C-reactive protein trajectory to predict colorectal anastomotic leak: PREDICT Study.

BACKGROUND: Anastomotic leak is a common complication after colorectal surgery, associated with increased morbidity and mortality, and poorer long-term survival after oncological resections. Early diagnosis improves short-term outcomes, and may translate into reduced cancer recurrence. Multiple studies have attempted to identify biomarkers to enable earlier diagnosis of anastomotic leak. One study demonstrated that the trajectory of C-reactive protein (CRP) levels was highly predictive of anastomotic leak requiring intervention, with an area under the curve of 0·961. The aim of the present study was to validate this finding externally. METHODS: This was a prospective international multicentre observational study of adults undergoing elective colorectal resection with an anastomosis. CRP levels were measured before operation and for 5 days afterwards, or until day of discharge if earlier than this. The primary outcome was anastomotic leak requiring operative or radiological intervention. RESULTS: Between March 2017 and July 2018, 933 patients were recruited from 20 hospitals across Australia, New Zealand, England and Scotland. Some 833 patients had complete CRP data and were included in the primary analysis, of whom 41 (4·9 per cent) developed an anastomotic leak. A change in CRP level exceeding 50 mg/l between any two postoperative days had a sensitivity of 0·85 for detecting a leak, and a high negative predictive value of 0·99 for ruling it out. A change in CRP concentration of more than 50 mg/l between either days 3 and 4 or days 4 and 5 after surgery had a high specificity of 0·96-0·97, with positive likelihood ratios of 4·99-6·44 for a leak requiring intervention. CONCLUSION: This study confirmed the value of CRP trajectory in accurately ruling out an anastomotic leak after colorectal resection.

ANTECEDENTES: La fuga anastomótica es una complicación frecuente después de la cirugía colorrectal que se asocia con morbilidad y mortalidad, con una peor supervivencia a largo plazo tras resecciones oncológicas. El diagnóstico precoz mejora los resultados a corto plazo y puede traducirse en una reducción de la recidiva del cáncer. Múltiples estudios han tratado de identificar biomarcadores para lograr un diagnóstico precoz de la fuga anastomótica. Un estudio demostró que la evolución de la proteína C reactiva (PCR) era altamente predictiva de una fuga anastomótica que requería intervención, con un área bajo la curva de 0,961. Nuestro estudio tuvo como objetivo validar externamente este hallazgo. MÉTODOS: Se llevó a cabo un estudio internacional prospectivo observacional y multicéntrico de pacientes adultos sometidos a resección colorrectal electiva con anastomosis. Los niveles de PCR se midieron antes de la operación y diariamente hasta el día 5 después de la cirugía, o hasta el día del alta si fue anterior. El criterio de valoración principal fue la fuga anastomótica que requirió intervención quirúrgica o radiológica. RESULTADOS: Entre marzo de 2017 y julio de 2018, se reclutaron 933 pacientes de 20 hospitales de Australia, Nueva Zelanda, Inglaterra y Escocia. Se obtuvieron datos completos de PCR en 833 pacientes y se incluyeron en el análisis primario, de los cuales 41 (4,9%) presentaron una fuga anastomótica. Un aumento de la PCR > 50 mg/L entre dos días del postoperatorio fue sensible para detectar una fuga (0,85) y tuvo un alto valor predictivo negativo para descartarla (0,99). El porcentaje de cambio de PCR > 50 mg/L por día entre los días 3-4 o 4-5 después de la operación fue altamente específico (0,96) con un cociente de probabilidad positivo > 5,0 para las fugas que requirieron una intervención. CONCLUSIÓN: Este estudio confirma la utilidad de la evolución de la PCR para descartar con precisión una fuga anastomótica después de una resección colorrectal.

The LAPLAP study: a randomized placebo-controlled clinical trial assessing postoperative functional recovery using intraperitoneal local anaesthetic in laparoscopic colorectal surgery.

AIM: Postoperative pain remains a major factor in recovery from colorectal resection. There is increasing interest in opioid-sparing analgesia, and intraperitoneal local anaesthetic (IPLA) has recently been shown to be useful in minor laparoscopic and open colorectal procedures. The aim of this study was to evaluate the impact of IPLA on functional recovery following major laparoscopic surgery. In this controlled trial, mobility, as measured by the De Morton Mobility Index (DEMMI), was used as a surrogate for postoperative functional recovery. METHOD: Patients undergoing laparoscopic colorectal resection were randomized either to continuous ropivacaine (0.2% at 4-6 ml/h) or to saline (0.9%) which were administered via intraperitoneal catheter for 3 days postoperatively. Results were analysed in a double-blind manner. DEMMIs were assessed on postoperative days 1, 2, 3, 7 and 30, and data on pain, opioid consumption, gut and respiratory function, length of stay (LOS) and complications were recorded. RESULTS: Ninety-six patients were recruited. There was no difference in primary outcome (i.e., functional recovery) between IPLA and placebo groups. Opioid consumption and LOS were similar between groups, and no differences were found for any secondary outcome measure. There were no adverse events related to ropivacaine. CONCLUSION: Infusional intraperitoneal local anaesthetic appears to be safe but does not improve functional recovery or analgesic consumption following elective laparoscopic colorectal surgery, in the setting of an established enhanced recovery programme.

Cost-effectiveness of generic celecoxib in knee osteoarthritis for average-risk patients: a model-based evaluation.

OBJECTIVE: The cost-effectiveness of the recently-introduced generic celecoxib in knee OA has not been examined. METHOD: We used the Osteoarthritis Policy (OAPol) Model, a validated computer simulation of knee OA, to evaluate long-term clinical outcomes, costs, and cost-effectiveness of generic celecoxib in persons with knee OA. We examined eight treatment strategies consisting of generic celecoxib, over-the-counter (OTC) naproxen, or prescription naproxen, with or without prescription or OTC proton-pump-inhibitors (PPIs) to reduce gastrointestinal (GI) toxicity. In the base case, we assumed that annual cost was $130 for OTC naproxen, $360 for prescription naproxen, and $880 for generic celecoxib. We considered a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY) and discounted costs and benefits at 3% annually. In sensitivity analyses we varied celecoxib toxicity, discontinuation, cost, and pain level. RESULTS: In the base case analysis of the high pain cohort (WOMAC 50), celecoxib had an incremental cost-effectiveness ratio (ICER) of $284,630/QALY compared with OTC naproxen. Only under highly favorable cost, toxicity, and discontinuation assumptions (e.g., annual cost below $360, combined with a reduction in the cardiovascular (CV) event rates below baseline values) was celecoxib likely to be cost-effective. Celecoxib might also be cost-effective at an annual cost of $600 if CV toxicity were eliminated completely. In subjects with moderate pain (WOMAC 30), at the base case CV event rate of 0.2%, generic celecoxib was only cost-effective at the lowest plausible cost ($190). CONCLUSION: In knee OA patients with no comorbidities, generic celecoxib is not cost-effective at its current price.

Investigating the effects of Orexin-A on thermogenesis in human deep neck brown adipose tissue.

BACKGROUND: Despite successful preclinical testing, 85% of early clinical trials for novel drugs fail. Most futilities originate from molecular mechanisms of the drug(s) tested. It is critically important to develop validated human cell-based model systems in which animal-based research can be translated in order to complement the preclinical in vivo findings prior to implementation of a clinical trial. Obesity is associated with reduced circulating levels of Orexin-A (OX-A) in humans. OX-A increases thermogenesis in rodent brown adipose tissue (AT), yet this phenomenon has not been explored in humans. METHODS: We established a cell-based model system of human brown and white adipocytes and tested the effects of OX-A on thermogenesis. RESULTS: Contrary to published in vivo and in vitro reports in rodents, OX-A treatment alone or in combination with an adrenergic stimulus did neither enhance thermogenesis nor its related transcriptional program in a human in vitro model of brown adipocytes or AT explants. CONCLUSIONS: Translating preclinical findings in human model systems poses a challenge that must be overcome for the development of effective therapeutic compounds and targets.

Verification of an alternative sludge treatment process for pathogen reduction at two wastewater treatment plants in Victoria, Australia.

At South East Water wastewater treatment plants (WwTPs) in Victoria, Australia, biosolids are stockpiled for three years in compliance with the State guidelines to achieve the highest pathogen reduction grade (T1), suitable for unrestricted use in agriculture and landscaping. However, extended stockpiling is costly, may increase odour nuisance and greenhouse gas emissions, and reduces the fertiliser value of the biosolids. A verification programme of sampling and analysis for enteric pathogens was conducted at two WwTPs where sludge is treated by aerobic and anaerobic digestion, air drying (in drying pans or solar drying sheds) and stockpiling, to enumerate and, if present, monitor the decay of a range of enteric pathogens and parasites. The sludge treatment processes at both WwTPs achieved T1 grade biosolids with respect to prescribed pathogenic bacterial numbers (<1 Salmonella spp. 50 g-1 dry solids (DS) and <100 Escherichia coli g-1 DS) and >3 log10 enteric virus reduction after a storage period of one year. No Ascaris eggs were detected in the influent to the WwTPs, confirming previous studies that the presence of helminth infections in Victoria is extremely low and that Ascaris is not applicable as a control criterion for the microbiological quality of biosolids in the region.

Two-year changes in circulating adiponectin, ectopic fat distribution and body composition in response to weight-loss diets: the POUNDS Lost Trial.

BACKGROUND/OBJECTIVES: Adiponectin has a pivotal role in linking fat distribution with cardiometabolic disorders. We investigated the associations of long-term changes in circulating adiponectin with body composition and fat distribution at different abdominal depots in response to weight-loss dietary interventions, as well as the modification effect of sex. SUBJECTS/METHODS: In the 2-year Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) Trial, 811 overweight or obese adults were randomly assigned to one of four diets varying in macronutrient intakes. Circulating concentrations of adiponectin were repeatedly measured at baseline, 6 months and 2 years. Body composition and fat distribution were repeatedly measured by dual-energy X-ray absorptiometry scan (n=424) and computed tomography (n=195). RESULTS: Over the 2-year intervention, after adjustment for age, sex, ethnicity, follow-up time, diet group, baseline body mass index and baseline level of respective outcome trait, increase of adiponectin was significantly associated with reduction of total fat mass (FM), total fat-free mass (FFM), whole body total percentage of fat mass (FM%), percentage of trunk fat (TF%), total adipose tissue (TAT), and adipose tissue mass at different depots including visceral (VAT), deep subcutaneous (DSAT) and superficial subcutaneous (SSAT; P<0.03 for each). The relations with FM, FM%, TF%, VAT and DSAT were significantly modified by sex (P for interaction=0.02, 0.005 and <0.001, 0.002, 0.03, respectively) with greater reductions associated with increase of adiponectin in men than in women. CONCLUSIONS: Long-term changes in circulating adiponectin were differentially associated with improvement of body composition and abdominal fat distribution in men and women.

Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: systematic analytic review.

OBJECTIVE: Summarize the comparative effectiveness of oral non-steroidal anti-inflammatory drugs (NSAIDs) and opioids in reducing knee osteoarthritis (OA) pain. METHODS: Two reviewers independently screened reports of randomized controlled trials (RCTs), published in English between 1982 and 2015, evaluating oral NSAIDs or opioids for knee OA. Included studies were at least 8 weeks duration, conducted in Western Europe, the Americas, New Zealand, or Australia, and reported baseline and follow-up pain using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale (0-100, 100-worst). Effectiveness was evaluated as reduction in pain, accounting for study dropout and heterogeneity. RESULTS: Twenty-seven treatment arms (nine celecoxib, four non-selective NSAIDs [diclofenac, naproxen, piroxicam], eleven less potent opioids [tramadol], and three potent opioids [hydromorphone, oxycodone]) from 17 studies were included. NSAID and opioid studies reported similar baseline demographics and efficacy withdrawal rates; NSAID studies reported lower baseline pain and toxicity withdrawal rates. Accounting for efficacy-related withdrawals, all drug classes were associated with similar pain reductions (NSAIDs: -18; less potent opioids: -18; potent opioids: -19). Meta-regression did not reveal differential effectiveness by drug class but found that study cohorts with a higher proportion of male subjects and worse mean baseline pain had greater pain reduction. Similarly, results of the network meta-analysis did not find a significant difference in WOMAC Pain reduction for the three analgesic classes. CONCLUSION: NSAIDs and opioids offer similar pain relief in OA patients. These data could help clinicians and patients discuss likely benefits of alternative analgesics.

Cost-effectiveness of nonsteroidal anti-inflammatory drugs and opioids in the treatment of knee osteoarthritis in older patients with multiple comorbidities.

OBJECTIVE: To evaluate long-term clinical and economic outcomes of naproxen, ibuprofen, celecoxib or tramadol for OA patients with cardiovascular disease (CVD) and diabetes. DESIGN: We used the Osteoarthritis Policy Model to examine treatment with these analgesics after standard of care (SOC) - acetaminophen and corticosteroid injections - failed to control pain. NSAID regimens were evaluated with and without proton pump inhibitors (PPIs). We evaluated over-the-counter (OTC) regimens where available. Estimates of treatment efficacy (pain reduction, occurring in ∼57% of patients on all regimens) and toxicity (major cardiac or gastrointestinal toxicity or fractures, risk ranging from 1.09% with celecoxib to 5.62% with tramadol) were derived from published literature. Annual costs came from Red Book Online(®). Outcomes were discounted at 3%/year and included costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios (ICERs). Key input parameters were varied in sensitivity analyses. RESULTS: Adding ibuprofen to SOC was cost saving, increasing QALYs by 0.07 while decreasing cost by $800. Incorporating OTC naproxen rather than ibuprofen added 0.01 QALYs and increased costs by $300, resulting in an ICER of $54,800/QALY. Using prescription naproxen with OTC PPIs led to an ICER of $76,700/QALY, while use of prescription naproxen with prescription PPIs resulted in an ICER of $252,300/QALY. Regimens including tramadol or celecoxib cost more but added fewer QALYs and thus were dominated by several of the naproxen-containing regimens. CONCLUSIONS: In patients with multiple comorbidities, naproxen- and ibuprofen-containing regimens are more effective and cost-effective in managing OA pain than opioids, celecoxib or SOC.

Multicentre observational study of outcomes after drainage of acute perianal abscess.

INTRODUCTION: Management of perianal abscesses has remained largely unchanged for over 50 years. The evidence for postoperative wound packing is limited and may expose patients to painful procedures with no clinical benefit and at considerable increased cost. METHODS: Patients were recruited in 15 UK centres between December 2013 and October 2014. Outcome measures included number of dressing (pack) changes, healing, recurrence, return to work/normal function, postoperative fistula in ano and health utility scores (EQ-5D™). Pain was measured before, during and after dressing change on a visual analogue scale. RESULTS: Some 141 patients were recruited (median age 39 (range 18-86) years). The mean number of dressing changes in the first 3 weeks was 13 (range 0-21), equating to an annual cost to the National Health Service of €6 453 360 in England alone per annum. Some 43·8 per cent of wounds were healed by 8 weeks after surgery and 86 per cent of patients had returned to normal function. Some 7·6 per cent of abscesses had recurred and 26·7 per cent of patients developed a fistula in ano by 6 months following surgery. Patients reported a twofold to threefold increase in pain scores during and after dressing changes. CONCLUSION: Recurrent abscess is rare and fistula occurs in one-quarter of the patients. Packing is painful and costly.

Dietary patterns and cognitive decline in an Australian study of ageing.

The aim of this paper was to investigate the association of three well-recognised dietary patterns with cognitive change over a 3-year period. Five hundred and twenty-seven healthy participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing completed the Cancer Council of Victoria food frequency questionnaire at baseline and underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months follow-up. Individual neuropsychological test scores were used to construct composite scores for six cognitive domains and a global cognitive score. Based on self-reported consumption, scores for three dietary patterns, (1) Australian-style Mediterranean diet (AusMeDi), (2) western diet and (3) prudent diet were generated for each individual. Linear mixed model analyses were conducted to examine the relationship between diet scores and cognitive change in each cognitive domain and for the global score. Higher baseline adherence to the AusMeDi was associated with better performance in the executive function cognitive domain after 36 months in apolipoprotein E (APOE) ɛ4 allele carriers (P<0.01). Higher baseline western diet adherence was associated with greater cognitive decline after 36 months in the visuospatial cognitive domain in APOE ɛ4 allele non-carriers (P<0.01). All other results were not significant. Our findings in this well-characterised Australian cohort indicate that adherence to a healthy diet is important to reduce risk for cognitive decline, with the converse being true for the western diet. Executive function and visuospatial functioning appear to be particularly susceptible to the influence of diet.

Examining the potential clinical value of curcumin in the prevention and diagnosis of Alzheimer's disease.

Curcumin derived from turmeric is well documented for its anti-carcinogenic, antioxidant and anti-inflammatory properties. Recent studies show that curcumin also possesses neuroprotective and cognitive-enhancing properties that may help delay or prevent neurodegenerative diseases, including Alzheimer's disease (AD). Currently, clinical diagnosis of AD is onerous, and it is primarily based on the exclusion of other causes of dementia. In addition, phase III clinical trials of potential treatments have mostly failed, leaving disease-modifying interventions elusive. AD can be characterised neuropathologically by the deposition of extracellular ß amyloid (Aß) plaques and intracellular accumulation of tau-containing neurofibrillary tangles. Disruptions in Aß metabolism/clearance contribute to AD pathogenesis. In vitro studies have shown that Aß metabolism is altered by curcumin, and animal studies report that curcumin may influence brain function and the development of dementia, because of its antioxidant and anti-inflammatory properties, as well as its ability to influence Aß metabolism. However, clinical studies of curcumin have revealed limited effects to date, most likely because of curcumin's relatively low solubility and bioavailability, and because of selection of cohorts with diagnosed AD, in whom there is already major neuropathology. However, the fresh approach of targeting early AD pathology (by treating healthy, pre-clinical and mild cognitive impairment-stage cohorts) combined with new curcumin formulations that increase bioavailability is renewing optimism concerning curcumin-based therapy. The aim of this paper is to review the current evidence supporting an association between curcumin and modulation of AD pathology, including in vitro and in vivo studies. We also review the use of curcumin in emerging retinal imaging technology, as a fluorochrome for AD diagnostics.

Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance.

BACKGROUND/OBJECTIVES: Limited numbers of studies demonstrated obesity-induced macrophage infiltration in skeletal muscle (SM), but dynamics of immune cell accumulation and contribution of T cells to SM insulin resistance are understudied. SUBJECTS/METHODS: T cells and macrophage markers were examined in SM of obese humans by reverse transcription-PCR (RT-PCR). Mice were fed high-fat diet (HFD) for 2-24 weeks, and time course of macrophage and T-cell accumulation was assessed by flow cytometry and quantitative RT-PCR. Extramyocellular adipose tissue (EMAT) was quantified by high-resolution micro-computed tomography (CT), and correlation to T-cell number in SM was examined. CD11a-/- mice and C57BL/6 mice were treated with CD11a-neutralizing antibody to determine the role of CD11a in T-cell accumulation in SM. To investigate the involvement of Janus kinase/signal transducer and activator of transcription (JAK/STAT), the major pathway for T helper I (TH1) cytokine interferon-γ, in SM and adipose tissue inflammation and insulin resistance, mice were treated with a JAK1/JAK2 inhibitor, baricitinib. RESULTS: Macrophage and T-cell markers were upregulated in SM of obese compared with lean humans. SM of obese mice had higher expression of inflammatory cytokines, with macrophages increasing by 2 weeks on HFD and T cells increasing by 8 weeks. The immune cells were localized in EMAT. Micro-CT revealed that EMAT expansion in obese mice correlated with T-cell infiltration and insulin resistance. Deficiency or neutralization of CD11a reduced T-cell accumulation in SM of obese mice. T cells polarized into a proinflammatory TH1 phenotype, with increased STAT1 phosphorylation in SM of obese mice. In vivo inhibition of JAK/STAT pathway with baricitinib reduced T-cell numbers and activation markers in SM and adipose tissue and improved insulin resistance in obese mice. CONCLUSIONS: Obesity-induced expansion of EMAT in SM was associated with accumulation and proinflammatory polarization of T cells, which may regulate SM metabolic functions through paracrine mechanisms. Obesity-associated SM 'adiposopathy' may thus have an important role in the development of insulin resistance and inflammation.

Commonality versus specificity among adiposity traits in normal-weight and moderately overweight adults.

BACKGROUND: Many adiposity traits have been related to health complications and premature death. These adiposity traits are intercorrelated but their underlying structure has not been extensively investigated. We report on the degree of commonality and specificity among multiple adiposity traits in normal-weight and moderately overweight adult males and females (mean body mass index (BMI)=22.9 kg m(-2), s.d.=2.4). METHODS: A total of 75 healthy participants were assessed for a panel of adiposity traits including leg, arm, trunk, total fat masses and visceral adipose tissue (VAT) derived from dual energy X-ray absorptiometry (DXA), hepatic and muscle lipids from proton magnetic resonance spectroscopy, fat cell volume from an abdominal subcutaneous adipose tissue biopsy (n=36) and conventional anthropometry (BMI and waist girth). Spearman's correlations were calculated and were subjected to factor analysis. RESULTS: Arm, leg, trunk and total fat masses correlated positively (r=0.78-0.95) with each other. VAT correlated weakly with fat mass indicators (r=0.24-0.31). Intrahepatic lipids (IHL) correlated weakly with all fat mass traits (r=0.09-0.34), whereas correlations between DXA depots and intramyocellular lipids (IMCL) were inconsequential. The four DXA fat mass measures, VAT, IHL and IMCL depots segregated as four independent factors that accounted for 96% of the overall adiposity variance. BMI and waist girth were moderately correlated with the arm, leg, trunk and total fat and weakly with VAT, IHL and IMCL. CONCLUSION: Adiposity traits share a substantial degree of commonality, but there is considerable specificity across the adiposity variance space. For instance, VAT, IHL and IMCL are typically poorly correlated with each other and are poorly to weakly associated with the other adiposity traits. The same is true for BMI and waist girth, commonly used anthropometric indicators of adiposity. These results do not support the view that it will be possible to identify adequate anthropometric indicators of visceral, hepatic and muscle lipid content in normal-weight and moderately overweight individuals.

Physical activity and amyloid-ß plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing.

Previous studies suggest physical activity improves cognition and lowers Alzheimer's disease (AD) risk. However, key AD pathogenic factors that are thought to be influenced by physical activity, particularly plasma amyloid-ß (Aß) and Aß brain load, have yet to be thoroughly investigated. The objective of this study was to determine if plasma Aß and amyloid brain deposition are associated with physical activity levels, and whether these associations differed between carriers and non-carriers of the apolipoprotein E (APOE) ε4 allele. Five-hundred and forty six cognitively intact participants (aged 60-95 years) from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were included in these analyses. Habitual physical activity levels were measured using the International Physical Activity Questionnaire (IPAQ). Serum insulin, glucose, cholesterol and plasma Aß levels were measured in fasting blood samples. A subgroup (n=116) underwent (11)C-Pittsburgh compound B (PiB) positron emission tomography (PET) scanning to quantify brain amyloid load. Higher levels of physical activity were associated with higher high density lipoprotein (HDL) (P=0.037), and lower insulin (P<0.001), triglycerides (P=0.019) and Aß1-42/1-40 ratio (P=0.001). After stratification of the cohort based on APOE ε4 allele carriage, it was evident that only non-carriers received the benefit of reduced plasma Aß from physical activity. Conversely, lower levels of PiB SUVR (standardised uptake value ratio) were observed in higher exercising APOE ε4 carriers. Lower plasma Aß1-42/1-40 and brain amyloid was observed in those reporting higher levels of physical activity, consistent with the hypothesis that physical activity may be involved in the modulation of pathogenic changes associated with AD.

Do contaminants compromise the use of recycled nutrients in organic agriculture? A review and synthesis of current knowledge on contaminant concentrations, fate in the environment and risk assessment.

Use of nutrients recycled from societal waste streams in agriculture is part of the circular economy, and in line with organic farming principles. Nevertheless, diverse contaminants in waste streams create doubts among organic farmers about potential risks for soil health. Here, we gather the current knowledge on contaminant levels in waste streams and recycled nutrient sources, and discuss associated risks. For potentially toxic elements (PTEs), the input of zinc (Zn) and copper (Cu) from mineral feed supplements remains of concern, while concentrations of PTEs in many waste streams have decreased substantially in Europe. The same applies to organic contaminants, although new chemical groups such as flame retardants are of emerging concern and globally contamination levels differ strongly. Compared to inorganic fertilizers, application of organic fertilizers derived from human or animal feces is associated with an increased risk for environmental dissemination of antibiotic resistance. The risk depends on the quality of the organic fertilizers, which varies between geographical regions, but farmland application of sewage sludge appears to be a safe practice as shown by some studies (e.g. from Sweden). Microplastic concentrations in agricultural soils show a wide spread and our understanding of its toxicity is limited, hampering a sound risk assessment. Methods for assessing public health risks for organic contaminants must include emerging contaminants and potential interactions of multiple compounds. Evidence from long-term field experiments suggests that soils may be more resilient and capable to degrade or stabilize pollutants than often assumed. In view of the need to source nutrients for expanding areas under organic farming, we discuss inputs originating from conventional farms vs. non-agricultural (i.e. societal) inputs. Closing nutrient cycles between agriculture and society is feasible in many cases, without being compromised by contaminants, and should be enhanced, aided by improved source control, waste treatment and sound risk assessments.

Combination therapy with naltrexone and bupropion for obesity reduces total and visceral adiposity.

The effects of combination naltrexone/bupropion therapy on body composition and visceral adipose tissue (VAT) mass were examined in a subset (n = 107) of obese subjects from a Phase 2 trial that compared the efficacy and safety of placebo, naltrexone monotherapy, bupropion monotherapy or one of three naltrexone/bupropion dose combinations for 24 weeks. Body composition data were obtained using dual-energy X-ray absorptiometry and computed tomography. Eighty subjects completed the substudy. Naltrexone/bupropion resulted in weight loss and a greater reduction in body fat (-14.0 ± 1.3%) than placebo (-4.0 ± 2.0%), naltrexone monotherapy (-3.2 ± 2.5%) and bupropion monotherapy (-4.1 ± 2.9%; all p < 0.01). Reduction in VAT mass was also greater with naltrexone/bupropion (-15.0 ± 1.8%) than placebo (-4.6 ± 2.7%), naltrexone monotherapy (-0.1 ± 3.5%) and bupropion monotherapy (-2.3 ± 4.2%; all p < 0.01). Reductions in body fat and VAT mass with naltrexone/bupropion were proportional with weight loss. Weight loss with naltrexone/bupropion was not associated with a greater relative reduction in lean mass than placebo or the monotherapies.

Effect of pioglitazone on body composition and bone density in subjects with prediabetes in the ACT NOW trial.

AIMS: This study examined the effects of pioglitazone on body weight and bone mineral density (BMD) prospectively in patients with impaired glucose tolerance as pioglitazone (TZD) increases body weight and body fat in diabetic patients and increases the risk of bone fractures. METHODS: A total of 71 men and 163 women aged 49.3 (10.7) years [mean (s.d.)]; body mass index (BMI), 34.5 (5.9) kg/m(2) were recruited at five sites for measurements of body composition by dual energy X-ray absorptiometry at baseline and at conversion to diabetes or study end, if they had not converted. RESULTS: Mean follow-up was 33.6 months in the pioglitazone group and 32.1 months in the placebo group. Body weight increased 4.63 ± 0.60 (m ± s.e.) kg in the pioglitazone group compared to 0.98 ± 0.62 kg in the PIO group (p < 0.0001). Body fat rose 4.89 ± 0.42 kg in the pioglitazone group compared to 1.41 ± 0.44 kg, (p < 0.0001) in placebo-treated subjects. The increase in fat was greater in legs and trunk than in the arms. BMD was higher in all regions in men and significantly so in most. PIO decreased BMD significantly in the pelvis in men and women, decreased BMD in the thoracic spine and ribs of women and the lumbar spine and legs of men. Bone mineral content also decreased significantly in arms, legs, trunk and in the total body. CONCLUSIONS: Pioglitazone increased peripheral fat more than truncal fat and decreased BMD in several regions of the body.

Measurement of 24-h continuous human CH4 release in a whole room indirect calorimeter.

We describe the technology and validation of a new whole room indirect calorimeter (WRIC) methodology to quantify volume of methane (VCH4) released from the human body over 24 h concurrently with the assessment of energy expenditure and substrate utilization. The new system extends the assessment of energy metabolism by adding CH4, a downstream product of microbiome fermentation that could contribute to energy balance. Our new system consists of an established WRIC combined with the addition of off-axis integrated-cavity output spectroscopy (OA-ICOS) to measure CH4 concentration ([CH4]). Development, validation, and reliability of the system included environmental experiments to measure the stability of the atmospheric [CH4], infusing CH4 into the WRIC and human cross-validation studies comparing [CH4] quantified by OA-ICOS and mid-infrared dual-comb spectroscopy (MIR DCS).Our infusion data indicated that the system measured 24-h [CH4] and VCH4 with high sensitivity, reliability, and validity. Cross-validation studies showed good agreement between OA-ICOS and MIR DCS technologies (r = 0.979, P < 0.0001). Human data revealed 24-h VCH4 was highly variable between subjects and within/between days. Finally, our method to quantify VCH4 released by breath or colon suggested that over 50% of the CH4 was eliminated through the breath. The method allows, for the first time, measurement of 24-h VCH4 (in kcal) and therefore the measurement of the proportion of human energy intake fermented to CH4 by the gut microbiome and released via breath or from the intestine; also, it allows us to track the effects of dietary, probiotic, bacterial, and fecal microbiota transplantation on VCH4.NEW & NOTEWORTHY This is the first time that continuous assessment of CH4 is reported in parallel with measurements of O2 consumption and CO2 production inside a whole room indirect calorimeter in humans and over 24 h. We provide a detailed description of the whole system and its parts. We carried out studies of reliability and validity of the whole system and its parts. CH4 is released in humans during daily activities.

Multi-Domain Interventions for Dementia Prevention - A Systematic Review.

OBJECTIVES: There is a growing incidence of cognitive decline and dementia associated with the ageing population. Lifestyle factors such as diet, physical activity, and cognitive activities may individually or collectively be undertaken to increase one's odds of preventing cognitive decline and future dementia. This study will examine whether clinical trials using multidomain lifestyle intervention can significantly decrease the risk of cognitive decline and therefore dementia. DESIGN, SETTING AND PARTICIPANTS: This systematic literature review of multidomain lifestyle interventions for the prevention of cognitive decline and dementia followed the PRISMA guidelines. Clinical trials involving multidomain intervention (i.e., diet and physical activity, or without cognitive training) in older adults (≥ 49 years old) at higher risk of dementia were identified through 5 electronic databases (EMBASE, MEDLINE, CINAHL, Cochrane, and Scopus). A comprehensive search was performed to identify and retrieve publications until 15 November 2022. Trials were published in English. RESULTS: The included studies (n=15) assessed change in cognition in response to a multidomain lifestyle intervention. However, the cognitive outcome measures used in these studies were heterogeneous. Despite this heterogeneity, two thirds of the studies showed improvement in cognition following a multidomain intervention (n=10 with a total of 9,439 participants). However, five studies reported no improvement in cognition following the multidomain intervention. The most common form of dietary intervention included higher amount of fruit and vegetable intake; whole-grain cereal products instead of refined; low fat options in milk and meat products; and limiting sucrose intake to less than 50 g/day. Most clinical trial studies were powered to examining the effects of multidomain interventions in cognition but were not designed to test the contribution of individual domains (i.e., dietary changes, increased physical activity, or increased cognitive stimulation alone). CONCLUSION: This systematic review aimed to determine the effect of multimodal lifestyle interventions on cognitive outcomes in older adults at risk of dementia. We found that participants with conditions that may increase the risk of dementia, (e.g., hypertension, cardiovascular fragility) do benefit from multi-modal lifestyle changes including diet, physical activity, and cognitive training. Two thirds of studies using multidomain lifestyle interventions showed improvements in cognitive function. Trials with a focus on cognitive training, dietary improvement, and physical activity may prevent or delay cognitive decline in older adults including those at risk of developing dementia. Future studies should consider longer follow-up periods and adequate power to be able to examine the effects of each lifestyle component in the context of multimodal interventions.

Two-Year Prognostic Utility of Plasma p217+tau across the Alzheimer's Continuum.

BACKGROUND: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid-ß (Aß) and tau in Alzheimer's Disease (AD). However, its association with longitudinal cognition and comparative performance to PET Aß and tau in predicting cognitive decline are unknown. OBJECTIVES: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on Aß (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET Aß (A+) and tau (T+) with and without p217+tau pre-screening. DESIGN: A prospective observational cohort study. SETTING: Participants of the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT). PARTICIPANTS: 153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals. MEASUREMENTS: Baseline p217+tau Simoa® assay, 18F-MK6240 tau-PET and 18F-NAV4694 Aß-PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 ± 0.8 years. RESULTS: In CI, p217+tau was a significant predictor of change in MMSE (ß = -0.55, p < 0.001) and CDR-SB (ß =0.61, p < 0.001) with an effect size similar to Aß Centiloid (MMSE ß = -0.48, p = 0.002; CDR-SB ß = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: ß = -0.62, p < 0.001; CDR-SB: ß = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (ß = -0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6-13% compared to screening with PET for T+ (different regions). This would translate to an 81-83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26-38% biomarker test cost-saving in the CU. CONCLUSIONS: Substantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing.