Cardiopulmonary and cerebrovascular acclimatization in children and adults at 3800 m.

Maturational differences exist in cardiopulmonary and cerebrovascular function at sea-level, but the impact of maturation on acclimatization responses to high altitude is unknown. Ten children (9.8 ± 2.5 years) and 10 adults (34.7 ± 7.1 years) were assessed at sea-level (BL), 3000 m and twice over 4 days at 3800 m (B1, B4). Measurements included minute ventilation ( V ̇ E ${\dot{V}}_{\rm{E}}$ ), end-tidal partial pressures of oxygen ( P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ ) and carbon dioxide, echocardiographic assessment of pulmonary artery systolic pressure (PASP) and stroke volume (SV) and ultrasound assessment of blood flow through the internal carotid and vertebral arteries was performed to calculate global cerebral blood flow (gCBF). At 3000 m, V ̇ E ${\dot{V}}_{\rm{E}}$ was increased from BL by 19.6 ± 19.1% (P = 0.031) in children, but not in adults (P = 0.835); SV was reduced in children (-11 ± 13%, P = 0.020) but not adults (P = 0.827), which was compensated for by a larger increase in heart rate in children (+26 beats min-1 vs. +13 beats min-1 , P = 0.019). Between B1 and B4, adults increased V ̇ E ${\dot{V}}_{\rm{E}}$ by 38.5 ± 34.7% (P = 0.006), while V ̇ E ${\dot{V}}_{\rm{E}}$ did not increase further in children. The rise in PASP was not different between groups; however, ∆PASP from BL was related to ∆ P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ in adults (R2  = 0.288, P = 0.022), but not children. At BL, gCBF was 43% higher in children than adults (P = 0.017), and this difference was maintained at high altitude, with a similar pattern and magnitude of change in gCBF between groups (P = 0.845). Despite V ̇ E ${\dot{V}}_{\rm{E}}$ increasing in children but not adults at a lower altitude, the pulmonary vascular and cerebrovascular responses to prolonged hypoxia are similar between children and adults. KEY POINTS: Children have different ventilatory and metabolic requirements from adults, which may present differently in the pulmonary and cerebral vasculature upon ascent to high altitude. Children (ages 7-14) and adults (ages 23-44) were brought from sea level to high altitude (3000 to 3800 m) and changes in ventilation, pulmonary artery systolic pressure (PASP) and cerebral blood flow (CBF) were assessed over 1 week. Significant increases in ventilation and decreases in left ventricle stroke volume were observed at a lower altitude in children than adults. PASP and CBF increased by a similar relative amount between children and adults at 3800 m. These results help us better understand age-related differences in compensatory responses to prolonged hypoxia in children, despite similar changes in pulmonary artery pressure and CBF between children and adults.

Cost-effectiveness analysis of tumor molecular classification in high-risk early-stage endometrial cancer.

PURPOSE: Tumor molecular analyses in endometrial cancer (EC) includes 4 distinct subtypes: (1) POLE-mutated, (2) mismatch repair protein (MMR) deficient, (3) p53 mutant, and (4) no specific molecular profile. Recently, a sub-analysis of PORTEC-3 demonstrated notable differences in treatment response between molecular classification (MC) groups. Cost of testing is one barrier to widespread adoption of MC. Therefore, we sought to determine the cost-effectiveness of MC in patients with stage I and II high-risk EC. METHODS: A Markov decision model was developed to compare tumor molecular classification (TMC) vs. no testing (NT). A healthcare payor's perspective and 5-year time horizon were used. Base case data were abstracted from PORTEC-3 and the molecular sub-analysis. Cost and utility data were derived from public databases, peer-reviewed literature, and expert input. Strategies were compared using the incremental cost-effectiveness ratio (ICER) with effectiveness in quality-adjusted life years (QALYs) and evaluated with a willingness-to-pay threshold of $100,000 per QALY gained. Sensitivity analyses were performed to test model robustness. RESULTS: When compared to NT, TMC was cost effective with an ICER of $25,578 per QALY gained; incremental cost was $1780 and incremental effectiveness was 0.070 QALYs. In one-way sensitivity analyses, results were most sensitive to the cost of POLE testing, but TMC remained cost-effective over all parameter ranges. CONCLUSIONS: TMC in early-stage high-risk EC is cost-effective, and the model results were robust over a range of parameters. Given that MC can be used to guide adjuvant treatment decisions, these findings support adoption of TMC into routine practice.

Efficacy of bivalent fimbrial vaccines to control and eliminate intermediate forms of footrot in sheep.

OBJECTIVE: The aim of this study was to determine the efficacy of serogroup-specific bivalent fimbrial vaccines in the control and elimination of relatively mild (intermediate) forms of footrot in sheep flocks in NSW, there being some evidence that such forms are difficult to control. METHODS: Four flocks of sheep with history of footrot of intermediate virulence were selected based on clinical and bacteriological diagnoses. Dichelobacter nodosus serogroups included in bivalent vaccines at each farm were based on on-farm serogroup-prevalence data. Two doses of bivalent vaccine were administered with a 4-week interval between doses. Repeated post-vaccination inspections of all feet of between 100 and 119 animals per mob were conducted and foot swabs were collected for bacteriological testing. Blood samples were collected from 10 to 24 individually identified animals per flock at each inspection to check for agglutinating antibody responses. RESULTS: In the majority of animals, antibody levels for serogroups included in each vaccine were above the level believed to be required for protective immunity. Footrot disappeared on farm 1 prior to vaccination, but did not reappear postvaccination. Footrot was controlled but not eliminated on farms 2, 3, and 4, where the prevalence and severity of the disease and number of serogroups present were reduced. CONCLUSION: Serogroup-specific bivalent vaccines can be effective at controlling footrot caused by intermediate strains of D. nodosus.

The severity of footrot lesions induced by aprV2-positive strains of Dichelobacter nodosus varies between strains.

OBJECTIVES: The primary objective of this study was to evaluate the clinical virulence of aprV2-positive lesser virulent field isolates of footrot bacteria Dichelobacter nodosus in comparison with an aprV2-positive clinically virulent reference strain. Correlations between the clinical expression of the disease and the presence of aprV2 (detected using PCR tests) have been inconsistent. A second objective was to evaluate the elimination of D. nodosus following treatment of sheep as some strains of D. nodosus have been reported to be difficult to eliminate. METHODS: The virulence of three aprV2-positive field isolates of D. nodosus which had lesser virulent phenotypes, and an aprV2-positive virulent reference strain was evaluated in a sheep trial using a pasture-based experimental infection model. In the second phase of the study, treatments including footbathing and a long-acting antibiotic were administered and their efficacy in elimination of these strains was evaluated. RESULTS: Severe underrun (score 4) lesions developed in sheep infected with the aprV2-positive virulent reference strain but not in sheep infected with the field isolates; they had mild lesions (score 2 or 3). The three field isolates and the virulent reference strain of D. nodosus were eliminated by intensive foot bathing and antibiotic therapy in combination with housing the animals in dry conditions post-treatment. CONCLUSION: The results suggest that the presence of aprV2 gene in isolates of D. nodosus may not be a reliable indicator of virulence and that further investigation of the factors that determine clinical virulence is required. While the treatment regime was successful, based on a range of considerations, the use of such an intensive treatment involving antibiotics should be limited to small groups of high-value animals, such as rams.

Youth diet quality and hazard of mood disorder in adolescence and adulthood among an Australian cohort.

BACKGROUND: Prospective studies on youth diet and mood disorders outcomes are limited. We examined if youth diet quality was associated with mood disorder onset over a 25-year follow-up period. METHODS: In 1985, Australian participants (aged 10-15 years) completed a 24-hour food record. A validated 100-point Dietary Guidelines Index (DGI) assessed diet quality. In 2009-11, 1005 participants (aged 33-41 years) completed the lifetime Composite International Diagnostic Interview for age of first DSM-IV defined mood disorder (depression or dysthymia). Cox proportional hazards regression estimated hazard of mood disorder during the 25-year follow-up according to baseline DGI score. Sensitivity analyses censored the study at 5, 10, and 15 years after baseline and used log binomial regression to estimate relative risk (RR). Covariates included baseline negative affect, BMI, academic performance, smoking, breakfast eating, physical activity, and socioeconomic status. RESULTS: The mean(SD) youth DGI score was 45.0(11.5). A 10-point higher DGI was not associated with hazard of mood disorder onset over the 25-year follow-up (Hazard Ratio (HR):1.00; 95% Confidence Interval (CI):0.89-1.13). The only indication that higher DGI might be associated with lower risk of mood disorder was within the first 5 years after baseline and this was not statistically significant (RR=0.85; 95% CI:0.60-1.18). LIMITATIONS: Loss-to-follow-up. A single 24-hour food record may not represent usual diet. CONCLUSION: Youth diet did not predict mood disorders in adulthood. The suggestions of a lower risk of mood disorder during late adolescence highlights that further prospective studies are needed.

An eating pattern characterised by skipped or delayed breakfast is associated with mood disorders among an Australian adult cohort.

BACKGROUND: Meal timing may influence food choices, neurobiology and psychological states. Our exploratory study examined if time-of-day eating patterns were associated with mood disorders among adults. METHODS: During 2004-2006 (age 26-36 years) and 2009-2011 (follow-up, age 31-41 years), N = 1304 participants reported 24-h food and beverage intake. Time-of-day eating patterns were derived by principal components analysis. At follow-up, the Composite International Diagnostic Interview measured lifetime mood disorder. Log binomial and adjacent categories log-link regression were used to examine bidirectional associations between eating patterns and mood disorder. Covariates included sex, age, marital status, social support, education, work schedule, body mass index and smoking. RESULTS: Three patterns were derived at each time-point: Grazing (intake spread across the day), Traditional (highest intakes reflected breakfast, lunch and dinner), and Late (skipped/delayed breakfast with higher evening intakes). Compared to those in the lowest third of the respective pattern at baseline and follow-up, during the 5-year follow-up, those in the highest third of the Late pattern at both time-points had a higher prevalence of mood disorder [prevalence ratio (PR) = 2.04; 95% confidence interval (CI) 1.20-3.48], and those in the highest third of the Traditional pattern at both time-points had a lower prevalence of first onset mood disorder (PR = 0.31; 95% CI 0.11-0.87). Participants who experienced a mood disorder during follow-up had a 1.07 higher relative risk of being in a higher Late pattern score category at follow-up than those without mood disorder (95% CI 1.00-1.14). CONCLUSIONS: Non-traditional eating patterns, particularly skipped or delayed breakfast, may be associated with mood disorders.

Interventions for sleep difficulties in adults with an intellectual disability: a systematic review.

BACKGROUND: Current literature highlights higher prevalence rates of sleep difficulties amongst adults with an intellectual disability. However, no synthesis has been conducted to assess the effectiveness of existing interventions in this population. Thus, the aim of this review was to assess the effectiveness of sleep interventions in adults with an intellectual disability (ID). METHOD: Eight databases were searched to identify interventions for sleep difficulties amongst adults with an ID. The study quality was assessed with the Risk Of Bias In Non-randomised Studies - of Interventions. Nine studies (n = 97) were eligible for inclusion in the review. RESULTS: There was a notable study on heterogeneity in terms of the population, study design, intervention studied, sleep assessment and outcome assessments used. Eight of the nine studies reported improvement in sleep following intervention. However, these findings need additional support as only 97 participants involving a variety of interventions and measurement systems were used across all studies. Furthermore, eight of the nine studies had serious to critical risk of bias. The only study identified as having low risk of bias was a placebo-controlled randomised controlled trial for the use of melatonin. CONCLUSIONS: This review highlights the need for objective measures such as actigraphy and studies with greater experimental control investigating sleep interventions in adults with ID.

Protection of cerebral microcirculation, mitochondrial function, and electrocortical activity by small-volume resuscitation with terlipressin in a rat model of haemorrhagic shock.

BACKGROUND: During early treatment of haemorrhagic shock, cerebral perfusion pressure can be restored by small-volume resuscitation with vasopressors. Whether this therapy is improved with additional fluid remains unknown. We assessed the value of terlipressin and lactated Ringer's solution (LR) on early recovery of microcirculation, tissue oxygenation, and mitochondrial and electrophysiological function in the rat cerebral cortex. METHODS: Animals treated with LR replacing three times (3LR) the volume bled (n=26), terlipressin (n=27), terlipressin plus 1LR (n=26), 2LR (n=16), or 3LR (n=15) were compared with untreated (n=36) and sham-operated rats (n=17). In vivo confocal microscopy was used to assess cortical capillary perfusion, changes in tissue oxygen concentration, and mitochondrial membrane potential and redox state. Electrophysiological function was assessed by cortical somatosensory evoked potentials, spinal cord dorsum potential, and peripheral electromyography. RESULTS: Compared with sham treatment, haemorrhagic shock reduced the mean (SD) area of perfused vessels [82% (sd 10%) vs 38% (12%); P<0.001] and impaired oxygen concentration, mitochondrial redox state [99% (4%) vs 59% (15%) of baseline; P<0.001], and somatosensory evoked potentials [97% (13%) vs 27% (19%) of baseline]. Administration of terlipressin plus 1LR or 2LR was able to recover these measures, but terlipressin plus 3LR or 3LR alone were not as effective. Spinal cord dorsum potential was preserved in all groups, but no therapy protected electromyographic function. CONCLUSIONS: Resuscitation from haemorrhagic shock using terlipressin with small-volume LR was superior to high-volume LR, with regard to cerebral microcirculation, and mitochondrial and electrophysiological functions.

Investigating the longitudinal association between diabetes and anxiety: a systematic review and meta-analysis.

AIM: Previous research has indicated an association between diabetes and anxiety. However, no synthesis has determined the direction of this association. The aim of this study was to determine the longitudinal relationship between anxiety and diabetes. METHODS: We searched seven databases for studies examining the longitudinal relationship between anxiety and diabetes. Two independent reviewers screened studies from a population aged 16 or older that examined either anxiety as a risk factor for incident diabetes or diabetes as a risk factor for incident anxiety. Studies that met eligibility criteria were put forward for data extraction and meta-analysis. RESULTS: In total 14 studies (n = 1 760 800) that examined anxiety as a risk factor for incident diabetes and two (n = 88 109) that examined diabetes as a risk factor for incident anxiety were eligible for inclusion in the review. Only studies examining anxiety as a risk factor for incident diabetes were put forward for the meta-analysis. The least adjusted (unadjusted or adjusted for age only) estimate indicated a significant association between baseline anxiety with incident diabetes (odds ratio 1.47, 1.23-1.75). Furthermore, most-adjusted analyses indicated a significant association between baseline anxiety and incident diabetes. Included studies that examined diabetes to incident anxiety found no association. CONCLUSIONS: There was an association between baseline anxiety and incident diabetes. The results also indicate the need for more research to examine the direction of association from diabetes to incident anxiety. This work adds to the growing body of evidence that poor mental health increases the risk of developing diabetes.

Robotic colorectal surgery: previous laparoscopic colorectal experience is not essential.

A background in minimally invasive colorectal surgery (MICS) has been thought to be essential prior to robotic-assisted colorectal surgery (RACS). Our aim was to determine whether MICS is essential prior to starting RACS training based on results from our initial experience with RACS. Two surgeons from our centre received robotic training through the European Academy of Robotic Colorectal Surgery (EARCS). One surgeon had no prior formal MICS training. We reviewed the first 30 consecutive robotic colorectal procedures from a prospectively maintained database between November 2014 and January 2016 at our institution. Fourteen patients were male. Median age was 64.5 years (range 36-82) and BMI was 27.5 (range 20-32.5). Twelve procedures (40%) were performed by the non-MICS-trained surgeon: ten high anterior resections (one conversion), one low anterior resection and one abdomino-perineal resection of rectum (APER). The MICS-trained surgeon performed nine high and four low anterior resections, one APER and in addition three right hemicolectomies and one abdominal suture rectopexy. There were no intra-operative complications and two patients required re-operation. Median post-operative stay was five days (range 1-26). There were two 30-day re-admissions. All oncological resections had clear margins and median node harvest was 18 (range 9-39). Our case series demonstrates that a background in MICS is not essential prior to starting RACS training. Not having prior MICS training should not discourage surgeons from considering applying for a robotic training programme. Safe and successful robotic colorectal services can be established after completing a formal structured robotic training programme.

Cost-effectiveness Analysis of Stereotactic Radiosurgery Alone Versus Stereotactic Radiosurgery with Upfront Whole Brain Radiation Therapy for Brain Metastases.

AIMS: Stereotactic radiosurgery (SRS) alone or upfront whole brain radiation therapy (WBRT) plus SRS are the most commonly used treatment options for one to three brain oligometastases. The most recent randomised clinical trial result comparing SRS alone with upfront WBRT plus SRS (NCCTG N0574) has favoured SRS alone for neurocognitive function, whereas treatment options remain controversial in terms of cognitive decline and local control. The aim of this study was to conduct a cost-effectiveness analysis of these two competing treatments. MATERIALS AND METHODS: A Markov model was constructed for patients treated with SRS alone or SRS plus upfront WBRT based on largely randomised clinical trials. Costs were based on 2016 Medicare reimbursement. Strategies were compared using the incremental cost-effectiveness ratio (ICER) and effectiveness was measured in quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were carried out. Strategies were evaluated from the healthcare payer's perspective with a willingness-to-pay threshold of $100 000 per QALY gained. RESULTS: In the base case analysis, the median survival was 9 months for both arms. SRS alone resulted in an ICER of $9917 per QALY gained. In one-way sensitivity analyses, results were most sensitive to variation in cognitive decline rates for both groups and median survival rates, but the SRS alone remained cost-effective for most parameter ranges. CONCLUSIONS: Based on the current available evidence, SRS alone was found to be cost-effective for patients with one to three brain metastases compared with upfront WBRT plus SRS.

Bi-directional associations between healthy lifestyles and mood disorders in young adults: The Childhood Determinants of Adult Health Study.

BACKGROUND: Healthy lifestyles prevent cardiovascular disease and are increasingly recognized in relation to mental health but longitudinal studies are limited. We examined bi-directional associations between mood disorders and healthy lifestyles in a cohort followed for 5 years. METHOD: Participants were aged 26-36 years at baseline (2004-2006) and 31-41 years at follow-up (2009-2011). At follow-up, lifetime mood disorders (depression or dysthymia) were retrospectively diagnosed with the Composite International Diagnostic Interview. A five-item lifestyle score (comprising body mass index, non-smoking, alcohol consumption, leisure time physical activity and healthy diet) was measured at both time points. Linear and log multinomial regression determined if mood disorder before baseline predicted changes in lifestyle (n = 1041). Log binomial regression estimated whether lifestyle at baseline predicted new episodes of mood disorder (n = 1233). Covariates included age, sex, socio-economic position, parental and marital status, social support, major life events, cardiovascular disease history, and self-rated physical and mental health. RESULTS: A history of mood disorder before baseline predicted unfavourable trajectories of lifestyle over follow-up, including somewhat lower risk of improvement [relative risk (RR) 0.76, 95% confidence interval (CI) 0.56-1.03] and greater risk of worsening (RR 1.46, 95% CI 0.99-2.15) of lifestyle independent of confounding factors. Higher lifestyle scores at baseline were associated with a 22% (RR 0.76, 95% CI 0.61-0.95) reduced risk of first episodes of mood disorder, independent of confounding factors. CONCLUSIONS: Healthy lifestyles and mood disorders are closely related. Our results suggest that healthy lifestyles may not only reduce cardiovascular disease but also promote mental health.

Depression and risk of type 2 diabetes: the potential role of metabolic factors.

The aim of the present study was to evaluate the interaction between depressive symptoms and metabolic dysregulations as risk factors for type 2 diabetes. The sample comprised of 2525 adults who participated in a baseline and a follow-up assessment over a 4.5-year period in the Emotional Health and Wellbeing Study (EMHS) in Quebec, Canada. A two-way stratified sampling design was used, on the basis of the presence of depressive symptoms and metabolic dysregulation (obesity, elevated blood sugar, high blood pressure, high levels of triglycerides and decreased high-density lipoprotein). A total of 87 (3.5%) individuals developed diabetes. Participants with both depressive symptoms and metabolic dysregulation had the highest risk of diabetes (adjusted odds ratio=6.61, 95% confidence interval (CI): 4.86-9.01), compared with those without depressive symptoms and metabolic dysregulation (reference group). The risk of diabetes in individuals with depressive symptoms and without metabolic dysregulation did not differ from the reference group (adjusted odds ratio=1.28, 95% CI: 0.81-2.03), whereas the adjusted odds ratio for those with metabolic dysregulation and without depressive symptoms was 4.40 (95% CI: 3.42-5.67). The Synergy Index (SI=1.52; 95% CI: 1.07-2.17) suggested that the combined effect of depressive symptoms and metabolic dysregulation was greater than the sum of individual effects. An interaction between depression and metabolic dysregulation was also suggested by a structural equation model. Our study highlights the interaction between depressive symptoms and metabolic dysregulation as a risk factor for type 2 diabetes. Early identification, monitoring and a comprehensive management approach of both conditions might be an important diabetes prevention strategy.

In Vivo Imaging of Flavoprotein Fluorescence During Hypoxia Reveals the Importance of Direct Arterial Oxygen Supply to Cerebral Cortex Tissue.

Live imaging of mitochondrial function is crucial to understand the important role played by these organelles in a wide range of diseases. The mitochondrial redox potential is a particularly informative measure of mitochondrial function, and can be monitored using the endogenous green fluorescence of oxidized mitochondrial flavoproteins. Here, we have observed flavoprotein fluorescence in the exposed murine cerebral cortex in vivo using confocal imaging; the mitochondrial origin of the signal was confirmed using agents known to manipulate mitochondrial redox potential. The effects of cerebral oxygenation on flavoprotein fluorescence were determined by manipulating the inspired oxygen concentration. We report that flavoprotein fluorescence is sensitive to reductions in cortical oxygenation, such that reductions in inspired oxygen resulted in loss of flavoprotein fluorescence with the exception of a preserved 'halo' of signal in periarterial regions. The findings are consistent with reports that arteries play an important role in supplying oxygen directly to tissue in the cerebral cortex, maintaining mitochondrial function.

Role of CO2 in the cerebral hyperemic response to incremental normoxic and hyperoxic exercise.

Cerebral blood flow (CBF) is temporally related to exercise-induced changes in partial pressure of end-tidal carbon dioxide (PetCO2 ); hyperoxia is known to enhance this relationship. We examined the hypothesis that preventing PetCO2 from rising (isocapnia) during submaximal exercise with and without hyperoxia [end-tidal Po2(PetO2 ) = 300 mmHg] would attenuate the increases in CBF. Additionally, we aimed to identify the magnitude that breathing, per se, influences the CBF response to normoxic and hyperoxic exercise. In 14 participants, CBF (intra- and extracranial) measurements were measured during exercise [20, 40, 60, and 80% of maximum workload (Wmax)] and during rest while ventilation (V̇e) was volitionally increased to mimic volumes achieved during exercise (isocapnic hyperpnea). While V̇ewas uncontrolled during poikilocapnic exercise, during isocapnic exercise and isocapnic hyperpnea, V̇ewas increased to prevent PetCO2 from rising above resting values (∼40 mmHg). Although PetCO2 differed by 2 ± 3 mmHg during normoxic poikilocapnic and isocapnic exercise, except for a greater poikilocapnic compared with isocapnic increase in blood velocity in the posterior cerebral artery at 60% Wmax, the between condition increases in intracranial (∼12-15%) and extracranial (15-20%) blood flow were similar at each workload. The poikilocapnic hyperoxic increases in both intra- and extracranial blood-flow (∼17-29%) were greater compared with poikilocapnic normoxia (∼8-20%) at intensities >40% Wmax(P< 0.01). During both normoxic and hyperoxic conditions, isocapnia normalized both the intracranial and extracranial blood-flow differences. Isocapnic hyperpnea did not alter CBF. Our findings demonstrate a differential effect of PetCO2 on CBF during exercise influenced by the prevailing PetO2.

Does youth adiposity, or change in adiposity from youth to adulthood, predict metabolically healthy obesity in adulthood?

BACKGROUND: Individuals with metabolically healthy obesity (MHO) do not have the metabolic complications usually associated with obesity. OBJECTIVE: To examine whether youth adiposity, or change in adiposity from youth to adulthood, predicts MHO 20 years later. METHODS: A national sample of 2410 Australian participants had height, weight and waist circumference (WC) measured in 1985 (7-15 years old) and 2004-2006 (26-36 years old). A fasting blood sample was taken in 2004-2006. MHO was defined as body mass index (BMI) ≥30 kg m(-2) , normal fasting glucose (<5.6 mmol L(-1) ), triglycerides (<1.695 mmol L(-1) ), high-density lipoprotein-cholesterol (>1.036 mmol L(-1) men, > 1.295 mmol L(-1) women), blood pressure (<130/85 mmHg) and no medication for these conditions. Relative risks (RR) were calculated using log binomial regression and expressed per unit of youth BMI (or WC) z-score or change in BMI (or WC) z-score from youth to adulthood, adjusted for sex and youth age. RESULTS: In total 323 individuals were obese at follow-up, 79 (24.5%) were MHO. Adult MHO was not associated with youth BMI (RR: 1.00, 95%CI: 0.85-1.19) or WC (RR: 0.93, 95%CI: 0.79-1.11). Individuals were less likely to be MHO if they had larger increases in BMI (BMI RR: 0.74, 95%CI: 0.57-0.97) or WC (RR: 0.70, 95%CI: 0.55-0.90) from youth to adulthood. CONCLUSIONS: Change in adiposity from youth to adulthood predicted adult MHO better than youth adiposity alone.

Depressive symptoms and glycated hemoglobin A1c: a reciprocal relationship in a prospective cohort study.

BACKGROUND: The aim of this study was to evaluate the dynamic association between depressive symptoms and glycated hemoglobin A1c (HbA1c) levels using data from the English Longitudinal Study of Ageing (ELSA). METHOD: The sample was comprised of 2886 participants aged ⩾50 years who participated in three clinical assessments over an 8-year period (21% with prediabetes and 7% with diabetes at baseline). Structural equation models were used to address reciprocal associations between depressive symptoms and HbA1c levels and to evaluate the mediating effects of lifestyle-related behaviors and cardiometabolic factors. RESULTS: We found a reciprocal association between depressive symptoms and HbA1c levels: depressive symptoms at one assessment point predicted HbA1c levels at the next assessment point (standardized ß = 0.052) which in turn predicted depressive symptoms at the following assessment point (standardized ß = 0.051). Mediation analysis suggested that both lifestyle-related behaviors and cardiometabolic factors might mediate the association between depressive symptoms and HbA1c levels: depressive symptoms at baseline predicted lifestyle-related behaviors and cardiometabolic factors at the next assessment, which in turn predicted HbA1c levels 4 years later. A similar association was observed for the other direction: HbA1c levels at baseline predicted lifestyle-related behaviors and cardiometabolic factors at the next assessment, which in turn predicted depressive symptoms 4 years later. CONCLUSIONS: Our results suggest a dynamic relationship between depressive symptoms and HbA1c which might be mediated by both lifestyle and cardiometabolic factors. This has important implications for investigating the pathways which could link depressive symptoms and increased risk of diabetes.

Cost-effectiveness of pediatric heart transplantation across a positive crossmatch for high waitlist urgency candidates.

Allosensitized children listed with a requirement for a negative prospective crossmatch have high mortality. Previously, we found that listing with the intent to accept the first suitable organ offer, regardless of the possibility of a positive crossmatch (TAKE strategy), results in a survival advantage from the time of listing compared to awaiting transplantation across a negative crossmatch (WAIT). The cost-effectiveness of these strategies is unknown. We used Markov modeling to compare cost-effectiveness between these waitlist strategies for allosensitized children listed urgently for heart transplantation. We used registry data to estimate costs and waitlist/posttransplant outcomes. We assumed patients remained in hospital after listing, no positive crossmatches for WAIT, and a base-case probability of a positive crossmatch of 47% for TAKE. Accepting the first suitable organ offer cost less ($405 904 vs. $534 035) and gained more quality-adjusted life years (3.71 vs. 2.79). In sensitivity analyses, including substitution of waitlist data from children with unacceptable antigens specified during listing, TAKE remained cost-saving or cost-effective. Our findings suggest acceptance of the first suitable organ offer for urgently listed allosensitized pediatric heart transplant candidates is cost-effective and transplantation should not be denied because of allosensitization status alone.

Comparison of listing strategies for allosensitized heart transplant candidates requiring transplant at high urgency: a decision model analysis.

Allosensitized children who require a negative prospective crossmatch have a high risk of death awaiting heart transplantation. Accepting the first suitable organ offer, regardless of the possibility of a positive crossmatch, would improve waitlist outcomes but it is unclear whether it would result in improved survival at all times after listing, including posttransplant. We created a Markov decision model to compare survival after listing with a requirement for a negative prospective donor cell crossmatch (WAIT) versus acceptance of the first suitable offer (TAKE). Model parameters were derived from registry data on status 1A (highest urgency) pediatric heart transplant listings. We assumed no possibility of a positive crossmatch in the WAIT strategy and a base-case probability of a positive crossmatch in the TAKE strategy of 47%, as estimated from cohort data. Under base-case assumptions, TAKE showed an incremental survival benefit of 1.4 years over WAIT. In multiple sensitivity analyses, including variation of the probability of a positive crossmatch from 10% to 100%, TAKE was consistently favored. While model input data were less well suited to comparing survival when awaiting transplantation across a negative virtual crossmatch, our analysis suggests that taking the first suitable organ offer under these circumstances is also favored.

Cost-effectiveness analysis of treatment strategies for initial Clostridium difficile infection.

Clostridium difficile infection (CDI) is costly. Current guidelines recommend metronidazole as first-line therapy and vancomycin as an alternative. Recurrence is common. Faecal microbiota transplantation (FMT) is an effective therapy for recurrent CDI (RCDI). This study explores the cost-effectiveness of FMT, vancomycin and metronidazole for initial CDI. We constructed a decision-analytic computer simulation using inputs from published literature to compare FMT with a 10-14-day course of oral metronidazole or vancomycin for initial CDI. Parameters included cure rates (baseline value (range)) for metronidazole (80% (65-85%)), vancomycin (90% (88-92%)) and FMT(91% (83-100%)). Direct costs of metronidazole, vancomycin and FMT, adjusted to 2011 dollars, were $57 ($43-72), $1347 ($1195-1499) and $1086 ($815-1358), respectively. Our effectiveness measure was quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were conducted from the third-party payer perspective. Analysis using baseline values showed that FMT($1669, 0.242 QALYs) dominated (i.e. was less costly and more effective) vancomycin ($1890, 0.241 QALYs). FMT was more costly and more effective than metronidazole ($1167, 0.238 QALYs), yielding an incremental cost-effectiveness ratio (ICER) of $124 964/QALY. One-way sensitivity analyses showed that metronidazole dominated both strategies if its probability of cure were >90%; FMT dominated if it cost <$584. In a probabilistic sensitivity analysis at a willingness-to-pay threshold of $100 000/QALY, metronidazole was favoured in 55% of model iterations; FMT was favoured in 38%. Metronidazole, as the first-line treatment for CDIs, is less costly. FMT and vancomycin are more effective. However, FMT is less likely to be economically favourable, and vancomycin is unlikely to be favourable as first-line therapy when compared with FMT.