Eating disorder behaviours amongst adolescents: investigating classification, persistence and prospective associations with adverse outcomes using latent class models.

Diagnostic criteria for eating disorders (ED) remain largely based on clinical presentations, but do not capture the full range of behaviours in the population. We aimed to derive an empirically based ED behaviour classification using behavioural and body mass index (BMI) indicators at three time-points in adolescence, and to validate classes investigating prospective associations with adverse outcomes. Adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) provided data on ED at age 14 (n = 6615), 16 (n = 5888), and 18 years (n = 5100), and had weight and height measured. Psychological and behavioural outcomes were assessed at 15.5/16 and 17.5/18 years. We fit gender- and age-stratified latent class models, and employed logistic regression to investigate associations between classes and later outcomes. One asymptomatic and two symptomatic (largely representing higher and lower frequency ED behaviours) classes were observed at each time-point, although their relative prevalence varied by age and gender. The majority of girls in symptomatic classes remained symptomatic at subsequent assessments. Girls in symptomatic classes had higher odds of subsequent anxiety and depressive disorders, binge drinking, drug use, and deliberate self-harm. Data analyses were underpowered amongst boys. The presence of two symptomatic classes (characterised by different ED behaviour frequency) and their prospective association with adverse outcomes suggest a need to refine diagnostic thresholds based on empirical data. Despite some instability of classes, particularly in mid-adolescence, evidence that half of girls in symptomatic classes remained symptomatic suggests persistence of ED behaviours in adolescence, and highlights a need for early identification to reduce chronicity.

Are We Missing Something Pertinent? A Bias Analysis of Unmeasured Confounding in the Firearm-Suicide Literature.

Despite the magnitude and consistency of risk estimates in the peer-reviewed literature linking firearm availability and suicide, inferring causality has been questioned on the theoretical basis that existing studies may have failed to account for the possibility that members of households with firearms differ from members of households without firearms in important ways related to suicide risk. The current bias analysis directly addresses this concern by describing the salient characteristics that such an unmeasured confounder would need to possess in order to yield the associations between firearm availability and suicide observed in the literature when, in fact, the causal effect is null. Four US studies, published between 1992 and 2003, met our eligibility criteria. We find that any such unmeasured confounder would need to possess an untenable combination of characteristics, such as being not only 1) as potent a suicide risk factor as the psychiatric disorders most tightly linked to suicide (e.g., major depressive and substance use disorders) but also 2) an order of magnitude more imbalanced across households with versus without firearms than is any known risk factor. No such confounder has been found or even suggested. The current study strongly suggests that unmeasured confounding alone is unlikely to explain the association between firearms and suicide.

Protein concentration and mitochondrial content in the gastrocnemius predicts mortality rates in patients with peripheral arterial disease.

OBJECTIVE: This study evaluated the hypothesis that protein concentration and mitochondrial content in gastrocnemius biopsies from patients with peripheral arterial disease (PAD) predict mortality rates. BACKGROUND: PAD patients experience advancing myopathy characterized by mitochondrial dysfunction, myofiber degradation, and fibrosis in their ischemic legs, along with increased mortality rates. METHODS: Samples from the gastrocnemius of PAD patients were used for all analyses. Protein concentration was normalized to muscle wet weight, and citrate synthase activity (standard measure of mitochondrial content in cells) was normalized to muscle wet weight and protein concentration. Protein and citrate synthase data were grouped into tertiles and 5-year, all-cause mortality for each tertile was determined with Kaplan-Meier curves and compared by the modified Peto-Peto test. A Cox-regression model for each variable controlled for the effects of clinical characteristics. RESULTS: Of the 187 study participants, 46 died during a mean follow-up of 23.0 months. Five-year mortality rate was highest for patients in the lowest tertile of protein concentration. Mortality was lowest for patients in the middle tertile of citrate synthase activity when normalized to either muscle wet weight or protein concentration. The mortality hazard ratios (HRs) from the Cox analysis were statistically significant for protein concentration normalized to muscle wet weight (lowest vs middle tertile; HR = 2.93; P = 0.008) and citrate synthase normalized to protein concentration (lowest vs middle tertile; HR = 4.68; P = 0.003; and lowest vs highest tertile; HR = 2.36; P = 0.027). CONCLUSIONS: Survival analysis of a contemporaneous population of PAD patients identifies protein and mitochondrial content of their gastrocnemius as predictors of mortality rate.

DEcrease STress through RESilience training for Students (DESTRESS) Study: Protocol for a randomized controlled trial nested in a longitudinal observational cohort study.

INTRODUCTION: Chronic stress and burnout are highly prevalent among academically trained healthcare professionals, negatively affecting their well-being and capacity to engage in their work. Resilience to stress develops early in one's career path, hence offering resilience training to university students in these professions is one approach to fostering well-being and mental health. The aim of this study is to assess whether offering mindfulness-based resilience training to university students in healthcare professions reduces their perceived chronic stress. METHODS AND ANALYSIS: The study has a hybrid design combining a longitudinal observational cohort with a nested randomized controlled trial (RCT) with sequential multiple assignment and multistage adaptive interventions while taking participants' preferences into account. All students in healthcare related programmes at the Erasmus University Rotterdam are invited to participate. Within the observational cohort, students with a score of 14 or higher on the Perceived Stress Scale (PSS) are invited to take part in the RCT (n = 706). Eligible participants are randomized to control or active intervention in a ratio of 1:6. Those randomized to the control group and non-randomized participants in the cohort receive passive web-based psychoeducation about chronic stress and burnout through referral to specific websites. Participants randomized to the intervention group receive one of 8 active mindfulness-based interventions. They select a rank order of 4 preferred interventions and are randomized across these with equal probability. Non-response to the intervention is followed by sequential randomized assignment to another intervention, for a total maximum of 3 sequential interventions. All participants receive questionnaires at baseline, before and after each 8-week intervention period, and at 1- and 2-year follow-up. The primary outcome is perceived chronic stress measured with the PSS. Secondary outcomes include mental well-being, burnout, quality of life, healthcare utilization, drug use, bodyweight, mental and physical stress-related symptoms, resilience, and study progress. ETHICS AND REGISTRATION: Approval from the Medical Ethics Review Committee was obtained under protocol number MEC-2018-1645. The trial is registered in the Netherlands National Trial Register by registration number NL7623, 22/03/2019, https://www.trialregister.nl/.

How should DSM-V classify eating disorder not otherwise specified (EDNOS) presentations in women with lifetime anorexia or bulimia nervosa?

OBJECTIVE: Anorexia nervosa (AN) and bulimia nervosa (BN) are marked by longitudinal symptom fluctuations. DSM-IV-TR does not address how to classify eating disorder (ED) presentations in individuals who no longer meet full criteria for these disorders. To consider this issue, we examined subthreshold presentations in women with initial diagnoses of AN and BN. METHOD: A total of 246 women with AN or BN were followed for a median of 9 years; weekly symptom data were collected at frequent intervals using the Longitudinal Interval Follow-up Evaluation of Eating Disorders (LIFE-EAT-II). Outcomes were ED presentations that were subthreshold for 3 months, including those narrowly missing full criteria for AN or BN, along with binge eating disorder (BED) and purging disorder. RESULTS: During follow-up, most women (77.6%) experienced a subthreshold presentation. Subthreshold presentation was related to intake diagnosis (Wald chi2=8.065, df=2, p=0.018). Individuals with AN most often developed subthreshold presentations resembling AN; those with BN were more likely to develop subthreshold BN. Purging disorder was experienced by half of those with BN and one-quarter of those with AN binge/purge type (ANBP); BED occurred in 20% with BN. Transition from AN or BN to most subthreshold types was associated with improved psychosocial functioning (p<0.001). CONCLUSIONS: Subthreshold presentations in women with lifetime AN and BN were common, resembled the initial diagnosis, and were associated with modest improvements in psychosocial functioning. For most with lifetime AN and BN, subthreshold presentations seem to represent part of the course of illness and to fit within the original AN or BN diagnosis.

Analysis of lymphoepithelioma and lymphoepithelioma-like carcinomas for Epstein-Barr viral genomes by in situ hybridization.

Lymphoepithelioma of the nasopharynx has a strong association with Epstein-Barr virus (EBV). To test the hypothesis that lymphoepithelioma-like carcinomas occurring at other sites are also associated with EBV virus, we used in situ hybridization to analyze 20 cases of lymphoepithelioma and histologically similar lesions and five basaloid squamous cell carcinomas for evidence of EBV genomes. EBV genomes were demonstrated in six of six lymphoepitheliomas of the nasopharynx but in none of five basaloid squamous cell carcinoma. Only one of 14 lymphoepithelioma-like carcinomas was found to contain EBV genomes. The single positive lymphoepithelioma-like carcinoma occurred in the lung of an Asian patient, suggesting that ethnic or geographic influences may be important in determining whether EBV is associated with these nonnasopharyngeal neoplasms. Despite their histologic similarity, most lymphoepithelioma-like carcinomas probably have a different pathogenesis from nasopharyngeal lymphoepithelioma.

Pyrethroid insecticides as phosphatase inhibitors.

In this study we tested the hypothesis that pyrethroid insecticides inhibit calcineurin directly and that inhibition is unaffected by the immunophilin cofactors necessary for calcineurin inhibition by cyclosporin A and FK506. The type II pyrethroid insecticides cis-cypermethrin (c-Cyp), trans-cypermethrin, deltamethrin (Delt), and fenvalerate A alpha (Fen), as well as the type I pyrethroid insecticides cis- and trans-permethrin and S-bioallethrin, were unable to inhibit the phosphatase activity of purified calcineurin under conditions of maximal activation by Ca2+ and calmodulin. Furthermore, c-Cyp, Delt, and Fen did not affect the Ca2+ dependence of calcineurin at 0.1 microM of calmodulin, indicating that Ca2+ binding to calmodulin was not affected by these agents. c-Cyp, Delt, and Fen also failed to inhibit calcineurin phosphatase activity in rat brain supernatant and cultured IMR-32 cells, although potent inhibition was displayed by both cyclosporin A and FK506 in each of these systems. Neither the Ca2+-dependent nor the okadaic acid-inhibitable phosphatase activity toward a 24-amino acid 32P-phospho-peptide substrate was affected by any of the pyrethroid insecticides, indicating that neither type-1 or type-2A phosphatase nor calcineurin is inhibited by pyrethroids. To determine if these results were dependent upon experimental conditions, experiments were repeated using polyethylene glycol-treated glass tubes in place of the standard polypropylene tubes. Regardless of the type of tube, no inhibition of calcineurin by any of the pyrethroid insecticides was observed. These data indicate that the pyrethroid insecticides are not effective inhibitors of calcineurin or other phosphatases.

Effect of 5-azacytidine on metallothionein inducibility and sensitivity to lethality of cadmium in rat osteosarcoma (ROS 17/2.8) cells.

ROS 17/2.8 cells, a cloned rat osteoblastic osteosarcoma cell line, were found to be extremely sensitive to the lethal effects of cadmium and to synthesize little, if any, metallothionein in response to cadmium exposure. Culture of cells for 24 h in the presence of 1 microM 5-azacytidine, a cytidine analog, increased the inducibility of metallothionein by cadmium and significantly reduced (P less than 0.001) cytotoxicity. Anion exchange chromatographic analysis of cadmium binding to low molecular mass cytotoxicity. Anion exchange chromatographic analysis of cadmium binding to low molecular mass cytosolic proteins showed that cells treated with cadmium and 5-azacytidine expressed at least 2 isoforms of metallothionein. One isoform of metallothionein with a low affinity for cadmium was constitutively expressed by these cells. The association of poor inducibility of metallothionein by cadmium with extreme sensitivity of cells to cadmium emphasizes the role of this protein in the cellular response to this toxic metal. The modulation of metallothionein inducibility and sensitivity to cadmium by 5-azacytidine treatment suggest that metallothionein gene structure and regulation are altered in ROS 17/2.8 cells.

Effect of sodium butyrate on metallothionein induction and cadmium cytotoxicity in ROS 17/2.8 cells.

ROS 17/2.8 cells, a cloned rat osteosarcoma cell line, are exceptionally sensitive to the cytotoxic effects of cadmium. This sensitivity is associated with the inability of this metal to induce the synthesis of metallothionein, a transition metal-binding protein, which detoxifies this metal by its sequestration. Sodium butyrate induces the synthesis of metallothionein in these cells in a concentration-dependent manner. Treatment with this agent also significantly increases the resistance of these cells to the cytotoxic effects of cadmium and the protective effect of butyrate is reversed upon its removal from culture medium. Butyrate treatment did not significantly alter the accumulation of cadmium by these cells. Hence, the increased synthesis of metallothionein in butyrate-treated cells is not due to increased cellular uptake of cadmium. Inhibition of DNA synthesis due to butyrate was not a sufficient condition to alter metallothionein synthesis or to protect against Cd-induced cytotoxicity. Equivalent inhibition of DNA synthesis with hydroxyurea failed to increase metallothionein synthesis in cadmium-treated cells. These results indicate that modulation of metallothionein gene expression in this cell line is the critical factor in determining cellular sensitivity to the cytotoxic effects of cadmium.

Cyclosporin A has low potency as a calcineurin inhibitor in cells expressing high levels of P-glycoprotein.

Cyclosporin A (CsA) is a widely-used immunosuppressant drug whose therapeutic and toxic actions are mediated through inhibition of calcineurin (CN), a calcium- and calmodulin-dependent phosphatase. Inhibition of CN by CsA requires drug binding to its protein cofactor in the inhibition, cyclophilin. Because cyclophilin is a high affinity target for CsA it is expected that this protein can act as a reservoir for the drug in the cell and may be able to inhibit cellular efflux of CsA. P-glycoprotein (P-gp) is known to increase the rate of CsA efflux from CsA loaded cells but it is not clear if the P-gp drug efflux pump can compete effectively with cyclophilin at therapeutically relevant concentrations of CsA. To test the hypothesis that increased expression of P-gp confers protection against CsA-dependent inhibition of CN phosphatase activity, KB-V cells expressing varying levels of P-gp were analyzed to determine the potency of CsA as a CN inhibitor. When intact cells were treated with CsA, a positive correlation was observed between P-gp expression and resistance to CsA-dependent inhibition of CN: the IC50 is approximately 20-fold higher in the multidrug resistant epidermal carcinoma cell line, KB-V, which expresses P-gp at a high level than in the parental, KB, cell line expressing very low levels of P-gp. The resistance displayed by KB-V cells is abrogated by co-administration of the P-gp inhibitor verapamil, whereas verapamil has no effect on CsA potency in control KB cells. In cell lysates from KB-V cells with different amounts of P-gp CsA exhibits equivalent potency, indicating that the difference in sensitivity to CsA among the cell types requires maintenance of cell integrity. These observations support the view that resistance to CN inhibition by CsA occurs in cells with moderately elevated P-gp activity. Therefore, P-gp activity appears to be an important determinant of CsA cellular specificity for both therapeutic and toxic effects.

Measurement of the microhardness and Young's modulus of human enamel and dentine using an indentation technique.

Conventional quasi-static and dynamic test methods have a number of limitations when used to measure the mechanical properties of enamel and dentine. These are due to the complex structure of the material and the small specimen size. In this investigation, a microindentation technique was used to measure the hardness and Young's modulus of human enamel and dentine and any variations with location. Freshly extracted molar teeth were sectioned, and the cut surfaces were ground and polished progressively to 1 micron. The polished surfaces were indented at different distances from the surface and amelodentinal junction with a Knoop indentor. Measurements of the length of the long indentation diagonal were used to calculate a value for hardness. It has been shown that the a-value for Young's modulus of a material can be calculated by comparing the ratio of the long and short diagonals on an indented specimen with the actual ratio of the indentor as any changes will be due to elastic recovery in the specimen. Values obtained for the Knoop hardness of enamel and dentine were in good agreement with those of other workers. It was also possible to show that there was a decrease in hardness with depth from the surface in enamel. The hardness of dentine increased with distance from the amelodentinal junction. Values for Young's modulus for dentine were in good agreement with those of other workers, and there was an increase in modulus with depth from the amelodentinal junction from 8.7 to 11.2 GNm-2. Values for Young's modulus of enamel were not as easy to calculate because of surface- and subsurface damage.

Polyethylene wear from retrieved acetabular cups.

Laboratory wear testing of ultra high molecular weight polyethylene from 12 Charnley acetabular cups, removed after periods of up to 17.5 years showed that the large patient-to-patient variations in clinical penetration rate cannot be explained by batch-to-batch variation in the wear resistance of the material. Nor was there any evidence of a time-dependent degradation in wear resistance of the material.

Contact pressures in the loaded human cadaver hip.

The purpose of the work described was to find the average pressure on each of several areas of the acetabular cartilage of the cadaver hip under physiological loads. By obtaining load-deflection curves for one chosen area of cartilage, firstly with all the cartilage present and then after the successive removal of other areas, the fractions of the original load carried by the several areas were found, and hence the average pressures on those areas. Seventeen hips (age range twenty-two to eighty-seven years) were examined. Local pressures varied from zero to 3.4 times the average pressure in each hip. The highest pressures in the series (about 4 to 5 megaNewtons per square metre) were on the areas of thin fibrocartilage which were identified at the zenith of certain acetabula. The results are too few to establish whether or not the pressure distribution was age-related. The higher pressures found are within the range which in other experiments has led to fatigue failure of femoral head cartilage, and it is suggested that hips in which such pressures exist under loads of three times body weight may be predisposed to osteoarthritis.

Mechanical tests on the tibial components of non-hinged knee prostheses.

Cadaveric knees replaced with the Geomedic, ICLH, Marmor and Total Condylar prostheses were tested in axial compression, in rotation and in hyperextension in order to observe the strength of fixation of the tibial components. In axial compression the strengths at failure varied widely, both with any one prosthesis and between prostheses. This is attributed largely to the strength of the cancellous bone of the tibia, which was measured in each case and also varied widely. Three natural knees failed at loads of 7300, 7600 and 8300 newtons respectively, whereas the strengths of replaced knees ranged from 3000 to 15750 newtons. At least one example of each design failed at less than 7300 newtons, suggesting little or no reserve of strength. The strength of fixation was greater when the tibial prosthesis was large enough to rest on the whole cross-section of the tibia. In rotation the three prostheses embodying rollers in troughs were stiffer than the Marmor which had a nearly flat tibial-bearing surface. The presence or absence of the cruciate ligaments had a negligible effect on torsional stiffness. In hyperextension, knees replaced with the ICLH, Marmor and Total Condylar prostheses failed by rupture of the posterior capsule at moments of about 60 newton-metres, compared with about 100 for natural knees. With the Marmor prosthesis the anterior cruciate ligament was avulsed at about 20 newton-metres compared with about 75 in natural knees, suggesting that in this respect the retention of the cruciate ligaments contributes little. None of the four knees tested after inserting a Geomedic prosthesis showed strengths as high as those replaced with the other three designs.

Traumatic false aneurysm of descending aorta with aortoesophageal fistula.

We report a case of traumatically induced false aneurysm with secondary bacterial aortitis of the descending aorta and fistula formation between the aorta and esophagus. This lesion was diagnosed at autopsy and caused death in a 68-year-old female 19 years after an automobile accident. Aortoesophageal fistula (AEF) formation as a result of any cause is rare. To our knowledge, this is the second reported case of traumatic aortic aneurysm as a result of an automobile accident with subsequent AEF formation.

Antidepressant class, age, and the risk of deliberate self-harm: a propensity score matched cohort study of SSRI and SNRI users in the USA.

BACKGROUND: The US Food and Drug Administration's meta-analyses of placebo-controlled antidepressant trials found approximately twice the rate of suicidal behaviors among children and adults aged 24 years and younger who were randomized to receive antidepressant medication than among those who were randomized to placebo. Rates of suicidal behavior were similar for subjects aged 25-64 years whether they received antidepressants or placebo, and subjects aged 65 years or older randomized to antidepressants were found to have lower rates of suicidal behavior. The age-stratified FDA meta-analyses did not have adequate power to investigate rates of suicidal behaviors by antidepressant drug class. OBJECTIVE: Our objective was to assess the risk of deliberate self-harm associated with the two most commonly prescribed classes of antidepressant agents. DESIGN: Propensity score matched cohort study of incident users of antidepressant agents. SETTING: Population-based healthcare utilization data of US residents. PATIENTS: US residents aged 10-64 years with a recorded diagnosis of depression who initiated use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) between 1 January 1998 and 31 December 2010. MAIN OUTCOME MEASURES: ICD-9 external cause of injury codes E950.x-E958.x (deliberate self-harm). RESULTS: A total of 102,647 patients aged between 10 and 24 years, and 338,021 aged between 25 and 64 years, initiated therapy with antidepressants. Among 10-24 year olds, prior to propensity score matching, 75,675 initiated therapy with SSRIs and 5,344 initiated SNRIs. After matching, there were 5,344 SNRI users and 10,688 SSRI users. Among the older cohort, 36,037 SNRI users were matched to 72,028 SSRI users (from an unmatched cohort of 225,952 SSRI initiators). Regardless of age cohort, patients initiating SSRIs and patients initiating SNRIs had similar rates of deliberate self-harm. Restriction to patients with no antidepressant use in the past 3 years did not alter our findings. CONCLUSIONS: Our findings of similar rates of deliberate self-harm for depressed patients who initiate treatment with either an SSRI or an SNRI suggests that physicians who have decided that their patients would benefit from initiating antidepressant therapy need not weigh differential suicide risk when deciding which class of antidepressant to prescribe.

The structured diagnostic interview for sleep patterns and disorders: rationale and initial evaluation.

OBJECTIVES: We aimed to describe and report the initial validity of a newly developed structured interview for sleep disorders (Diagnostic Interview for Sleep Patterns and Disorders [DISP]) administered by trained lay interviewers. METHODS: A total of 225 patients with various sleep disorders were recruited from two nationally recognized sleep centers in the United States. The International Classification of Sleep Disorders, second edition (ICSD-2) criteria, were used to classify sleep disorders (e.g., delayed sleep phase disorder, hypersomnia, narcolepsy with cataplexy [NC], restless legs syndrome [RLS], periodic limb movement disorder [PLMD], insomnia, rapid eye movement sleep behavior disorder [RBD], and obstructive sleep apnea [OSA]). Interview diagnoses were compared with final diagnoses by sleep specialists (reference diagnosis based on clinical history, examination, and polysomnography [PSG] when indicated). RESULTS: DISP diagnoses had fair to substantial concordance with clinician diagnoses for various sleep disorders, with area under the receiver operator characteristic curves (AUC) ranging from 0.65 to 0.84. Participants classified by the clinician as having a sleep disorder were moderately well-detected (sensitivity ranging from 0.50 for RBD disorder to 0.87 for insomnia). Substantial specificity (>0.8) also was seen for five of the eight sleep disorders (i.e., delayed sleep phase, hypersomnia, NC, PLMD, and RBD). Interviews were more likely than clinicians to detect disorders secondary to the primary sleep problem. CONCLUSIONS: The DISP provides an important tool for the detection of a wide range of sleep disorders in clinical settings and is particularly valuable in the detection of secondary disorders that were not the primary referral diagnosis.