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As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended health services (laboratory, imaging, and procedural testing) delivered within 12 months of return were compared among individuals with pathogenic or likely pathogenic (P/LP) findings to matched individuals with negative findings before and after return of results. Of 16,218 adults, 477 unselected individuals were found to have a monogenic risk for arrhythmia (n = 95), breast cancer (n = 96), cardiomyopathy (n = 95), colorectal cancer (n = 105), or familial hypercholesterolemia (n = 86). Individuals with P/LP results more frequently received services after return (43.8%) compared to before return (25.6%) of results and compared to individuals with negative findings (24.9%; p < 0.0001). The annual cost of qualifying healthcare services increased from an average of $162 before return to $343 after return of results among the P/LP group (p < 0.0001); differences in the negative group were non-significant. The mean difference-in-differences was $149 (p < 0.0001), which describes the increased cost within the P/LP group corrected for cost changes in the negative group. When stratified by individual conditions, significant cost differences were observed for arrhythmia, breast cancer, and cardiomyopathy. In conclusion, less than half of individuals received billed health services after monogenic return, which modestly increased healthcare costs for payors in the year following return.
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Neoplasias da Mama , Cardiomiopatias , Adulto , Humanos , Feminino , Estudos Prospectivos , Aceitação pelo Paciente de Cuidados de Saúde , Arritmias Cardíacas , Neoplasias da Mama/genética , Cardiomiopatias/genéticaRESUMO
Background: Traumatic shoulder instability is a common injury in athletes and military personnel. Surgical stabilization reduces recurrence, but athletes often return to sport before recovering upper extremity rotational strength and sport-specific abilities. Blood flow restriction (BFR) may stimulate muscle growth without the need for heavy resistance training post-surgically. Hypothesis/Purpose: To observe changes in shoulder strength, self-reported function, upper extremity performance, and range of motion (ROM) in military cadets recovering from shoulder stabilization surgery who completed a standard rehabilitation program with six weeks of BFR training. Study Design: Prospective case series. Methods: Military cadets who underwent shoulder stabilization surgery completed six weeks of upper extremity BFR training, beginning post-op week six. Primary outcomes were shoulder isometric strength and patient-reported function assessed at 6-weeks, 12-weeks, and 6-months postoperatively. Secondary outcomes included shoulder ROM assessed at each timepoint and the Closed Kinetic Chain Upper Extremity Stability Test (CKCUEST), the Upper Extremity Y-Balance Test (UQYBT), and the Unilateral Seated Shotput Test (USPT) assessed at the six-month follow-up. Results: Twenty cadets performed an average 10.9 BFR training sessions over six weeks. Statistically significant and clinically meaningful increases in surgical extremity external rotation strength (p < 0.001; mean difference, .049; 95% CI: .021, .077), abduction strength (p < 0.001; mean difference, .079; 95% CI: .050, .108), and internal rotation strength (p < 0.001; mean difference, .060; CI: .028, .093) occurred from six to 12 weeks postoperatively. Statistically significant and clinically meaningful improvements were reported on the Single Assessment Numeric Evaluation (p < 0.001; mean difference, 17.7; CI: 9.4, 25.9) and Shoulder Pain and Disability Index (p < 0.001; mean difference, -31.1; CI: -44.2, -18.0) from six to 12 weeks postoperatively. Additionally, over 70 percent of participants met reference values on two to three performance tests at 6-months. Conclusion: While the degree of improvement attributable to the addition of BFR is unknown, the clinically meaningful improvements in shoulder strength, self-reported function, and upper extremity performance warrant further exploration of BFR during upper extremity rehabilitation. Level of Evidence: 4, Case Series.
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CONTEXT: Recently, blood flow restriction (BFR) training has gained popularity as an alternative to high-load resistance training for improving muscle strength and hypertrophy. Previous BFR studies have reported positive treatment effects; however, clinical benefits to using BFR following meniscal repair or chondral surgery are unknown. The purpose of this study was to determine the effect of resistance exercises with BFR training versus exercises alone on self-reported knee function, thigh circumference, and knee flexor/extensor strength postmeniscal or cartilage surgery. DESIGN: Single-blinded randomized controlled trial in an outpatient military hospital setting. Twenty participants were randomized into 2 groups: BFR group (n = 11) and control group (n = 9). METHODS: Participants completed 12 weeks of postoperative thigh strengthening. The BFR group performed each exercise with the addition of BFR. Both groups continued with the prescribed exercises without BFR from 12 weeks until discharged from therapy. Thigh circumference and self-reported knee function were measured at 1, 6, 12, and 24 weeks postoperatively along with knee extensor and flexor strength at 12 and 24 weeks. Change scores between time points were calculated for knee function. Limb symmetry indices (LSI) were computed for thigh circumference and knee strength variables. RESULTS: Seventeen participants were included in the final analyses (BFR = 8 and control = 9) due to COVID-19 restrictions. There were no interactions or main effects for group. Time main effects were established for change in knee function scores, thigh circumference LSI, and knee extensor strength LSI. However, knee flexor strength LSI had no main effect for time. CONCLUSION: The outcomes of this trial suggest that resistance exercises with and without BFR training may result in similar changes to function, thigh atrophy, and knee extensor strength postmeniscus repair/chondral restoration, though further study with larger sample sizes is needed.
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COVID-19 , Militares , Treinamento Resistido , Terapia de Restrição de Fluxo Sanguíneo , Humanos , Força Muscular , Músculo Esquelético , Atrofia Muscular , Fluxo Sanguíneo Regional , SARS-CoV-2RESUMO
INTRODUCTION: There is a large incidence of shoulder instability among active young athletes and military personnel. Shoulder stabilization surgery is the commonly employed intervention for treating individuals with instability. Following surgery, a substantial proportion of individuals experience acute post-operative pain, which is usually managed with opioid pain medications. Unfortunately, the extended use of opioid medications can have adverse effects that impair function and reduce military operational readiness, but there are currently few alternatives. However, battlefield acupuncture (BFA) is a minimally invasive therapy demonstrating promise as a non-pharmaceutical intervention for managing acute post-operative pain. METHODS: This is a parallel, two-arm, single-blind randomized clinical trial. The two independent variables are intervention (2 levels, standard physical therapy and standard physical therapy plus battlefield acupuncture) and time (5 levels, 24 h, 48 h, 72 h, 1 week, and 4 weeks post shoulder stabilization surgery). The primary dependent variables are worst and average pain as measured on the visual analog scale. Secondary outcomes include medication usage, Profile of Mood States, and Global Rating of Change. DISCUSSION: The magnitude of the effect of BFA is uncertain; current studies report confidence intervals of between-group differences that include minimal clinically important differences between intervention and control groups. The results of this study may help determine if BFA is an effective adjunct to physical therapy in reducing pain and opioid usage in acute pain conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT04094246 . Registered on 16 September 2019.
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Terapia por Acupuntura , Instabilidade Articular , Articulação do Ombro , Terapia por Acupuntura/efeitos adversos , Humanos , Modalidades de Fisioterapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ombro/cirurgia , Método Simples-Cego , Resultado do TratamentoRESUMO
OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015. METHODS: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation. RESULTS: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts. CONCLUSIONS: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.
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Colágeno Tipo III/genética , Análise Mutacional de DNA , Síndrome de Ehlers-Danlos/diagnóstico , Mutação , Adolescente , Adulto , Estudos Transversais , Diagnóstico Diferencial , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/genética , Feminino , Predisposição Genética para Doença , Alemanha , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Estados Unidos , Adulto JovemRESUMO
OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder owing to pathogenic variants in COL3A1 that lead to impaired type III collagen production. We aim to describe the contemporary multi-institutional experience of aortic and arterial pathology in individuals with vEDS, to evaluate disease patterns and refine management recommendations. METHODS: This cross-sectional, retrospective study of individuals with genetically confirmed vEDS was conducted between 2000 and 2015 at multiple institutions participating in the Vascular Low Frequency Disease Consortium. Aortic and arterial events including aneurysms, pseudoaneurysms, dissections, fistulae, or ruptures were studied. Demographics, COL3A1 variants, management, and outcomes data were collected and analyzed. Individuals with and without arterial events were compared. RESULTS: Eleven institutions identified 86 individuals with pathogenic variants in COL3A1 (47.7% male, 86% Caucasian; median age, 41 years; interquartile range [IQR], 31.0-49.5 years; 65.1% missense COL3A1 variants). The median follow-up from the time of vEDS diagnosis was 7.5 years (IQR, 3.5-12.0 years). A total of 139 aortic/arterial pathologies were diagnosed in 53 individuals (61.6%; 50.9% male; 88.5% Caucasian; median age, 33 years; IQR, 25.0-42.3 years). The aortic/arterial events presented as an emergency in 52 cases (37.4%). The most commonly affected arteries were the mesenteric arteries (31.7%), followed by cerebrovascular (16.5%), iliac (16.5%), and renal arteries (12.2%). The most common management was medical management. When undertaken, the predominant endovascular interventions were arterial embolization of medium sized arteries (13.4%), followed by stenting (2.5%). Aortic pathology was noted in 17 individuals (32%; 58.8% male; 94.1% Caucasian; median age, 38.5 years; IQR, 30.8-44.7 years). Most notably, four individuals underwent successful abdominal aortic aneurysm repair with excellent results on follow-up. Individuals with missense mutations, in which glycine was substituted with a large amino acid, had an earlier onset of aortic/arterial pathology (median age, 30 years; IQR, 23.5-37 years) compared with the other pathogenic COL3A1 variants (median age, 36 years; IQR, 29.5-44.8 years; P = .065). There were 12 deaths (22.6%) at a median age of 36 years (IQR, 28-51 years). CONCLUSIONS: Most of the vEDS arterial manifestations were managed medically in this cohort. When intervention is required for an enlarging aneurysm or rupture, embolization, and less frequently stenting, seem to be well-tolerated. Open repair of abdominal aortic aneurysm seems to be as well-tolerated as in those without vEDS; vEDS should not be a deterrent to offering an operation. Future work to elucidate the role of surgical interventions and refine management recommendations in the context of patient centered outcomes is warranted.
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Aneurisma/epidemiologia , Aorta/patologia , Artérias/patologia , Colágeno Tipo III/genética , Síndrome de Ehlers-Danlos/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneurisma/genética , Aneurisma/patologia , Aneurisma/terapia , Aorta/cirurgia , Artérias/cirurgia , Criança , Pré-Escolar , Colágeno Tipo III/metabolismo , Estudos Transversais , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patologia , Embolização Terapêutica/estatística & dados numéricos , Procedimentos Endovasculares/métodos , Procedimentos Endovasculares/estatística & dados numéricos , Feminino , Seguimentos , Testes Genéticos/estatística & dados numéricos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To evaluate the prevalence of Noonan spectrum disorders (NSD) in a pediatric population with valvar pulmonary stenosis (vPS) and identify the clinical characteristics that differentiate those with NSD from those without NSD. DESIGN: A retrospective chart review of 204 patients diagnosed with vPS between 9/1/2012 and 12/1/2016 at a pediatric medical center was performed. The quantitative features of vPS, genetic diagnosis information, and phenotypic characteristics of Noonan syndrome were collected. Chi-square test, Fisher's exact test, t test, Wilcoxon rank-sum test, and ANOVA were used for comparisons among the groups. Logistic regression was used to test for the association between the clinical characteristics and the presence of NSD. RESULTS: Syndromic diagnoses were made in 10% of the children with vPS, with NSD accounting for 6%. Hypertrophic cardiomyopathy (P < .0001), short stature (P < .0001), developmental delay (P < .0001), ophthalmological abnormalities (P < .0001), pectus carinatum/excavatum (P = .01), neurological abnormalities (P = .022), and aortic stenosis (P = .031) were present more often in individuals with NSD compared to nonsyndromic vPS. A logistic regression analysis showed a 4.8-fold increase in odds for NSD for each additional characteristic (P < .0001). CONCLUSIONS: At least 6% of the children with vPS have an underlying NSD. Individuals with vPS and NSD were significantly more likely to have additional features known to be associated with NSD than those with vPS without NSD. We conclude that vPS in the presence of one or more significant characteristics should prompt referral for genetic evaluation as a guide to ascertain patients at risk for NSD while optimizing the use of clinical genetics evaluation and potential genetic testing.
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Anormalidades Múltiplas , Testes Genéticos/métodos , Síndrome de Noonan/epidemiologia , Estenose da Valva Pulmonar/epidemiologia , Ecocardiografia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Síndrome de Noonan/diagnóstico , Ohio/epidemiologia , Prevalência , Estenose da Valva Pulmonar/diagnóstico , Estudos RetrospectivosRESUMO
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant genetic channelopathy associated with exertional syncope and reproducible polymorphic ventricular tachycardia with exercise. Approximately 65% of patients with CPVT are found to have a disease causing mutation in the RYR2 gene. RYR2 encodes a calcium ion transporter in the sarcomeric reticulum, and is responsible for the calcium induced calcium release that results in ventricular contraction. Recently, exon 3 deletion of RYR2 has been reported to be associated with left ventricular noncompaction. Herein we describe a patient with a novel, de novo deletion of exon 3 in the RYR2 gene that resulted in a severe CPVT phenotype and sudden cardiac arrest (SCA), and the development of left ventricular non-compaction (LVNC) coinciding with worsening arrhythmias. This case is unique in that the patient initially presented with exertional syncope and developed LVNC that coincided with increasingly severe ventricular arrhythmias and multiple episodes of SCA. This case supports the idea that RYR2 deletions cause a severe subtype of CPVT associated with LVNC and suggests LVNC may play a role in exacerbating the arrhythmias of CPVT. Deletion duplication testing should be considered in the context of CPVT and LVNC or SCA.
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Morte Súbita Cardíaca/etiologia , Éxons/genética , Ventrículos do Coração/patologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Deleção de Sequência/genética , Taquicardia Ventricular/genética , Adulto , Arritmias Cardíacas/genética , Feminino , Humanos , Taquicardia Ventricular/patologia , Adulto JovemRESUMO
OBJECTIVE: Depression may be associated with increased mortality risk, but there are substantial limitations to existing studies assessing this relationship. We sought to overcome limitations of existing studies by conducting a large, national, longitudinal study to assess the impact of depression on all-cause and cause-specific risk of death. METHODS: We used Cox regression models to estimate hazard ratios associated with baseline depression diagnosis (N=849,474) and three-year mortality among 5,078,082 patients treated in Veterans Health Administration (VHA) settings in fiscal year (FY) 2006. Cause of death was obtained from the National Death Index (NDI). RESULTS: Baseline depression was associated with 17% greater hazard of all-cause three-year mortality (95% CI hazard ratio [HR]: 1.15, 1.18) after adjusting for baseline patient demographic and clinical characteristics and VHA facility characteristics. Depression was associated with a higher hazard of three-year mortality from heart disease, respiratory illness, cerebrovascular disease, accidents, diabetes, nephritis, influenza, Alzheimer's disease, septicemia, suicide, Parkinson's disease, and hypertension. Depression was associated with a lower hazard of death from malignant neoplasm and liver disease. Depression was not associated with mortality due to assault. CONCLUSIONS: In addition to being associated with suicide and injury-related causes of death, depression is associated with increased risk of death from nearly all major medical causes, independent of multiple major risk factors. Findings highlight the need to better understand and prevent mortality seen with multiple medical disorders associated with depression.
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Causas de Morte , Depressão/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Veteranos/estatística & dados numéricos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia , United States Department of Veterans AffairsRESUMO
Although it is well known that under-referral of colon cancer patients to cancer genetics clinics is a chronic problem, no study has yet examined why physicians may be ordering testing independently rather than referring patients to cancer genetics clinics. The current study explored variables which may impact a physician's preference for ordering testing independently or referring patients to outside cancer genetics experts. An online questionnaire, distributed to the membership of the American College of Gastroenterology and the American Society of Colorectal Surgeons, yielded responses from 298 physicians. Motivations to refer to cancer genetics clinics rather than order testing independently included fear of genetic discrimination and a belief that patients benefit from genetic counseling about the risks, benefits and consequences of testing. These results suggest that in order to increase referrals, genetic counselors must educate physicians about the unique benefits patients receive from participating in genetic counseling.
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Aconselhamento Genético , Motivação , Neoplasias/genética , Padrões de Prática Médica , Encaminhamento e Consulta , Humanos , Inquéritos e QuestionáriosRESUMO
Deep-vein thrombosis (DVT) resolution is thought to be primarily a urokinase plasminogen activator (uPA) -dependent mechanism, although observations suggest other non-fibrinolytic mechanisms may exist. We explored the role of matrix metalloproteinase (MMP) -2 and -9 in early DVT resolution in uPA-deficient mice. Male B6/SVEV (WT) and genetically matched uPA -/- mice underwent inferior vena cava (IVC) ligation to create stasis venous thrombi, with IVC and thrombus harvest. Thrombus size was similar between WT and uPA -/- mice at day 4, suggesting early non uPA-dependent resolution. Intrathrombus neutrophils and monocytes were reduced 3- and 3.5-fold in uPA -/- mice as compared with WT. By ELISA, tumour necrosis factor α and interleukin 1ß were not altered, while interferon (IFN)γ was significantly elevated in uPA -/- mice. A compensatory increase in thrombus tPA was not observed, plasmin activity was reduced and PAI-1 was elevated 2.5-fold in uPA -/- mice. Active MMP2, but not MMP9, was elevated 3-fold in uPA -/- mice as compared with WT as well as MMP-14, an MMP2 activator. Collagen type IV and fibrinogen were reduced in uPA -/- mice thrombi as compared with WT. IFNγ induces MMP2, and blockade of IFNγ was associated with larger venous thrombi and reduced active MMP2, as compared with WT. Consistently, MMP2 -/- mice had larger VT as compared with WT controls, despite normal thrombus plasmin levels. Taken together, early experimental venous thrombus resolution is independent of uPA, and, in part, inflammatory cell influx. MMP2-dependent thrombolysis is an important compensatory mechanism of venous thrombus resolution, possibly by collagen type IV metabolism, and may represent an exploitable therapeutic avenue.
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Metaloproteinase 2 da Matriz/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Trombose Venosa/enzimologia , Animais , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Fibrinogênio/metabolismo , Interferon gama/metabolismo , Interleucina-1beta/metabolismo , Leucócitos/imunologia , Ligadura , Masculino , Metaloproteinase 2 da Matriz/deficiência , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/deficiência , Ativador de Plasminogênio Tipo Uroquinase/genética , Veia Cava Inferior/cirurgia , Trombose Venosa/genética , Trombose Venosa/imunologiaRESUMO
CONTEXT: Depression negatively affects health and well being among older adults, but there have been no nationally representative comparisons of depression prevalence among older adults in England and the United States. OBJECTIVE: The authors sought to compare depressive symptoms among older adults in these countries and identify sociodemographic and clinical correlates of depression in these countries. DESIGN AND SETTING: The authors assessed depressive symptoms in non-Hispanic whites aged 65 years and older in 2002 in two nationally representative, population-based studies: the U.S. Health and Retirement Study and English Longitudinal Study of Ageing. PARTICIPANTS: A total of 8,295 Health and Retirement Study respondents and 5,208 English Longitudinal Study of Ageing respondents. MAIN OUTCOME MEASURES: The authors measured depressive symptoms using the eight-item Center for Epidemiologic Studies Depression Scale. The authors determined whether depressive symptom differences between the United States and England were associated with sociodemographic characteristics, chronic health conditions, and health behaviors. RESULTS: Significant depressive symptoms (Center for Epidemiologic Studies Depression Scale score ≥4) were more prevalent in English than U.S. adults (17.6% versus 14.6%, adjusted Wald test F([1, 1593]) = 11.4, p < 0.001). Adjusted rates of depressive symptoms in England were 19% higher compared with the United States (odds ratio: 1.19, 95% confidence interval: 1.01-1.40). U.S. adults had higher levels of education, and net worth, but lower levels of activities of daily living/instrumental activities of daily living impairments, tobacco use, and cognitive impairment, which may have contributed to relatively lower levels of depressive symptoms in the United States. CONCLUSIONS: Older adults in the United States had lower rates of depressive symptoms than their English counterparts despite having more chronic health conditions. Future cross-national studies should identify how depression treatment influences outcomes in these populations.