On the importance of being clear about the level of analysis of interest: An illustration using the case of self-compassion.

OBJECTIVE: Theories about within-person (WP) variation are often tested using between-person (BP) research, despite the well-established fact that results may not generalize across levels of analysis. One possible explanation is vague theories that do not specify which level of analysis is of interest. We illustrate such a case using the construct of self-compassion. The factor structure at the BP level has been highly debated, although the theory is actually concerned with relationships at the WP level. METHOD: Multilevel confirmatory factor analysis was applied to experience-sampling data of self-compassion (N = 213, with n = 4052 measurement occasions). RESULTS: At both levels of analysis, evidence for a two-factor model was found. However, the factors were moderately related at the WP level (r = 0.37, p < 0.001) but largely independent at the BP level (r = 0.04, p = 0.696). Exploratory analyses revealed considerable heterogeneity in the WP relationship among individuals. CONCLUSION: We discuss how our results provide new impulses to move the debate around self-compassion forward. Lastly, we outline how the WP level-which is of major interest for self-compassion and other constructs in psychology-can guide the conceptualization and assessment to promote advancements of the theory and resulting applications.

Comparison of low-dose maximal-intent versus controlled-tempo resistance training on quality-of-life, functional capacity, and strength in untrained healthy adults: a comparative effectiveness study.

Lack of physical activity is a global issue for adults that can lead to sedentary behaviour and a higher prevalence of health complications and chronic diseases, resulting in reduced quality-of-life (QoL) and functional capacity (FC). A potential strategy to mitigate this inactivity is low-dose resistance training (RT); however, physiological, and psychological responses are limited in evidence. Twenty untrained participants aged 30-60 years old (mean ± SD age 42 ± 7 years, mass 77 ± 13 kg, stature 166 ± 8 cm; 18 females and two males) were recruited and randomly assigned to maximal velocity-intent (MI, n = 10) or controlled-tempo (CT, n = 10) RT according to CONsolidated Standards of Reporting Trials (CONSORT) guidelines. Participants attended one training session per week for 6 weeks, consisting of five sets of five repetitions at 60% of one-repetition maximum (1RM) leg press. The interventions differed only during the concentric phase, with MI group pushing with maximal intent, and CT group pushing in a time-controlled manner (3 s). Outcome measures assessed pre- and post-RT included body mass, body mass index (BMI), strength-to-mass ratio, bipedal balance, 6-minute walk test (6MWT), 30-second sit-to-stand (30s-STS), timed up and go (TUG), and leg press 1RM. Time effects were observed for all demographics and FC-related outcomes, such as identical reductions in mass and BMI (- 2%), improvements in strength-to-mass ratio (25%) leg press 1RM (22%), 6MWT (3%), and 30s-STS (14%), as well as a 9% improvement in both TUG-clockwise and anticlockwise. Results show low-dose once-weekly RT is effective in improving QoL, FC, and strength in untrained healthy adults, regardless of modality. Positive responses from participants suggest an increased likelihood of consistent participation for low-dose once-weekly RT over more intense modalities. Retrospective ClinicalTrials.gov ID (TRN): NCT06107855, 24/10/2023.

Hwiccewyrm trispiculum gen. et sp. nov., a new leptopleuronine procolophonid from the Late Triassic of southwest England.

The fissure fill localities of southwest England and South Wales are well-known for preserving rich assemblages of predominantly small-bodied Late Triassic to Early Jurassic tetrapods, but many aspects of these assemblages remain contentious. The age of the Late Triassic fissures is disputed, with some lines of argument suggesting a latest Triassic (Rhaetian) age, whereas other evidence suggests they may be as old as Carnian. The fissures have been hypothesized by some workers to have formed on an archipelago, with island effects invoked to explain aspects of the assemblages such as the abundance of small-bodied species. Procolophonids were a successful group of Triassic parareptiles, best known from Early to early Late Triassic assemblages, but have only recently been described from one of the fissure fill sites (Ruthin) based upon fragmentary remains. Here, we describe new procolophonid specimens from another fissure (Cromhall) that represent at least six individuals of different sizes, with much of the skeleton represented including well-preserved skull material. The Cromhall procolophonid shows strong similarities to Late Triassic procolophonids from Scotland, Brazil and North America, but both autapomorphies and a unique character combination demonstrate that it represents a new species, which we name as Hwiccewyrm trispiculum gen. et sp. nov. Phylogenetic analysis places Hwiccewyrm in a derived clade within Leptopleuroninae, together with Leptopleuron, Hypsognathus, and Soturnia. The largest specimens of Hwiccewyrm demonstrate a body size that is similar to Leptopleuron and Hypsognathus, supporting other recent work that has questioned the insular dwarfism hypothesis for the fissure fill assemblages.

The appendicularian Oikopleura dioica can enhance carbon export in a high CO2 ocean.

Gelatinous zooplankton are increasingly recognized to play a key role in the ocean's biological carbon pump. Appendicularians, a class of pelagic tunicates, are among the most abundant gelatinous plankton in the ocean, but it is an open question how their contribution to carbon export might change in the future. Here, we conducted an experiment with large volume in situ mesocosms (~55-60 m3 and 21 m depth) to investigate how ocean acidification (OA) extreme events affect food web structure and carbon export in a natural plankton community, particularly focusing on the keystone species Oikopleura dioica, a globally abundant appendicularian. We found a profound influence of O. dioica on vertical carbon fluxes, particularly during a short but intense bloom period in the high CO2 treatment, during which carbon export was 42%-64% higher than under ambient conditions. This elevated flux was mostly driven by an almost twofold increase in O. dioica biomass under high CO2 . This rapid population increase was linked to enhanced fecundity (+20%) that likely resulted from physiological benefits of low pH conditions. The resulting competitive advantage of O. dioica resulted in enhanced grazing on phytoplankton and transfer of this consumed biomass into sinking particles. Using a simple carbon flux model for O. dioica, we estimate that high CO2 doubled the carbon flux of discarded mucous houses and fecal pellets, accounting for up to 39% of total carbon export from the ecosystem during the bloom. Considering the wide geographic distribution of O. dioica, our findings suggest that appendicularians may become an increasingly important vector of carbon export with ongoing OA.

Physiological mechanisms associated with the use of a passive heat intervention: positive implications for soccer substitutes.

PURPOSE: Soccer substitutes are exposed to periods of limited activity before entering match-play, likely negating benefits of active warm-ups. This study aimed to determine the effects of using a passive heat intervention following a pre-match, and half-time warm-up, on muscle and core temperature in soccer players during ambient (18 °C) and cold (2 °C) conditions. METHODS: On four occasions, 8 male players, completed a pre-match warm-up, followed by 45 min of rest. Following this, participants completed a half-time re-warm-up followed by an additional 45 min of rest, simulating a full match for an unplaying substitute. During periods of rest, participants wore either standardised tracksuit bottoms (CON), or heated trousers (HEAT), over typical soccer attire. RESULTS: Vastus lateralis temperature declined less in HEAT compared to CON following the 1st half in 2 °C (Δ - 4.39 ± 0.81 vs. - 6.21 ± 1.32 °C, P = 0.002) and 18 °C (Δ - 2.48 ± 0.71 vs. - 3.54 ± 0.88 °C, P = 0.003). These findings were also observed in the 2nd half for the 2 °C (Δ - 4.36 ± 1.03 vs. - 6.26 ± 1.04 °C, P = 0.002) and 18 °C (Δ - 2.85 ± 0.57 vs. - 4.06 ± 1 °C, P = 0.018) conditions. In addition, core temperature declined less in HEAT compared to CON following the 1st (Δ - 0.41 ± 0.25 vs. - 0.84 ± 0.41 °C, P = 0.037) and 2nd (Δ - 0.25 ± 0.33 vs. - 0.64 ± 0.34 °C, P = 0.028) halves of passive rest in 2 °C, with no differences in the 18 °C condition. Perceptual data confirmed that participants were more comfortable in HEAT vs. CON in 2 °C (P < 0.01). CONCLUSIONS: Following active warm-ups, heated trousers attenuate the decline in muscle temperature in ambient and cold environments.

The effect of lower inter-limb asymmetries on athletic performance: A systematic review and meta-analysis.

Inter-limb asymmetry refers to an imbalance in performance between the left and right limbs. Discrepancies throughout asymmetry research does not allow practitioners to confidently understand the effect of inter-limb asymmetries on athletic performance. Therefore, this review summarized the current literature using a meta-analytic approach, conforming to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines to identify the association between inter-limb asymmetry and athletic performance. A literature search using PubMed, Web of Science and SPORTDiscus databases yielded 11-studies assessing the effect of inter-limb asymmetries, measured via unilateral jump performance, on bilateral jump, change of direction (COD) and sprint performance in adult sports players. The quality of evidence was assessed via a modified Downs and Black checklist and in compliance with the Grading of Recommendations Assessment Development and Evaluation. Correlation coefficients were transformed via Fishers z (Zr), meta-analysed and then re-converted to correlation coefficients. Egger's regression presented no significant risk of bias. Vertical jump performance was not significantly affected by asymmetry (Zr = 0.053, r = 0.05; P = 0.874), whereas COD and sprint both presented significant weak associations (COD, Zr = 0.243, r = 0.24; Sprint, Zr = 0.203, r = 0.2; P < 0.01). The results demonstrate that inter-limb asymmetries seem to present a negative impact to COD and sprint performance but not vertical jump performance. Practitioners should consider implementing monitoring strategies to identify, monitor and possibly address inter-limb asymmetries, specifically for performance tests underpinned by unilateral movements such as COD and sprint performance.

Modeling dynamic personality theories in a continuous-time framework: An illustration.

OBJECTIVE: Personality psychology has traditionally focused on stable between-person differences. Yet, recent theoretical developments and empirical insights have led to a new conceptualization of personality as a dynamic system (e.g., Cybernetic Big Five Theory). Such dynamic systems comprise several components that need to be conceptually distinguished and mapped to a statistical model for estimation. METHOD: In the current work, we illustrate how common components from these new dynamic personality theories may be implemented in a continuous time-modeling framework. RESULTS: As an empirical example, we reanalyze experience sampling data with N = 180 persons (with on average T = 40 [SD = 8] measurement occasions) to investigate four different effects between momentary happiness, momentary extraverted behavior, and the perception of a situation as social: (1) between-person effects, (2) contemporaneous effects, (3) autoregressive effects, and (4) cross-lagged effects. CONCLUSION: We highlight that these four effects must not necessarily point in the same direction, which is in line with assumptions from dynamic personality theories.

The SCF-FBXW7 E3 ubiquitin ligase triggers degradation of histone 3 lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage.

During prolonged mitotic arrest induced by antimicrotubule drugs, cell fate decision is determined by two alternative pathways, one leading to cell death and the other inducing premature escape from mitosis by mitotic slippage. FBWX7, a member of the F-box family of proteins and substrate-targeting subunit of the SKP1-CUL1-F-Box E3 ubiquitin ligase complex, promotes mitotic cell death and prevents mitotic slippage, but molecular details underlying these roles for FBWX7 are unclear. In this study, we report that WDR5 (WD-repeat containing protein 5), a component of the mixed lineage leukemia complex of histone 3 lysine 4 methyltransferases, is a substrate of FBXW7. We determined by coimmunoprecipitation experiments and in vitro binding assays that WDR5 interacts with FBXW7 in vivo and in vitro. SKP1-CUL1-F-Box-FBXW7 mediates ubiquitination of WDR5 and targets it for proteasomal degradation. Furthermore, we find that WDR5 depletion counteracts FBXW7 loss of function by reducing mitotic slippage and polyploidization. In conclusion, our data elucidate a new mechanism in mitotic cell fate regulation, which might contribute to prevent chemotherapy resistance in patients after antimicrotubule drug treatment.

Individual differences in contingencies between situation characteristics and personality states.

Contingencies between situational variables and psychological states have been proposed as key individual difference variables by many theoretical approaches to personality. Despite their relevance, the basic properties, nomological correlates, and factor structure of individual differences in contingencies have not been examined so far. We address these fundamental questions in five studies with overall N = 952 participants and N = 32,052 unique assessments. Individual differences in situation characteristic-state contingencies (SCSCs) between DIAMONDS situation characteristics and Big Five personality states were examined in everyday life. SCSCs showed substantial variation across participants, and individual differences in them were moderately reliable (average meta-analytic reliability = .47) and short-term stable (average meta-analytic latent stability = .43). They were weakly and inconsistently related to average personality states, self-reported personality traits, subjective happiness, and sociodemographic variables across studies. However, there were meaningful intercorrelations among SCSCs that could be described by four factors: contingencies involving (1) positive states and situational problems, (2) positive states and situational rewards, (3) thinking/work and requirements of thinking/work, and (4) neurotic states. Overall, our findings support the notion of SCSCs as potentially important individual difference variables, and we sketch future lines of research on contingencies. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Digital twin of a continuous direct compression line for drug product and process design using a hybrid flowsheet modelling approach.

The pharmaceutical industry is continuously overcoming ways to reduce its development times to market and bring new medicines to patients with the highest quality standards faster. This can be achieved with continuous manufacturing and digital design by minimising the amount of active pharmaceutical ingredient (API) needed in drug product design, early project de-risking, and reducing the use of clinical manufacturing equipment, rework, and quality investigations. This paper presents the digital twin of a continuous direct compression line combining first-principles models, residence time distribution (RTD) models obtained from discrete element method (DEM) simulations, science of scale tools and data-driven models from process data in a hybrid flowsheet approach. The flowsheet predicts critical process parameters in the feeders, blender, and tablet press, and critical quality attributes, like tablet composition, weight, thickness, and hardness. It allows the study of the steady state operation in the design space, the impact of operating conditions, material and process parameters, and the dynamic response to disturbances. This is used to de-risk and optimise drug product and process development while reducing the number of experiments. The digital twin also has the potential to guide manufacturing runs and respond to new drug product market approval queries using flowsheet modelling.

Evaluation of liver fibrosis and cirrhosis on the basis of quantitative T1 mapping: Are acute inflammation, age and liver volume confounding factors?

PURPOSE: To evaluate potential confounding factors in the quantitative assessment of liver fibrosis and cirrhosis using T1 relaxation times. METHODS: The study population is based on a radiology-information-system database search for abdominal MRI performed from July 2018 to April 2019 at our institution. After applying exclusion criteria 200 (59 ±â€¯16 yrs) remaining patients were retrospectively included. 93 patients were defined as liver-healthy, 40 patients without known fibrosis or cirrhosis, and 67 subjects had a clinically or biopsy-proven liver fibrosis or cirrhosis. T1 mapping was performed using a slice based look-locker approach. A ROI based analysis of the left and the right liver was performed. Fat fraction, R2*, liver volume, laboratory parameters, sex, and age were evaluated as potential confounding factors. RESULTS: T1 values were significantly lower in healthy subjects without known fibrotic changes (1.5 T MRI: 575 ±â€¯56 ms; 3 T MRI: 857 ±â€¯128 ms) compared to patients with acute liver disease (1.5 T MRI: 657 ±â€¯73 ms, p < 0.0001; 3 T MRI: 952 ±â€¯37 ms, p = 0.028) or known fibrosis or cirrhosis (1.5 T MRI: 644 ±â€¯83 ms, p < 0.0001; 3 T MRI: 995 ±â€¯150 ms, p = 0.018). T1 values correlated moderately with the Child-Pugh stage at 1.5 T (p = 0.01, ρ = 0.35). CONCLUSION: T1 mapping is a capable predictor for detection of liver fibrosis and cirrhosis. Especially age is not a confounding factor and, hence, age-independent thresholds can be defined. Acute liver diseases are confounding factors and should be ruled out before employing T1-relaxometry based thresholds to screen for patients with liver fibrosis or cirrhosis.

Continuous Mixing Technology: Characterization of a Vertical Mixer Using Residence Time Distribution.

Continuous powder mixing technology (CMT) application during continuous direct compression has emerged as a leading technology used in the development and manufacture of solid oral dosage forms. The critical quality attributes of the final product are heavily dependent on the performance of the mixing step as the quality of mixing directly influences the drug product quality attributes. This study investigates the impact of blend material properties (bulk density, API particle size distribution) and process parameters (process throughput, hold up mass and impeller speed) on the mixing performance. Mixing of the blend was characterized using the Residence Time Distribution (RTD) of the process by trending the outlet stream of the mixer using a near-infrared (NIR) probe after the injection of a small mass of tracer at the inlet stream. The outcomes of this study show that the RTDs of the mixer with throughput ranging between 15 and 30 kg/h; impeller speed ranging between 400 and 600 rpm and hold up mass (HUM) ranging between 500 and 850 g can be described by a series of two ideal Continuous Stirred Tank Reactors (CSTRs) with different volumes, and correspondingly, different mean residence times. It is also observed that the mixing is mainly occurring in the lower chamber of the CMT and the normalized RTDs of the mixer are similar across the range of process conditions and material attributes studied. The results also showed that the formulation blend with different API particle sizes and bulk properties, like bulk density and flowability, provide insignificant impact on the mixing performance. The CMT allows independent selection of target set points for HUM, impeller rotational speed and line throughput and it shows great robustness and flexibility for continuous blending in solid oral dose manufacturing.

Who does or does not use the 'Corona-Warn-App' and why?

To slow the spread of SARS-CoV-2, the German government released the 'Corona-Warn-App', a smartphone application that warns users if they have come into contact with other users tested positive for SARS-CoV-2. Since using the 'Corona-Warn-App' is health-relevant behavior, it is essential to understand who is (and who is not) using it and why. In N = 1972 German adults, we found that non-users were on average older, female, healthier, in training and had low general trust in others. The most frequently named reasons by non-users were privacy concerns, doubts about the effectiveness of the app and lack of technical equipment.

Unveiling an exclusive link: Predicting behavior with personality, situation perception, and affect in a preregistered experience sampling study.

Affect and situation perception are intertwined in any given situation, but the extent to which both predict behavior jointly and uniquely has not yet been systematically examined so far. Using 2 studies with experience sampling methodology (ESM), we examine how trait-like variables (Big Six, trait affect, general situation experience) and state-like variables (momentary affect, happiness, and situation perception) account for variance in self-reported behavioral states of the Big Six. In Study 1, we reanalyzed data from Sherman, Rauthmann, Brown, Serfass, and Jones (2015) and found that situation perception explained variance in self-reported behavior in logically coherent ways, but only after considering happiness as an additional predictor. These results were replicated in preregistered Study 2, in which positive and negative affect were additionally assessed as distinct variables. Based on both studies, we conclude that personality traits, affect, and situation perception contribute uniquely to the explanation of self-reported behavior in daily life. Importantly, situation perceptions and affect do overlap, but they are neither the same nor redundant with each other. Indeed, theoretically justified and logically coherent links between situation perceptions and behavioral states remain intact once affect is controlled for, while the links not predicted by theory disappear. These results have implications for personality theories as well as appraisal theories of emotion. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Changes in daily loneliness for German residents during the first four weeks of the COVID-19 pandemic.

RATIONALE: The coronavirus disease 2019 (COVID-19) outbreak has dramatically altered people's social lives due to social restriction measures taken to control the coronavirus spread. Early on, increased loneliness has been publicly discussed as a harmful psychological side effect of these measures. Due to the serious adverse health consequences of loneliness, it is essential to take these concerns seriously and investigate them systematically to allow for evidence-based decision making. Thus far, however, high-resolution empirical evidence of such harmful side effects is rare. METHODS: The present preregistered large-scale daily diary study assessed daily loneliness in 4,844 German adults between March 16 and April 12, 2020. RESULTS AND CONCLUSION: Daily loneliness slightly increased during the first two weeks since implementing the pandemic-related measures and slightly decreased thereafter. With increasing age, daily loneliness increased more strongly over the four weeks. Moreover, daily loneliness increased more strongly for parents compared to people without children. Thus, despite some increases in loneliness in some individuals, there was no linear increase in loneliness in response to the first pandemic-related measures in the present sample.

Molecular and pathogenicity of infectious bronchitis virus (Gammacoronavirus) in Japanese quail (Coturnix japonica).

Infectious bronchitis virus (IBV) infection is highly infectious respiratory disease in poultry industry with significant economic importance. The prevalence of IBV in quail industry in Malaysia was not well documented; therefore, its actual role in the epidemiology of the disease is relatively unknown. This study was to determine the susceptibility of Japanese quail, as one of the species in commercial poultry industry, toward IBV. In addition, it will also give a potential impact on the overall health management in the quail industry even though it had been established that quail are resistant to diseases affecting poultry. Moreover, to the best of our knowledge, it is the first experimental study on IBV inoculation in quail. In this experimental study, 20 quails were divided into 4 groups (n = 5 for group A, B, and C, n = 5 for control group). The quails in group A, B, and C were infected via intraocular and intranasal routes with 0.2 mL of 10 × 5 EID50 of the virus. Clinical signs, gross lesions, positive detection of virus, and trachea histopathological scoring were used to assess the susceptibility of these Japanese quails. The results have indicated mild ruffled feathers and watery feces in these inoculated birds. Trachea, lung, and kidney were subjected to one-step reverse transcription polymerase chain reaction for virus detection. The virus was found from trachea and lung samples, whereas it was absent from all kidney samples. Only 3 quails were found with gross lesions. There was a significant difference of tracheal lesion by 0.009 ± 0.845 (P < 0.05) within the treatment groups. In summary, Japanese quails might be susceptible to IBV.

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease.

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.

FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation.

Cell fate decision upon prolonged mitotic arrest induced by microtubule-targeting agents depends on the activity of the tumor suppressor and F-box protein FBXW7. FBXW7 promotes mitotic cell death and prevents premature escape from mitosis through mitotic slippage. Mitotic slippage is a process that can cause chemoresistance and tumor relapse. Therefore, understanding the mechanisms that regulate the balance between mitotic cell death and mitotic slippage is an important task. Here we report that FBXW7 protein levels markedly decline during extended mitotic arrest. FBXO45 binds to a conserved acidic N-terminal motif of FBXW7 specifically under a prolonged delay in mitosis, leading to ubiquitylation and subsequent proteasomal degradation of FBXW7 by the FBXO45-MYCBP2 E3 ubiquitin ligase. Moreover, we find that FBXO45-MYCBP2 counteracts FBXW7 in that it promotes mitotic slippage and prevents cell death in mitosis. Targeting this interaction represents a promising strategy to prevent chemotherapy resistance.

Molecular autopsy and family screening in a young case of sudden cardiac death reveals an unusually severe case of FHL1 related hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy with a prevalence of about 1:200. It is characterized by left ventricular hypertrophy, diastolic dysfunction and interstitial fibrosis; HCM might lead to sudden cardiac death (SCD) especially in the young. Due to low autopsy frequencies of sudden unexplained deaths (SUD) the true prevalence of SCD and especially of HCM among SUD remains unclear. Even in cases of proven SCD genetic testing is not a routine procedure precluding appropriate risk stratification and counseling of relatives. METHODS: Here we report a case of SCD in a 19-year-old investigated by combined forensic and molecular autopsy. RESULTS: During autopsy of the index-patient HCM was detected. As no other possible cause of death could be uncovered by forensic autopsy the event was classified as SCD. Molecular autopsy identified two (probably) pathogenic genetic variants in FHL1 and MYBPC3. The MYBPC3 variant had an incomplete penetrance. The FHL1 variant was a de novo mutation. We detected reduced FHL1 mRNA levels and no FHL1 protein in muscle samples suggesting nonsense-mediated mRNA decay and/or degradation of the truncated protein in the SCD victim revealing a plausible disease mechanism. CONCLUSION: The identification of the genetic cause of the SCD contributed to the rational counseling of the relatives and risk assessment within the family. Furthermore our study revealed evidences for the pathomechanism of FHL1 mutations.

Association between altitude, prescription opioid misuse, and fatal overdoses.

OBJECTIVE: Prescription opioid misuse and fatal overdoses have increased significantly over the last two decades. Living at altitude has been linked to greater reward benefits of other drugs of abuse, and living at altitude may also exacerbate the respiratory depression linked to opioid use. Therefore, we examined the relationships between living at altitude, and prescription opioid misuse and fatal overdoses. METHOD: State-level past year rates of prescription opioid misuse were retrieved from the Substance Abuse and Mental Health Services Administration. County-level overdose data were extracted from the Centers for Disease Control and Prevention. Multiple linear regression models were fit to determine the relationship between average state elevation and state rates of opioid misuse. Logistic regression models were fit to determine the relationship between county elevation and county-level fatal opioid overdose prevalence. RESULTS: After controlling for state opioid prescribing rates and other confounders, we identified a significant positive association between mean state altitude and state-level opioid misuse rates for women, but not men. We also found a significant positive association between county-level altitude and prevalence of fatal opioid overdose. CONCLUSIONS: Living at altitude is thus demographically associated with increasing rates of misuse of prescription opioids, as well as of cocaine and methamphetamine. Animal studies suggest that the hypobaric hypoxia exposure involved with living at altitude may disrupt brain neurochemistry, to increase reward benefits of drugs of abuse. This increased misuse of both stimulants and opioids may increase likelihood of overdose at altitude, with overdoses by opioid use also potentially facilitated by altitude-related hypoxia.