Cost-effectiveness intervention thresholds for romosozumab and teriparatide in the treatment of osteoporosis in the UK.

Sequential romosozumab-to-alendronate or sequential teriparatide-to-alendronate can be a cost-effective treatment option for postmenopausal women at very high risk of fracture. PURPOSE: To estimate the 10-year probability of a major osteoporotic fracture (MOF) at which sequential treatment with romosozumab or teriparatide followed by alendronate, compared with alendronate alone, becomes cost-effective in a UK setting. METHODS: A microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), in women receiving sequential treatment with either romosozumab or teriparatide followed by alendronate, compared with alendronate alone. Patients aged 50 to 90 years with a recent MOF, hip or spine fracture were followed from the start of a 5-year treatment until the age of 100 years or death. The analysis had a healthcare perspective. Efficacy of romosozumab, teriparatide and alendronate was derived from phase III randomised controlled trials. Resource use and unit costs were derived from the literature. Cost-effectiveness intervention threshold (CEIT), defined as the 10-year probability of a major osteoporotic fracture at which treatment becomes cost-effective, was compared with clinically appropriate intervention thresholds for bone-forming treatment in women with very high fracture risk as recommended by the UK National Osteoporosis Guideline Group (NOGG). RESULTS: The base case analysis showed that sequential romosozumab-to-alendronate treatment was cost-effective from a 10-year MOF probability of 18-35% and above depending on age and site of sentinel fracture at a willingness to pay (WTP) of £30,000. For teriparatide-to-alendronate, treatment was cost-effective at a 10-year MOF probability of 27-57%. The results were sensitive to pricing of the drugs but relatively insensitive to treatment duration, romosozumab persistence assumptions, and site of sentinel fracture. The CEITs for romosozumab-to-alendronate treatment were lower than the clinical thresholds from the age of 70 years meaning that treatment could be considered both cost-effective and aligned with the NOGG treatment guidelines. By contrast, for teriparatide-to-alendronate the CEITs were higher than the clinical thresholds irrespective of age. However, cost-effective scenarios were found in the presence of strong clinical risk factors in addition to a recent sentinel fracture. CONCLUSION: The results of this study indicate that sequential romosozumab-to-alendronate or teriparatide-to-alendronate treatment can be a cost-effective treatment option for postmenopausal women at very high risk of fracture.

Left ventricular systolic function after inhalation of beta-2 agonists in healthy athletes.

Inhaled beta-2 adrenoceptor agonists (iß2A) are routinely used as bronchodilators in the treatment of asthma. However, their cardiac effects in athletes are scarcely examined. Thus, the aim of this study was to evaluate the effects of iß2A on left ventricular (LV) systolic function (SF) by echocardiography in healthy, non-asthmatic female and male endurance athletes. A randomized, double-blinded, placebo-controlled, balanced, 4-way complete block cross-over study was conducted. Twenty-four healthy athletes (12f/12m: 22.9 ± 2.7/24.4 ± 4.6 years) randomly completed 4 study arms (placebo; salbutamol; formoterol; formoterol + salbutamol). After inhalation of the study medication, the participants performed a 10-min time trial (TT) on a bicycle ergometer. After each TT an echocardiography was performed to determine LVSF. Blood samples were collected pre, post, 3 h and 24 h post TT. In females, total serum concentrations for salbutamol and formoterol were higher. LV ejection fraction (LVEF) and LV global longitudinal strain (LVendoGLS) showed a treatment effect for the whole study group (p < 0.0001) and a sex effect on LVEF (p = 0.0085). In women, there was a significant treatment effect for all medication arms (at least p ≤ 0.01) both on LVEF and LVendoGLS. In men only formoterol and formoterol + salbutamol displayed a treatment effect on LVEF (p = 0.0427, p = 0.0330; respectively), whereas on LVendoGLS only formoterol + salbutamol was significant (p = 0.0473). The iß2A significantly influenced LVSF after an acute bout of exercise in healthy endurance athletes. These effects were even more pronounced when combining both iß2A that supports a dose-dependent effect on cardiac function. Moreover, female athletes had higher serum concentrations of ß2 agonists and stronger effects on LVSF compared to male athletes. This is mainly explained by differences in body weight and related plasma volume and may indicate a potential risk when increasing dose above the tested concentrations. Trial registration: At the European Union Drug Regulating Authorities Clinical Trials (Eudra CT) with the number 201,500,559,819 (registered prospectively on 09/12/2015) and at the German register for clinical studies (DRKS number 00010574 registered retrospectively on 16/11/2021).

Improving multiple stressor-response models through the inclusion of nonlinearity and interactions among stressor gradients.

Stressor-response models are used to detect and predict changes within ecosystems in response to anthropogenic and naturally occurring stressors. While nonlinear stressor-response relationships and interactions between stressors are common in nature, predictive models often do not account for them due to perceived difficulties in the interpretation of results. We used Irish river monitoring data from 177 river sites to investigate if multiple stressor-response models can be improved by accounting for nonlinearity, interactions in stressor-response relationships and environmental context dependencies. Out of the six models of distinct biological responses, five models benefited from the inclusion of nonlinearity while all six benefited from the inclusion of interactions. The addition of nonlinearity means that we can better see the exponential increase in Trophic Diatom Index (TDI3) as phosphorus increases, inferring ecological conditions deteriorating at a faster rate with increasing phosphorus. Furthermore, our results show that the relationship between stressor and response has the potential to be dependent on other variables, as seen in the interaction of elevation with both siltation and nutrients in relation to Ephemeroptera, Plecoptera and Trichoptera (EPT) richness. Both relationships weakened at higher elevations, perhaps demonstrating that there is a decreased capacity for resilience to stressors at lower elevations due to greater cumulative effects. Understanding interactions such as this is vital to managing ecosystems. Our findings provide empirical support for the need to further develop and employ more complex modelling techniques in environmental assessment and management.

Neuronal Threshold Functions: Determining Symptom Onset in Neurological Disorders.

Synaptic networks determine brain function. Highly complex interconnected brain synaptic networks provide output even under fluctuating or pathological conditions. Relevant to the treatment of brain disorders, understanding the limitations of such functional networks becomes paramount. Here we use the example of Parkinson's Disease (PD) as a system disorder, with PD symptomatology emerging only when the functional reserves of neurons, and their interconnected networks, are unable to facilitate effective compensatory mechanisms. We have denoted this the "threshold theory" to account for how PD symptoms develop in sequence. In this perspective, threshold functions are delineated in a quantitative, synaptic, and cellular network context. This provides a framework to discuss the development of specific symptoms. PD includes dysfunction and degeneration in many organ systems and both peripheral and central nervous system involvement. The threshold theory accounts for and explains the reasons why parallel gradually emerging pathologies in brain and peripheral systems generate specific symptoms only when functional thresholds are crossed, like tipping points. New and mounting evidence demonstrate that PD and related neurodegenerative diseases are multisystem disorders, which transcends the traditional brain-centric paradigm. We believe that representation of threshold functions will be helpful to develop new medicines and interventions that are specific for both pre- and post-symptomatic periods of neurodegenerative disorders.

Estimating thresholds of nitrogen, phosphorus and potassium fertilizer rates for rice cropping systems in China.

Determining the fertilization rate plays a pivotal role in agronomic practices as they directly impact yield targets, soil fertility, and environmental risks. In this study, we proposed a method that utilizes allowed ranges of partial nutrient balance and yield to estimate the threshold of nitrogen (N), phosphorus (P), and potassium (K) fertilizer applied to rice (Oryza sativa L.) fields in China. Based on a dataset of 6792 observations from rice fields, we determined the minimum and maximum rates of N, P and K suggested for single (mono-season rice), middle (summer-season rice rotated with winter-season upland crop), early and late (double-season rice cropping system) rice, ranging between 114-146 and 220-292 kg N ha-1 per season, 56-74 and 112-149 kg P2O5 ha-1 per season, and 170-230 and 329-347 kg K2O ha-1 per season, respectively. These values serve as the lower and upper fertilization thresholds, guiding yield goals and environmental protection. Furthermore, if rice straw is returned to fields, the demand for K fertilizer can theoretically decrease by 183 kg K2O ha-1, with corresponding decreases of 50 kg N ha-1 and 26 kg P2O5 ha-1, respectively. A recommended fertilization approach, excluding returned straw nutrients from the upper fertilization thresholds, suggested average application rates of 194 kg N ha-1, 105 kg P2O5 ha-1, and 157 kg K2O ha-1, which align well with the nutrient requirements of rice. Additionally, substituting organic N for chemical N is an effective approach to conserve chemical fertilizer N, potentially reducing chemical N usage by 20%-40%. Utilizing slow-release N is also a favorable option to enhance N use efficiency and optimize N balance. This study offers valuable insights into the development of fertilization restriction indicators, aiming to achieve a delicate balance between environmental impact and agricultural productivity through the adoption of balanced fertilization rates and utilization of organic residues.

Femtosecond Laser Ablation and Delamination of Functional Magnetic Multilayers at the Nanoscale.

Laser nanostructuring of thin films with ultrashort laser pulses is widely used for nanofabrication across various fields. A crucial parameter for optimizing and understanding the processes underlying laser processing is the absorbed laser fluence, which is essential for all damage phenomena such as melting, ablation, spallation, and delamination. While threshold fluences have been extensively studied for single compound thin films, advancements in ultrafast acoustics, magneto-acoustics, and acousto-magneto-plasmonics necessitate understanding the laser nanofabrication processes for functional multilayer films. In this work, we investigated the thickness dependence of ablation and delamination thresholds in Ni/Au bilayers by varying the thickness of the Ni layer. The results were compared with experimental data on Ni thin films. Additionally, we performed femtosecond time-resolved pump-probe measurements of transient reflectivity in Ni to determine the heat penetration depth and evaluate the melting threshold. Delamination thresholds for Ni films were found to exceed the surface melting threshold suggesting the thermal mechanism in a liquid phase. Damage thresholds for Ni/Au bilayers were found to be significantly lower than those for Ni and fingerprint the non-thermal mechanism without Ni melting, which we attribute to the much weaker mechanical adhesion at the Au/glass interface. This finding suggests the potential of femtosecond laser delamination for nondestructive, energy-efficient nanostructuring, enabling the creation of high-quality acoustic resonators and other functional nanostructures for applications in nanosciences.

Detrended fluctuation analysis to determine physiologic thresholds, investigation and evidence from incremental cycling test.

PURPOSE: Training zones are generally assessed by gas-exchange thresholds (GET). Several mathematical analyses of heart rate variability (HRV) are proposed for indirect GET determination. Our study aimed to investigate the accordance of the detrend fluctuation analysis (DFA α1) for determining GET with first (VT1) and second ventilatory (VT2) thresholds in well-trained subjects. METHODS: Eighteen female and 38 male sub-elite cyclists performed a maximal incremental cycling test of 2-min stage duration with continuous gas exchange and HR measurements. Power output (PO), Oxygen uptake ( V ˙ O2) and HR at VT1 and VT2 were compared with DFA α1 0.75 (HRVT1) and 0.50 (HRVT2). Agreements between PO, V ˙ O2 and HR values were analyzed using Bland-Altman analysis. RESULTS: Large limits of agreement between VT1 and HRVT1 were observed for measures of V ˙ O2 expressed in mL.min-1.kg-1 [- 21.3; + 14.1], HR [ 39.2; + 26.9] bpm and PO [- 118; + 83] watts. Indeed, agreements were also low between VT2 and HRVT2 for measures of V ˙ O2 [- 26.7; + 4.3] mL.min-1.kg-1, HR [- 45.5; + 10.6] bpm and PO [- 157; + 35] watts. Our results also showed a sex effect: women obtained worst predictions based on DFA α1 than men for HR (p = 0.014), PO (p = 0.044) at VT1 and V ˙ O 2 (p = 0.045), HR (p = 0.003) and PO (p = 0.004) at VT2. CONCLUSION: There was unsatisfactory agreement between the GET and DFA α1 methods for VT1 and VT2 determination in both sex well-trained cyclists. Trial registration number 2233534 on 2024/03/05 retrospectively registered.

Decision threshold models in medical decision making: a scoping literature review.

BACKGROUND: Decision thresholds play important role in medical decision-making. Individual decision-making differences may be attributable to differences in subjective judgments or cognitive processes that are captured through the decision thresholds. This systematic scoping review sought to characterize the literature on non-expected utility decision thresholds in medical decision-making by identifying commonly used theoretical paradigms and contextual and subjective factors that inform decision thresholds. METHODS: A structured search designed around three concepts-individual decision-maker, decision threshold, and medical decision-was conducted in MEDLINE (Ovid) and Scopus databases from inception to July 2023. ProQuest (Dissertations and Theses) database was searched to August 2023. The protocol, developed a priori, was registered on Open Science Framework and PRISMA-ScR guidelines were followed for reporting on this study. Titles and abstracts of 1,618 articles and the full texts for the 228 included articles were reviewed by two independent reviewers. 95 articles were included in the analysis. A single reviewer used a pilot-tested data collection tool to extract study and author characteristics, article type, objectives, theoretical paradigm, contextual or subjective factors, decision-maker, and type of medical decision. RESULTS: Of the 95 included articles, 68 identified a theoretical paradigm in their approach to decision thresholds. The most common paradigms included regret theory, hybrid theory, and dual processing theory. Contextual and subjective factors that influence decision thresholds were identified in 44 articles. CONCLUSIONS: Our scoping review is the first to systematically characterizes the available literature on decision thresholds within medical decision-making. This study offers an important characterization of the literature through the identification of the theoretical paradigms for non-expected utility decision thresholds. Moreover, this study provides insight into the various contextual and subjective factors that have been documented within the literature to influence decision thresholds, as well as these factors juxtapose theoretical paradigms.

Improving the Agreement Between the First Heart-Rate-Variability Threshold and the Gas-Exchange Threshold.

PURPOSE: The first heart-rate (HR) -variability (HRV) -derived threshold based on detrended fluctuation analysis alpha 1 (DFA a1) has shown inconsistent agreement with the gas-exchange threshold (GET). This study examined whether a custom method of computing the first HRV threshold (HRVT1) based on individual HRV characteristics would improve agreement. METHODS: Fourteen participants underwent ramp incremental testing measuring gas-exchange variables and RR intervals. Comparisons were made between the oxygen consumption (V˙O2)/HR at the GET versus the V˙O2/HR at the standard DFA a1 = 0.75 (HRVT1s) or a custom value (HRVT1c) based on the DFA a1 midway between the maximum seen during the early ramp incremental and 0.5. RESULTS: Mean values for GET V˙O2 versus HRVT1s V˙O2 and GETHR versus HRVT1sHR were statistically different (25.4 [3.3] vs 29.8 [6.8] mL·kg-1·min-1, P = .01, d = 0.80; 131 [11] vs 146 [22] beats·min-1, P = .005, d = 0.91). There were no statistical differences when using the HRVT1c (25.4 [3.3] vs 25.1 [5.7] mL·kg-1·min-1, P = .77, d = 0.08; 131 [11] vs 132 [17] beats·min-1, P = .65, d = 0.12). Equivalence between GET and HRVT1c V˙O2/HR was also verified. Mean maximal DFA a1 during the early ramp incremental was 1.52 (0.22) with mean HRVT1c of 1.01 (0.11). Pearson r correlation coefficients were between .67 and .70 for all GET to HRVT1 comparisons. The second HRV threshold and respiratory compensation point parameters showed agreement and correlations in line with prior studies. CONCLUSIONS: The HRVT1c showed stronger agreement to GET parameters than seen using the HRVT1s. It is recommended that evaluations of the HRVT1 consider this approach in determining the HR and V˙O2 at this threshold.

Investigation of Skeletal Muscle Indices Affecting Anaerobic Thresholds after Acute Myocardial Infarction.

OBJECTIVE: To investigate skeletal muscle indices influencing the anaerobic threshold (AT) measured by cardiopulmonary exercise testing (CPX). METHODS: This study included 125 consecutive men (median age: 66.0 years) diagnosed with acute myocardial infarction who underwent CPX before discharge. Participants were categorized into two groups based on their AT: the AT-lowering and AT-maintaining groups, comprising those with AT <11 and ≥11 ml/min/kg, respectively. Skeletal muscle indices that influenced AT, strengths of such influences, and respective cutoff values were investigated using multiple logistic regression analysis, decision-tree analysis, and the random-forest method. Skeletal muscle indices included grip strength, knee extension strength, lower-limb skeletal muscle index, phase angle (PhA), lower-limb PhA, arm circumference (AC), and calf circumference. RESULTS: Lower-limb PhA, AC, age, and body mass index (BMI) influenced AT (model X2 test: p <0.05; Hosmer-Lemeshow test: p = 0.98). Among the skeletal muscle indices, Gini impurity reduction was the highest in the lower-limb PhA. The cutoff values for AT were ≥4.0° for BMI <24 kg/m2 and ≥6.4° for BMI ≥24 kg/m2. CONCLUSION: Lower-limb PhA was the most influential skeletal muscle index affecting AT. PhA measured using body composition analyzers is useful to identify exercise-limiting factors and determine the effectiveness of exercise because it can be easily performed shortly.

Contribution of kelp dashi liquid to sustainable maintenance of taste sensation and promotion of healthy eating in older adults throughout the umami-taste salivary reflex.

Introduction: Taste decline, including taste loss in older adults, leads to malnutrition and frailty. In a super-aging society, improving taste decline and maintaining taste sensation are crucial for the wellbeing of older adults. Hyposalivation frequently affects older individuals and is the leading cause of taste decline in older adults. Treating taste decline, including taste loss, in older adults presents challenges due to the limited sustainable methods for increasing saliva production, except for drug therapy, which may lead to adverse effects. Umami-taste stimulation results in a prolonged increase in both the whole salivary flow rate (WF), more than 90% of which is secreted from the major salivary glands, and the minor salivary gland flow rate (MF) in healthy volunteers through the umami-taste salivary reflex. We hypothesized that umami-rich kelp dashi liquid (KDL), commonly used in Japanese cuisine, may alleviate taste decline and sustain normal taste sensation in older adults with hyposalivation. This study investigated whether KDL stimulation could improve taste decline. Materials and methods: A non-randomized controlled trial was conducted at the dental department of a university hospital, involving those who presented with dry mouth between May 2017 and December 2021. Before and after repeated KDL stimulation, characteristics like changes in WF and MF, the recognition thresholds (RTs) for five basic tastes, and subjective eating and swallowing difficulties were assessed. Statistical comparisons were performed between the values measured before and after KDL stimulation. Result: A total of 35 older patients were included. Patients with reduced MF and with or without reduced WF exhibited umami-taste loss. Repeated stimulation with KDL increased MF and WF and improved taste loss, including umami, decreased RTs, and normalized each taste. Furthermore, subjective taste impairment, subjective eating and swallowing difficulties, and burning sensations in the oral mucosa were alleviated. Conclusion: These findings indicate that KDL stimulation improved umami-taste loss and normalized each taste sensation, further alleviating eating difficulties via the umami-taste salivary reflex. Importantly, umami-taste loss was also observed in patients with normal WF but decreased MF, who are typically not diagnosed with hyposalivation. Therefore, KDL has the potential to sustain taste sensations and promote healthy eating habits in older individuals.

Pain Is Modulated Differently Between Females with and without Patellofemoral Pain: Factors Related to Sensitization.

CONTEXT: Patellofemoral pain (PFP) has poor long-term recovery outcomes. Central sensitization describes central nervous system changes altering pain modulation, which can complicate recovery (poorer prognosis, worse function). Signs of central sensitization include amplified pain facilitation, pain hypersensitivity, and impaired pain inhibition, which can be measured with temporal summation of pain (TSP), pressure pain thresholds (PPTs) and conditioned pain modulation (CPM), respectively. Sex differences exist for these test responses, but female-only PFP investigations of sensitization are uncommon. Understanding pain modulation in females with PFP could improve treatment protocols. OBJECTIVE: To determine whether females with PFP exhibit signs of central sensitization (greater TSP, lower PPTs, reduced CPM) compared to pain-free females. DESIGN: Cross-sectional Setting: Laboratory Patients or Other Participants: Thirty-three females [(20 PFP, 13 pain-free); Age: PFP 29.2 ± 7 years, pain-free 28 ± 7 years; Height: PFP 166.7 ± 5.9cm, pain-free 166 ± 9.5cm, Mass: PFP 66.7 ± 9.6kg, pain-free 69.3 ± 7.5kg). MAIN OUTCOME MEASURES: TSP was assessed with ten punctate stimuli applied to the knee and calculated by the difference in pain intensity between beginning and end responses. PPTs were tested at four sites [3 for local hypersensitivity (knee), 1 for widespread hypersensitivity (hand)]. CPM was conducted by comparing PPTs during two conditions (baseline, ice immersion). CPM response was defined as the percent difference between conditions. Between-group differences in TSP response were analyzed with a Welch's test. Separate Welch's tests analyzed group comparisons of PPTs and CPM responses at four sites. RESULTS: Females with PFP exhibited greater TSP response (P=0.019) and lower CPM response at patella center (P=0.010) and hand sites (P=0.007) than pain-free females. PPT group differences were not observed at any site (P>0.0125). CONCLUSIONS: Females with PFP modulate pain differently than pain-free females. Clinicians should recognize signs of central sensitization and their potential impact on treatment options.

Characterizing cancer-related cognitive impairments and impact on quality of life in women with metastatic breast cancer.

PURPOSE: Little is known about cancer-related cognitive impairments (CRCI) in women with metastatic breast cancer (MBC). The purpose of this study is to (1) comprehensively describe CRCI and any associated psychosocial and behavioral symptoms, (2) determine observable sociodemographic and clinical risk factors for CRCI, and (3) explore cognitive and psychosocial predictors of quality of life and social functioning in women living with MBC. METHODS: Using a cross-sectional design, women with MBC completed assessments (objective and subjective measures of CRCI including 3 open-ended questions, measures of psychosocial and behavioral factors, and assessments of quality of life and social function), and data were analyzed using descriptive statistics, qualitative content analysis, correlation analyses, t tests, analysis of variance, and linear regression models. RESULTS: Data from 52 women were analyzed. 69.2% of the sample reported clinically significant CRCI and 46% of the sample scored < 1 standard deviation below the standardized mean on one or more cognitive tests. Those with triple-negative MBC (compared to HER2+), recurrent MBC (compared to de novo), and no history of chemotherapy had worse subjective CRCI, and those without history of surgery and older age had worse objective CRCI. Subjective CRCI, but not objective CRCI, was significantly associated with quality of life and social functioning. CONCLUSION: Subjective and objective CRCI are likely a common problem for those with MBC. Subjective CRCI is associated with poorer quality of life and lower social functioning. Healthcare providers should acknowledge cognitive symptoms, continually assess cognitive function, and address associated unmet needs across the MBC trajectory.

The ANTI-LAMBDA: A Non-statical Tonal Indicator Low-Frequency Air-Bone Gap of Ménière's Bouts and Disease Activity.

INTRODUCTION:  There have been reports of patients with Ménière´s disease (MD) showing unexplained audiometric air-bone gaps at low frequencies. Little is known about the clinical significance of this finding. The objective of this study was to describe this phenomenon while relating it with clinical features, namely the incidence of attacks. METHODS: Unilateral MD patients were selected and cerebral magnetic resonance imaging (cMRI) was assessed to exclude structural pathology. A retrospective longitudinal analysis regarding disease activity and audiometric details was performed. A coincidence index and regression predictive models were considered to assess the relationship between the air-bone gap and MD activity. RESULTS:  A total of 70 MD patients were enrolled and 252 audiograms were assessed. Low-frequency air-bone gaps (LFABGs) were significantly associated with unstable MD (p < 0.001), demonstrating a sensitivity and specificity of 93.8% and 82.7%, respectively. The incidence of unstable disease with the presence of LFABG was 89.1 %. A higher LFABG magnitude correlated with increased disease activity (p < 0.001) and was particularly pronounced at 250 Hz and 500 Hz. CONCLUSION: The typical LFABG encountered was here called ANTI-LAMBDA (A Non-statical Tonal Indicator Low-Frequency Air-Bone Gap of Ménière's Bouts and Disease Activity). It relates to MD activity and is a potential new tool to assess MD stability/need for additional therapeutics.

Performance of cut-offs of the ASAS Health Index to discriminate between treatment groups in patients with axial spondyloarthritis in the TICOSPA trial.

OBJECTIVE: To test trial and longitudinal known group discrimination of thresholds of meaning for improvement and health states of the ASAS Health Index (ASAS HI) in patients with active axSpA treated in a randomized study. METHODS: Data from baseline and week 48 from the tight-controlled, treat-to-target trial TICOSPA study were used. The performance of different thresholds to assess change or health states of the ASAS HI were evaluated between arms and against changes in patients' relevant outcomes and various external responder criteria. Analyses were performed by comparing the mean values t-tests or proportion of responders of continuous and dichotomous external criteria respectively. Trial discrimination of the ASAS HI thresholds were assessed by odds ratios and Phi coefficient in a large number of potential ASAS HI thresholds. Differences in health states in relevant external outcomes between ASAS HI responders and non-responders was assessed by comparing the best performing improvement and state thresholds by using t-tests and chi-square, as appropriate. Missing data on outcomes was handled by non-responder imputation (NRI). RESULTS: All 160 patients had available ASAS HI data. Trial discrimination was larger for absolute ASAS HI change of ≥2.0, ≥2.5, and ≥3.0 points followed by ASAS HI 20 % improvement. Odds ratio ranged between 1.27 and 1.75 for absolute and between 1.0 and 1.64 for relative improvement outcomes. Longitudinal discrimination of ASAS HI improvement ≥30 % or ≥ 3.0 points had a larger reduction in patient global and disease activity and reached more often remission compared to patients with no significant improvement in global functioning. Patients who achieved ASAS HI ≤ 5.0 compared with patients who did not achieve such states were more likely to have ASAS partial remission, ASDAS inactive disease or ASDAS low activity at week 48. CONCLUSIONS: The data-driven thresholds of the ASAS HI identified in a longitudinal observational setting perform well in the context of a randomized trial.

A lifecycle model approach for predicting mangrove extent.

Tidal dynamics are a well-known driver of mangrove distribution, with most predictive measures using some form of tidal parameter (tidal plane or hydroperiod) to define mangrove extent. However, these methods often fail to consider the causative reason why mangroves thrive or perish at a specific elevation or how mangrove survivability thresholds can differ across a species' lifecycle. The lack of understanding of the drivers influencing mangrove establishment has resulted in poor success rates for mangrove restoration and creation projects worldwide. A novel mangrove lifecycle model that uses a multi-forcing threshold approach is proposed to simulate Avicennia marina viability across establishment and development phases. The lifecycle model includes critical threshold stages for reproduction, seed dispersal, seedling establishment and development, and mature tree survival. The model was validated at 37 sites in eastern Australia to predict mangrove extent across various estuary types and tidal dynamic conditions. The model accurately calculated the upper (RMSE = 0.0676, R2 = 0.8932) and lower (RMSE = 0.0899, R2 = 0.7417) mangrove surface elevations, providing physiological reasoning for establishment and development. Based on the various conditions tested, the model results highlight the highly dynamic spatial and temporal conditions where Avicennia forests thrive. It was found that stressors influencing mangrove establishment were the primary factor for mangrove extent across all sites. However, estuarine typology is important in forcing threshold limits and establishment opportunities. Estuaries with limited tidal decay (from the oceanic forcing) provide more opportunities for mangroves to establish than estuaries with significant tidal attenuation. Regardless of estuary typology, all sites tested had substantial spatial variability through time. Results from the lifecycle model suggest that mature Avicennia forests establish and thrive under a wide range of hydrologic conditions. This resilience suggests that mature mangroves may be able to withstand increases in climatic and hydrologic pressures via biophysical adaptations, although the upper thresholds and acceptable rates of change are difficult to predict. Overall, this study highlights the value of a new causal method for estimating mangrove extent across various lifecycle stages, locations, and time periods.

Saturation of intracellular phosphorus uptake and prevalence of extracellular phosphorus entrapment in fluvial biofilms after long-term P pulses: Implications for river self-purification.

Microbial consortia in riverbed substrates and their extracellular matrix (biofilms) play a key role in phosphorus (P) entrapment. When P entrapment saturates, the benthic compartment changes from a P sink to a P source thus increasing eutrophication risk. P entrapment saturation is expected to differ between intracellular and extracellular P entrapment and between different magnitudes and durations of P inputs. We studied biofilm P-entrapment following short (48 h) and long (14 days) P loading events in stream bypass flumes supplied with a gradient of dissolved P concentrations. This allowed us to link local biofilm processes in sediments to potential effects on river self-purification, via quantifying the P removal efficiency in the flumes. We found that in short-term events, biofilms develop intracellular mechanisms to cope with P inputs, while long-term events and high P inputs suppress the intracellular uptake mechanisms and increase the prevalence of extracellular entrapment. Specifically, long-term events lowered the threshold for intracellular P entrapment saturation, and decreased the ratio between intracellular and extracellular entrapment resulting in lower removal efficiency for dissolved phosphorus. Our results highlight the risk that aquatic ecosystems may face as the ratio of intracellular to extracellular P entrapment decreases, which may reduce their ability to deal with P inputs, thereby increasing risks of eutrophication.

An Objective Injury Threshold for the Maximum Principal Strain Criterion for Brain Tissue in the Finite Element Head Model and Its Application.

Although the finite element head model (FEHM) has been widely utilized to analyze injury locations and patterns in traumatic brain injury, significant controversy persists regarding the selection of a mechanical injury variable and its corresponding threshold. This paper aims to determine an objective injury threshold for maximum principal strain (MPS) through a novel data-driven method, and to validate and apply it. We extract the peak responses from all elements across 100 head impact simulations to form a dataset, and then determine the objective injury threshold by analyzing the relationship between the combined injury degree and the threshold according to the stationary value principle. Using an occipital impact case from a clinical report as an example, we evaluate the accuracy of the injury prediction based on the new threshold. The results show that the injury area predicted by finite element analysis closely matches the main injury area observed in CT images, without the issue of over- or underestimating the injury due to an unreasonable threshold. Furthermore, by applying this threshold to the finite element analysis of designed occipital impacts, we observe, for the first time, supra-tentorium cerebelli injury, which is related to visual memory impairment. This discovery may indicate the biomechanical mechanism of visual memory impairment after occipital impacts reported in clinical cases.

Signal Detection Theoretic Estimates of the Murine Absolute Visual Threshold Are Independent of Decision Bias.

Decision bias influences estimates of the absolute visual threshold. However, most psychophysical estimates of the murine absolute visual threshold have not taken bias into account. Here we developed a one-alternative forced choice (1AFC) assay to assess the decision bias of mice at the absolute visual threshold via the theory of signal detection and compared our approach with the more conventional high-threshold theoretic approach. In the 1AFC assay, mice of both sexes were trained to signal whether they detected a flash stimulus. We directly measured both hit and false alarm rates, which were used to estimate d' Using the theory of signal detection, we obtained absolute thresholds by interpolating the intensity where d' = 1 from d'-psychometric functions. This gave bias-independent estimates of the absolute visual threshold which ranged over sixfold, averaging ∼1 R* in 1,000 rods (n = 7 mice). To obtain high-threshold theoretic estimates of the absolute visual threshold from the same mice, we estimated threshold intensities from the frequency of seeing curves, corrected for guessing. This gave us thresholds that were strongly correlated with decision bias, ranging over 13-fold and averaged ∼1 R* in 2,500 rods. We conclude that the theory of signal detection uses false alarms to overcome decision bias and narrow the range of threshold estimates in mice, providing a powerful tool for understanding detection behavior near absolute visual threshold.