Social network participation towards enactment of self-care in people with chronic obstructive pulmonary disease: A qualitative meta-ethnography.

BACKGROUND: How people with chronic obstructive pulmonary disease (COPD) engage with supportive social networks to enhance self-care is not understood. The personal rationales for participation in socially directed support have not been addressed in the literature. To determine how people with COPD identify, engage and participate in socially supportive self-care practices, we conducted a systematic review and meta-ethnography of qualitative studies. METHODS: A systematic literature search was conducted between June 2010 and June 2021. Of 3536 articles, 8 fulfilled the inclusion criteria. Using a meta-ethnography approach to the qualitative synthesis, new concepts were derived from the data to identify aligning themes and develop a conceptual model. FINDINGS: Interpretations from the papers yielded concepts of (1) accountability and personal responsibility in self-care, (2) valued positive relationships with clinicians, (3) understanding of illness through shared and personal experiences and (4) acknowledging social networks in fostering self-care engagement in people with COPD. The independence-experience (Index) model of synthesized (third order) interpretations highlighted the processes of social networks and self-care practices: (a) fear or avoidance of dependency, (b) learning from experiences of adaptive self-care behaviours and (c) including valued practices in self-care. Self-care strategies are formed through illness experiences and relatable social encounters. CONCLUSION: The model derived from the third-order interpretations is a framework to describe socially supported self-care and can be used to direct future self-care strategies and target interventions for people with COPD. PATIENT OR PUBLIC CONTRIBUTION: The findings and model were presented to the long-term conditions patient and public involvement group. The manuscript is coauthored by a public representative.

Factors associated with study completion in patients with premature acute coronary syndrome.

BACKGROUND: Factors associated with study completion in younger adults are not well understood. This study sought to describe psychosocial, clinical, and demographic features associated with completion of a study of men and women with premature acute coronary syndrome. METHODS: As part of the GENdEr and Sex determInantS of cardiovascular disease: From bench to beyond-Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, demographic, psychosocial, and clinical variables were assessed in 1213 patients hospitalized for acute coronary syndrome (≤ 55 years; 30% women). Patients were followed for 12 months. Dropouts withdrew from the study or were lost to follow-up after 12 months; completers were still enrolled after 12 months. RESULTS: Of 1213 patients initially enrolled, 777 (64.1%) completed 12-month follow-up. Fully adjusted models suggested that being older (OR = 1.04, 95% CI [1.01, 1.06]), higher subjective social status within one's country (OR = 1.11, 95% CI [1.01, 1.22]), being free of type II diabetes, (OR = 0.66, 95% CI [0.45, 0.97]), non-smoking status (OR = 0.70, 95% CI [0.51, 0.95]) and being free of depression (OR = 1.52, 95% CI [1.11, 2.07]) were independently associated with study completion. CONCLUSIONS: Recruitment/retention strategies targeting individuals who smoke, are younger, have low subjective social status within one's country, have diabetes, or have depression may improve participant follow-up in cardiovascular cohort studies.

Positive and Negative Affect Is Related to Experiencing Chest Pain During Exercise-Induced Myocardial Ischemia.

OBJECTIVE: Silent myocardial ischemia is thought to be associated with worse cardiovascular outcomes due to a lack of perception of pain cues that initiate treatment seeking. Negative affect (NA) has been associated with increased pain reporting and positive affect (PA) with decreased pain reporting, but these psychological factors have not been examined within the context of myocardial ischemia. This study evaluated the associations between PA, NA, and chest pain reporting in patients with and without ischemia during exercise testing. METHODS: A total of 246 patients referred for myocardial perfusion single-photon emission computed tomography exercise stress testing completed the positive and negative affect schedule-expanded version, a measure of PA and NA. Presence of chest pain and myocardial ischemia were evaluated using standardized protocols. RESULTS: Logistic regression analyses revealed that for every 1-point increase in NA, there was a 13% higher chance for ischemic patients (odds ratio [OR] = 1.13; 95% confidence interval [CI] = 1.02 to 1.26) and an 11% higher chance in nonischemic patients (OR = 1.11; 95% CI = 1.03 to 1.19) to report chest pain. A significant interaction of PA and NA on chest pain reporting (ß = 0.02; 95% CI = 0.002 to 0.031) was also observed; nonischemic patients with high NA and PA reported more chest pain (57%) versus patients with low NA and low PA (13%), with high NA and low PA (17%), and with high PA and low NA (7%). CONCLUSIONS: Patients who experience higher NA are more likely to report experiencing chest pain. In patients without ischemia, high NA and PA was also associated with a higher likelihood of reporting chest pain. Results suggest that high levels of PA as well as NA may increase the experience and/or reporting of chest pain.

PI(3)P-p40phox binding regulates NADPH oxidase activation in mouse macrophages and magnitude of inflammatory responses in vivo.

Mutations in the leukocyte NADPH oxidase that abrogate superoxide production result in chronic granulomatous disease (CGD), an inherited immunodeficiency associated with recurrent infections and inflammatory complications. The cytosolic regulatory subunit p40phox plays a specialized role in stimulating NADPH oxidase activity on intracellular membranes via its phosphatidylinositol 3-phosphate [PI(3)P]-binding domain, as revealed by studies largely focused on neutrophils. Whether PI(3)P-p40phox-regulated superoxide production contributes to regulating inflammatory responses is not well understood. Here, we report that mice expressing p40phox R58A, which lacks PI(3)P binding, had impaired macrophage NADPH oxidase activity and increased sterile inflammation. p40phoxR58A/R58A macrophages exhibited diminished phagosome reactive oxygen species (ROS) in response to certain particulate and soluble ligands, including IgG-opsonized particles and a TLR2 agonist, along with unexpected defects in plasma membrane oxidase activity. Compared with wild-type (WT) mice, p40phoxR58A/R58A mice had elevated numbers of newly recruited neutrophils and monocytes in peritoneal inflammation elicited by zymosan, monosodium urate (MSU) crystals, or sodium periodate. At later time points, higher numbers of inflammatory macrophages in p40phoxR58A/R58A mice were consistent with delayed resolution. Our studies demonstrate a critical role of PI(3)P-p40phox binding for optimal activation of the NADPH oxidase in macrophages. Furthermore, selective loss of PI(3)P-regulated NADPH oxidase activity was sufficient to enhance significantly responses to inflammation and delay resolution.

NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1α/G-CSF axis.

The leukocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase generates reactive oxygen species essential in microbial killing and regulation of inflammation. Inactivating mutations in this enzyme lead to chronic granulomatous disease (CGD), associated with increased susceptibility to both pyogenic infections and to inflammatory disorders. The role of the NADPH oxidase in regulating inflammation driven by nonmicrobial stimuli is poorly understood. Here, we show that NADPH oxidase deficiency enhances the early local release of interleukin-1α (IL-1α) in response to damaged cells, promoting an excessive granulocyte colony-stimulating factor (G-CSF)-regulated neutrophilic response and prolonged inflammation. In peritoneal inflammation elicited by tissue injury, X-linked Cybb-null (X-CGD) mice exhibited increased release of IL-1α and IL-1 receptor -mediated G-CSF production. In turn, higher levels of systemic G-CSF increased peripheral neutrophilia, which amplified neutrophilic peritoneal inflammation in X-CGD mice. Dampening early neutrophil recruitment by neutralization of IL-1α, G-CSF, or neutrophil depletion itself promoted resolution of otherwise prolonged inflammation in X-CGD. IL-1ß played little role. Thus, we identified an excessive IL-1α/G-CSF response as a major driver of enhanced sterile inflammation in CGD in the response to damaged cells. More broadly, these results provide new insights into the regulation of sterile inflammation, and identify the NADPH oxidase in regulating the amplitude of the early neutrophilic response.

Plasma volume and flight duration effects on post-spaceflight soluble adhesion molecules.

BACKGROUND: We examined the effects of plasma volume (PV) changes and flight duration on circulating soluble adhesion markers (sP-selection, sE-selection, and sICAM-1). METHODS: Study participants were 22 astronauts (2 women). Missions ranged from 5 to 16 d. Astronauts were split into two groups: those who spent less than 8 d in space and those who spent more than 8 d in space. Soluble adhesion markers and PV were assessed 10 d prelaunch, immediately after landing, and 2-4 d postflight. RESULTS: Compared to prelaunch, PV significantly decreased by 4.9% after landing and increased by 9.9% 2-4 d postflight. After landing, sICAM-1 decreased (233.15 vs. 226.78 ng · ml⁻¹) and remained lowered 2-4 d after landing (223.25 ng · ml⁻¹). Adjusting for PV changes, sICAM-1 upon landing was less than prelaunch (218.23 ng · ml⁻¹), but became greater 2-4 d postflight (250.30 ng · ml⁻¹). From prelaunch to landing, sE-selection decreased significantly (30.25 vs. 28.51 ng · ml⁻¹) and returned to prelaunch levels 2-4 d postflight (30.10 ng · ml⁻¹). Adjusting for PV changes, sE-selection was significantly greater 2-4 d postflight (33.48 ng · ml⁻¹) compared to prelaunch. In those who spent less than 8 d in space only, sP-selection increased from prelaunch levels to landing day (31.66 vs. 48.06 ng · ml⁻¹), with and without adjustment for PV changes. Flight duration did not influence PV, sICAM-1, or sE-selection. DISCUSSION: Spaceflight leads to an internal environment that decreases PV during flight but rebounds after flight, leading to a dilution of sICAM-1 and sE-selection, but does not appear to affect sP-selection. Flight duration only affected sP-selection.

Cupric yersiniabactin is a virulence-associated superoxide dismutase mimic.

Many Gram-negative bacteria interact with extracellular metal ions by expressing one or more siderophore types. Among these, the virulence-associated siderophore yersiniabactin (Ybt) is an avid copper chelator, forming stable cupric (Cu(II)-Ybt) complexes that are detectable in infected patients. Here we show that Ybt-expressing E. coli are protected from intracellular killing within copper-replete phagocytic cells. This survival advantage is highly dependent upon the phagocyte respiratory burst, during which superoxide is generated by the NADPH oxidase complex. Chemical fractionation links this phenotype to a previously unappreciated superoxide dismutase (SOD)-like activity of Cu(II)-Ybt. Unlike previously described synthetic copper-salicylate (Cu(II)-SA) SOD mimics, the salicylate-based natural product Cu(II)-Ybt retains catalytic activity at physiologically plausible protein concentrations. These results reveal a new virulence-associated adaptation based upon spontaneous assembly of a non-protein catalyst.

Comparison of stress-hemoconcentration correction techniques for stress-induced coagulation.

When examining stress effects on coagulation, arithmetic correction is typically used to adjust for concomitant hemoconcentration but may be inappropriate for coagulation activity assays. We examined a new physiologically relevant method of correcting for stress-hemoconcentration. Blood was drawn from healthy men (N = 40) during baseline, mental stress, and recovery, and factor VII activity (FVII:C), factor VIII activity (FVIII:C), activated partial thromboplastin time (APTT), prothrombin time (PT%), fibrinogen, D-dimer, and plasma volume were determined. Three hemoconcentration correction techniques were assessed: arithmetic correction and two reconstitution techniques using baseline plasma or physiological saline. Area-under-the-curve (AUC) was computed for each technique. For FVII:C, uncorrected AUC was significantly greater than AUC corrected arithmetically. For PT%, uncorrected AUC was significantly greater than AUC corrected with saline or arithmetically. For APTT, uncorrected AUC was significantly less than AUC corrected with saline and greater than AUC corrected arithmetically. For fibrinogen, uncorrected AUC was significantly greater than AUC corrected with saline or arithmetically. For D-dimer, uncorrected AUC was significantly greater than AUC corrected arithmetically. No differences in AUC were observed for FVIII:C. Saline reconstitution seems most appropriate when adjusting for hemoconcentration effects on clotting time and activity. Stress-hemoconcentration accounted for the majority of coagulation changes.

Stress and hemostasis: an update.

Numerous naturalistic, experimental, and mechanistic studies strongly support the notion that-as part of fight-or-flight response-hemostatic responses to acute psychosocial stress result in net hypercoagulability, which would protect a healthy organism from bleeding in case of injury. Sociodemographic factors, mental states, and comorbidities are important modulators of the acute prothrombotic stress response. In patients with atherosclerosis, exaggerated and prolonged stress-hypercoagulability might accelerate coronary thrombus growth following plaque rupture. Against a background risk from acquired prothrombotic conditions and inherited thrombophilia, acute stress also might trigger venous thromboembolic events. Chronic stressors such as job strain, dementia caregiving, and posttraumatic stress disorder as well as psychological distress from depressive and anxiety symptoms elicit a chronic low-grade hypercoagulable state that is no longer viewed as physiological but might impair vascular health. Through activation of the sympathetic nervous system, higher order cognitive processes and corticolimbic brain areas shape the acute prothrombotic stress response. Hypothalamic-pituitary-adrenal axis and autonomic dysfunction, including vagal withdrawal, are important regulators of hemostatic activity with longer lasting stress. Randomized placebo-controlled trials suggest that several cardiovascular drugs attenuate the acute prothrombotic stress response. Behavioral interventions and psychotropic medications might mitigate chronic low-grade hypercoagulability in stressed individuals, but further studies are clearly needed. Restoring normal hemostatic function with biobehavioral interventions bears the potential to ultimately decrease the risk of thrombotic diseases.

Bovine spongiform encephalopathy: the effect of oral exposure dose on attack rate and incubation period in cattle - an update.

BACKGROUND: To provide information on dose-response and aid in modelling the exposure dynamics of the BSE epidemic in the United Kingdom groups of cattle were exposed orally to a range of different doses of brainstem homogenate of known infectious titre from clinical cases of classical bovine spongiform encephalopathy (BSE). Interim data from this study was published in 2007. This communication documents additional BSE cases, which occurred subsequently, examines possible influence of the bovine prion protein gene on disease incidence and revises estimates of effective oral exposure. FINDINGS: Following interim published results, two further cattle, one dosed with 100 mg and culled at 127 months post exposure and the other dosed with 10 mg and culled at 110 months post exposure, developed BSE. Both had a similar pathological phenotype to previous cases. Based on attack rate and incubation period distribution according to dose, the dose estimate at which 50% of confirmed cases would be clinically affected was revised to 0.15 g of the brain homogenate used in the experiment, with a 95% confidence interval of 0.03-0.79 g. Neither the full open reading frame nor the promoter region of the prion protein gene of dosed cattle appeared to influence susceptibility to BSE, but this may be due to the sample size. CONCLUSIONS: Oral exposure of cattle to a large range of doses of a BSE brainstem homogenate produced disease in all dose groups. The pathological presentation resembled natural disease. The attack rate and incubation period were dependent on the dose.

Stress-induced alterations in coagulation: assessment of a new hemoconcentration correction technique.

OBJECTIVE: For the examination of psychological stress effects on coagulation, the Dill and Costill correction (DCC) for hemoconcentration effects has been used to adjust for stress-induced plasma volume changes. Although the correction is appropriate for adjusting concentrations of various large blood constituents, it may be inappropriate for time-dependent or functional coagulation assays. Two new plasma reconstitution techniques for correcting hemoconcentration effects on stress-induced changes in coagulation were compared with the DCC. METHODS: Blood was collected from 31 men during baseline, the Trier Social Stress Test (TSST), and after 20-minute recovery. For the reconstitution techniques, TSST plasma samples were reconstituted with either baseline plasma or physiological saline equal to the amount of plasma lost during stress. RESULTS: Uncorrected activated partial thromboplastin time (APTT) decreased, whereas fibrinogen, factor VIII clotting activity (FVIII:C), D-dimer and prothrombin time (PT%) increased significantly during the TSST. The DCC produced a significantly greater decrease in APTT during stress compared to uncorrected APTT, a significant decrease in PT% compared to uncorrected PT%, and stress D-dimer and fibrinogen and FVIII:C being no different than baseline. APTT, fibrinogen, D-dimer and PT% after saline reconstitution were not different from baseline, whereas FVIII:C after saline reconstitution remained elevated. APTT, PT%, fibrinogen and D-dimer after plasma reconstitution were no different from uncorrected values, whereas FVIII:C remained significantly elevated. CONCLUSIONS: The observed changes in coagulation are likely in part a consequence of stress and hemoconcentration, but the DCC seems to be an inappropriate hemoconcentration correction technique of time-dependent assays. The saline reconstitution technique may be more biologically relevant when examining stress-hemoconcentration effects on coagulation.

Long-term reduction in implicit race bias: A prejudice habit-breaking intervention.

We developed a multi-faceted prejudice habit-breaking intervention to produce long-term reductions in implicit race bias. The intervention is based on the premise that implicit bias is like a habit that can be reduced through a combination of awareness of implicit bias, concern about the effects of that bias, and the application of strategies to reduce bias. In a 12-week longitudinal study, people who received the intervention showed dramatic reductions in implicit race bias. People who were concerned about discrimination or who reported using the strategies showed the greatest reductions. The intervention also led to increases in concern about discrimination and personal awareness of bias over the duration of the study. People in the control group showed none of the above effects. Our results raise the hope of reducing persistent and unintentional forms of discrimination that arise from implicit bias.

A Phex mutation in a murine model of X-linked hypophosphatemia alters phosphate responsiveness of bone cells.

Mutations in the PHEX gene cause X-linked hypophosphatemia (XLH). Hypophosphatemia in XLH results from increased circulating levels of a phosphaturic hormone, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D (calcitriol) synthesis. The current standard therapy for XLH--high-dose phosphate and calcitriol--further increases FGF23 concentrations, suggesting that patients with XLH may have an altered response to extracellular phosphate. To test for the presence of abnormal phosphate responsiveness, we compared serum biochemistries and femoral Fgf23 mRNA expression between wild-type mice, murine models of XLH (Phex(K496X)) and hyperphosphatemic tumoral calcinosis (Galnt3(-/-)), and Galnt3/Phex double-mutant mice. Phex mutant mice had not only increased Fgf23 expression but also reduced proteolytic cleavage of intact Fgf23 protein, resulting in markedly elevated intact Fgf23 levels and consequent hypophosphatemia. In contrast, despite markedly increased Fgf23 expression, Galnt3 knockout mice had significantly high proteolytic cleavage of Fgf23 protein, leading to low intact Fgf23 concentrations and hyperphosphatemia. Galnt3/Phex double-mutant mice had an intermediate biochemical phenotype between wild-type and Phex mutant mice, including slightly elevated intact Fgf23 concentrations with milder hypophosphatemia. Despite the hypophosphatemia, double-mutant mice attempted to reduce serum phosphate back to the level of Phex mutant mice by upregulating Fgf23 expression as much as 24-fold higher than Phex mutant mice. These data suggest that Phex mutations alter the responsiveness of bone cells to extracellular phosphate concentrations and may create a lower set point for "normal" phosphate levels.

Studies of the transmissibility of the agent of bovine spongiform encephalopathy to the domestic chicken.

BACKGROUND: Transmission of the prion disease bovine spongiform encephalopathy (BSE) occurred accidentally to cattle and several other mammalian species via feed supplemented with meat and bone meal contaminated with infected bovine tissue. Prior to United Kingdom controls in 1996 on the feeding of mammalian meat and bone meal to farmed animals, the domestic chicken was potentially exposed to feed contaminated with the causal agent of BSE. Although confirmed prion diseases are unrecorded in avian species a study was undertaken to transmit BSE to the domestic chicken by parenteral and oral inoculations. Transmissibility was assessed by clinical monitoring, histopathological examinations, detection of a putative disease form of an avian prion protein (PrP) in recipient tissues and by mouse bioassay of tissues. Occurrence of a progressive neurological syndrome in the primary transmission study was investigated by sub-passage experiments. RESULTS: No clinical, pathological or bioassay evidence of transmission of BSE to the chicken was obtained in the primary or sub-passage experiments. Survival data showed no significant differences between control and treatment groups. Neurological signs observed, not previously described in the domestic chicken, were not associated with significant pathology. The diagnostic techniques applied failed to detect a disease associated form of PrP. CONCLUSION: Important from a risk assessment perspective, the present study has established that the domestic chicken does not develop a prion disease after large parenteral exposures to the BSE agent or after oral exposures equivalent to previous exposures via commercial diets. Future investigations into the potential susceptibility of avian species to mammalian prion diseases require species-specific immunochemical techniques and more refined experimental models.

Dietary phosphate restriction normalizes biochemical and skeletal abnormalities in a murine model of tumoral calcinosis.

Mutations in the GALNT3 gene cause tumoral calcinosis characterized by ectopic calcifications due to persistent hyperphosphatemia. We recently developed Galnt3 knockout mice in a mixed background, which had hyperphosphatemia with increased bone mineral density (BMD) and infertility in males. To test the effect of dietary phosphate intake on their phenotype, Galnt3 knockout mice were generated in the C57BL/6J strain and fed various phosphate diets: 0.1% (low), 0.3% (low normal), 0.6% (normal), and 1.65% (high). Sera were analyzed for calcium, phosphorus, alkaline phosphatase, creatinine, blood urine nitrogen, 1,25-dihydroxyvitamin D, osteocalcin, tartrate-resistant acid phosphatase 5b, and fibroblast growth factor 23 (Fgf23). Femurs were evaluated by dual-energy x-ray absorptiometry, dynamic histomorphometry, and/or microcomputed tomography. Galnt3 knockout mice in C57BL/6J had the same biochemical phenotype observed in our previous study: hyperphosphatemia, inappropriately normal 1,25-dihydroxyvitamin D level, decreased alkaline phosphatase activity, and low intact Fgf23 concentration but high Fgf23 fragments. Skeletal analyses of their femurs revealed significantly high BMD with increased cortical bone area and trabecular bone volume. On all four phosphate diets, Galnt3 knockout mice had consistently higher phosphorus levels and lower alkaline phosphatase and intact Fgf23 concentrations than littermate controls. The low-phosphate diet normalized serum phosphorus, alkaline phosphatase, and areal BMD but failed to correct male infertility in Galnt3 knockout mice. The high-phosphate diet did not increase serum phosphorus concentration in either mutant or control mice due to a compensatory increase in circulating intact Fgf23 levels. In conclusion, dietary phosphate restriction normalizes biochemical and skeletal phenotypes of Galnt3 knockout mice and, thus, can be an effective therapy for tumoral calcinosis.

Hemoconcentration and hemostasis during acute stress: interacting and independent effects.

BACKGROUND: Acute psychological stress can produce significant hemoconcentration as well as prothrombotic changes in blood, both of which may have potentially harmful effects on the cardiovascular system. It is unclear whether these effects are independent or have influence on each other. PURPOSE: This review discusses research investigating the effects of acute psychological stress on hemoconcentration and hemostasis and explores future directions for psychohematology research. Physiology, associations with cardiovascular disease, and relationships between acute psychological stress are discussed independently for hemoconcentration and hemostasis, followed by an examination of the effects of stress-hemoconcentration on hemostasis. CONCLUSIONS: Traditional methods of adjusting for stress-hemoconcentration effects (e.g., calculated plasma volume or hematocrit level corrections) may not be appropriate when examining stress-induced changes in hemostasis. The effects of acute stress on hemostasis should be examined in conjunction with hemoconcentration.

Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations.

The GALNT3 gene encodes GalNAc-T3, which prevents degradation of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Biallelic mutations in either GALNT3 or FGF23 result in hyperphosphatemic familial tumoral calcinosis or its variant, hyperostosis-hyperphosphatemia syndrome. Tumoral calcinosis is characterized by the presence of ectopic calcifications around major joints, whereas hyperostosis-hyperphosphatemia syndrome is characterized by recurrent long bone lesions with hyperostosis. Here we investigated four patients with hyperphosphatemia and clinical manifestations including tumoral calcinosis and/or hyperostosis-hyperphosphatemia syndrome to determine underlying genetic cause and delineate phenotypic heterogeneity of these disorders. Mutational analysis of FGF23 and GALNT3 in these patients revealed novel homozygous mutations in GALNT3. Although the presence of massive calcifications, cortical hyperostosis, or dental anomalies was not shared by all patients, all had persistent hyperphosphatemia. Three of the patients also had inappropriately normal 1,25-dihyroxyvitamin D [1,25(OH)(2)D] and confirmed low circulating intact FGF23 concentrations. The four novel GALNT3 mutations invariably resulted in hyperphosphatemia as a result of low intact FGF23, but other clinical manifestations were variable. Therefore, tumoral calcinosis and hyperostosis-hyperphosphatemia syndrome represent a continuous spectrum of the same disease caused by increased phosphate levels, rather than two distinct disorders.