SD 4146) steps per day at 1 year (P=.003). The mean resting heart rate decreased from 79 (SD 7) beats per minute in the first month to 69 (SD 4) beats per minute at 1 year following discharge (P<.001). The MDT subgroup's mean step count increased more than that of the control group (176% increase vs 42% increase, respectively; +5474 steps vs +2181 steps, respectively; P=.04) over 1 year. Further, 71% (10/14) of smartwatch users at the MDT site and 48% (10/21) of those at the control sites strongly agreed that their Fitbit motivated them to recover, and 86% (12/14) and 48% (10/21), respectively, strongly agreed that they aimed to increase their activity levels over time. CONCLUSIONS: This is the first study to use smartwatch data to report on the 1-year recovery of patients who survived a COVID-19 critical illness. This is also the first study to report on smartwatch use within a post-critical care MDT. Future work could explore the role of smartwatches as part of a randomized controlled trial to assess clinical and economic effectiveness. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.12968/ijtr.2020.0102.

Identification of foods that affect the anti-cancer activity of pitavastatin in cells.

Statins inhibit the synthesis of mevalonate, a precursor isoprenoid molecule to geranylgeraniol that is necessary for the post-translational modification of several small GTPase oncogenes. Despite numerous preclinical studies suggesting that statins can be effective anticancer agents, prospective clinical trials have failed to demonstrate any clinical benefit in patients with cancer. We previously demonstrated that geranylgeraniol suppresses the activity of statins in cell culture studies, and that pitavastatin can cause regression of ovarian cancer xenografts in mice if the animals' diet is modified to avoid the inclusion of geranylgeraniol. Dietary sources of geranylgeraniol may consequently limit the activity of statins in cancer clinical trials. The present study tested several foods to identify those that affected the cytotoxic activity of pitavastatin towards ovarian cancer cells. Solvent extracts of several foods were tested for their ability to suppress the effects of pitavastatin in cell growth assays. The results revealed that pitavastatin induced cell death in ovarian cancer cells (IC50=5.2 µM) and this was blocked by geranylgeraniol whereas other products of the mevalonate pathway (coenzyme Q, dolichol or cholesterol) had no effect on the activity of pitavastatin in cell growth assays. Solvent extracts from several foods, especially oils (apart from rapeseed), also blocked the cytotoxic activity of pitavastatin. Several extracts from a range of fruit, vegetables and carbohydrate-rich foods also did not block the activity of pitavastatin. However, extracts from beans, lettuce, oats, eggs and various nuts reduced the activity of pitavastatin. These data identified foods that patients could eat to potentially improve the outcome of clinical trials of pitavastatin in cancer.

Towards circular phosphorus: The need of inter- and transdisciplinary research to close the broken cycle.

Phosphorus (P) is an essential element to all living beings but also a finite resource. P-related problems center around broken P cycles from local to global scales. This paper presents outcomes from the 9th International Phosphorus Workshop (IPW9) held 2019 on how to move towards a sustainable P management. It is based on two sequential discussion rounds with all participants. Important progress was reported regarding the awareness of P as finite mineable resource, technologies to recycle P, and legislation towards a circular P economy. Yet, critical deficits were identified such as how to handle legacy P, how climate change may affect ecosystem P cycling, or working business models to up-scale existing recycling models. Workshop participants argued for more transdisciplinary networks to narrow a perceived science-practice/policy gap. While this gap may be smaller in reality as illustrated with a Swiss example, we formulate recommendations how to bridge this gap more effectively.

Manipulating exudate composition from root apices shapes the microbiome throughout the root system.

Certain soil microorganisms can improve plant growth, and practices that encourage their proliferation around the roots can boost production and reduce reliance on agrochemicals. The beneficial effects of the microbial inoculants currently used in agriculture are inconsistent or short-lived because their persistence in soil and on roots is often poor. A complementary approach could use root exudates to recruit beneficial microbes directly from the soil and encourage inoculant proliferation. However, it is unclear whether the release of common organic metabolites can alter the root microbiome in a consistent manner and if so, how those changes vary throughout the whole root system. In this study, we altered the expression of transporters from the ALUMINUM-ACTIVATED MALATE TRANSPORTER and the MULTIDRUG AND TOXIC COMPOUND EXTRUSION families in rice (Oryza sativa L.) and wheat (Triticum aestivum L.) and tested how the subsequent release of their substrates (simple organic anions, including malate, citrate, and γ-amino butyric acid) from root apices affected the root microbiomes. We demonstrate that these exudate compounds, separately and in combination, significantly altered microbiome composition throughout the root system. However, the root type (seminal or nodal), position along the roots (apex or base), and soil type had a greater influence on microbiome structure than the exudates. These results reveal that the root microbiomes of important cereal species can be manipulated by altering the composition of root exudates, and support ongoing attempts to improve plant production by manipulating the root microbiome.

The Hyperlipidaemic Drug Fenofibrate Significantly Reduces Infection by SARS-CoV-2 in Cell Culture Models.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor-binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in enzyme-linked immunosorbent assay (ELISA) and whole cell-binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations, which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, this study identifies fenofibrate as a potential therapeutic agent requiring an urgent clinical evaluation to treat SARS-CoV-2 infection.

Digitally enhanced recovery from severe COVID-19: a new frontier?

During the first wave of intensive care unit admissions with COVID-19, in response to the constraints of social distancing we introduced a new digitally enabled critical care rehabilitation pathway. Using smartwatch technology, this pathway rapidly enabled our multidisciplinary team to observe the recovery of a COVID-19 cohort across eight NHS acute hospitals across the south of England. This represents one of the geographically largest smartwatch studies of its kind.

Critical phosphorus requirements of Trifolium species: The importance of root morphology and root acclimation in response to phosphorus stress.

Differences in root morphology and acclimation to low-phosphorus (P) soil were examined among eight legume species from the Trifolium Section Tricocephalum to understand how these root attributes determine P acquisition. Ornithopus sativus was included as a highly P-efficient benchmark species. Plants were grown as microswards in pots with five rates of P supplied in a topsoil layer to mimic uneven P distribution within a field soil profile. Topsoil and subsoil roots were harvested separately to enable measurement of the nutrient-foraging responses. Critical P requirement (lowest P supply for maximum yield) varied over a threefold range, reflecting differences in root morphology and acclimation of nutrient-foraging roots to P stress. Among the species, there was a 3.2-fold range in root length density, a 1.7-fold range in specific root length, and a 2.1-fold range in root hair length. O. sativus had the lowest critical P requirement, displayed a high root length density, the highest specific root length, and the longest root hairs. Acquisition of P from P-deficient soil was facilitated by development of a large root hair cylinder (i.e. a large root-soil interface). This, in turn, was determined by the intrinsic root morphology attributes of each genotype, and the plasticity of its root morphology response to internal P stress. Root acclimation in low-P soil by all species was mostly associated with preferential allocation of mass to nutrient-foraging roots. Only O. sativus and four of the Trifolium species adjusted specific root length beneficially, and only O. sativus increased its root hair length in low-P soil.

The microbiomes on the roots of wheat (Triticum aestivum L.) and rice (Oryza sativa L.) exhibit significant differences in structure between root types and along root axes.

There is increasing interest in understanding how the microbial communities on roots can be manipulated to improve plant productivity. Root systems are not homogeneous organs but are comprised of different root types of various ages and anatomies that perform different functions. Relatively little is known about how this variation influences the distribution and abundance of microorganisms on roots and in the rhizosphere. Such information is important for understanding how root-microbe interactions might affect root function and prevent diseases. This study tested specific hypotheses related to the spatial variation of bacterial and fungal communities on wheat (Triticum aestivum L.) and rice (Oryza sativa L.) roots grown in contrasting soils. We demonstrate that microbial communities differed significantly between soil type, between host species, between root types, and with position along the root axes. The magnitude of variation between different root types and along individual roots was comparable with the variation detected between different plant species. We discuss the general patterns that emerged in this variation and identify bacterial and fungal taxa that were consistently more abundant on specific regions of the root system. We argue that these patterns should be measured more routinely so that localised root-microbe interactions can be better linked with root system design, plant health and performance.

Soil microbial communities influencing organic phosphorus mineralization in a coastal dune chronosequence in New Zealand.

The Haast chronosequence in New Zealand is an ∼6500-year dune formation series, characterized by rapid podzol development, phosphorus (P) depletion and a decline in aboveground biomass. We examined bacterial and fungal community composition within mineral soil fractions using amplicon-based high-throughput sequencing (Illumina MiSeq). We targeted bacterial non-specific acid (class A, phoN/phoC) and alkaline (phoD) phosphomonoesterase genes and quantified specific genes and transcripts using real-time PCR. Soil bacterial diversity was greatest after 4000 years of ecosystem development and associated with an increased richness of phylotypes and a significant decline in previously dominant taxa (Firmicutes and Proteobacteria). Soil fungal communities transitioned from predominantly Basidiomycota to Ascomycota along the chronosequence and were most diverse in 290- to 392-year-old soils, coinciding with maximum tree basal area and organic P accumulation. The Bacteria:Fungi ratio decreased amid a competitive and interconnected soil community as determined by network analysis. Overall, soil microbial communities were associated with soil changes and declining P throughout pedogenesis and ecosystem succession. We identified an increased dependence on organic P mineralization, as found by the profiled acid phosphatase genes, soil acid phosphatase activity and function inference from predicted metagenomes (PICRUSt2).

Phosphate-solubilising microorganisms for improved crop productivity: a critical assessment.

Phosphate-solubilising microorganisms (PSM) are often reported to have positive effects on crop productivity through enhanced phosphorus (P) nutrition. Our aim was to evaluate the validity of this concept. Most studies that report 'positive effects' of PSM on plant growth have been conducted under controlled conditions, whereas field experiments more frequently fail to demonstrate a positive response. Many studies have indicated that the mechanisms seen in vitro do not translate into improved crop P nutrition in complex soil-plant systems. Furthermore, associated mechanisms are often not rigorously assessed. We suggest that PSM do not mobilise sufficient P to change the crops' nutritional environment under field conditions. The current concept, in which PSM solubilise P 'for the plant' should thus be revised. Although PSM have the capacity to solubilise P to meet their own needs, it is the turnover of the microbial biomass that subsequently provides P to plants over a longer time. Therefore, the existing concept of PSM function is unlikely to deliver a reliable strategy for increasing crop P nutrition. A further mechanistic understanding is needed to determine how P mobilisation by PSM as a component of the whole soil community can be manipulated to become more effective for plant P nutrition.

Association between collapse and serum creatinine and electrolyte concentrations in marathon runners: a 9-year retrospective study.

OBJECTIVE: Abnormal biochemical measurements have previously been described in runners following marathons. The incidence of plasma sodium levels outside the normal range has been reported as 31%, and the incidence of raised creatinine at 30%. This study describes the changes seen in electrolytes and creatinine in collapsed (2010-2019 events) and noncollapsed (during the 2019 event) runners during a UK marathon. METHODS: Point-of-care sodium, potassium, urea and creatinine estimates were obtained from any collapsed runner treated by the medical team during the Brighton Marathons, as part of their clinical care, and laboratory measurements from control subjects. RESULTS: Results from 224 collapsed runners were available. Serum creatinine was greater than the normal range in 68.9%. About 6% of sodium results were below, and 3% above the normal range, with the lowest 132 mmol/l. Seventeen percent of potassium readings were above the normal range; the maximum result was 8.4 mmol/l, but 97% were below 6.0 mmol/l. In the control group, mean creatinine was significantly raised in both the collapse and control groups, with 55.4% meeting the criteria for acute kidney injury, but had resolved to baseline after 24 h. Sodium concentration but not the potassium was significantly raised after the race compared with baseline, but only 15% were outside the normal range. CONCLUSION: In this study, incidence of a raised creatinine was higher than previously reported. However, the significance of such a rise remains unclear with a similar rise seen in collapsed and noncollapsed runners, and resolution noted within 24 h. Abnormal sodium concentrations were observed infrequently, and severely abnormal results were not seen, potentially reflecting current advice to drink enough fluid to quench thirst.