Concave likelihood-based regression with finite-support response variables.

We propose a unified framework for likelihood-based regression modeling when the response variable has finite support. Our work is motivated by the fact that, in practice, observed data are discrete and bounded. The proposed methods assume a model which includes models previously considered for interval-censored variables with log-concave distributions as special cases. The resulting log-likelihood is concave, which we use to establish asymptotic normality of its maximizer as the number of observations n tends to infinity with the number of parameters d fixed, and rates of convergence of L1 -regularized estimators when the true parameter vector is sparse and d and n both tend to infinity with log ( d ) / n → 0 $\log (d) / n \rightarrow 0$ . We consider an inexact proximal Newton algorithm for computing estimates and give theoretical guarantees for its convergence. The range of possible applications is wide, including but not limited to survival analysis in discrete time, the modeling of outcomes on scored surveys and questionnaires, and, more generally, interval-censored regression. The applicability and usefulness of the proposed methods are illustrated in simulations and data examples.

Impact of modern systemic therapies and clinical markers on treatment outcome for metastatic melanoma in a real-world setting.

BACKGROUND: The survival in metastatic melanoma has dramatically improved after the introduction of immune checkpoint- (ICIs) and MAPKinase inhibitors (MAPKis). OBJECTIVE: Our aim was to describe therapy response and survival in a real-world population as well as to assess the associations between clinical variables and therapy outcome for patients with metastatic melanoma receiving first-line ICIs or MAPKis. METHODS: A total of 252 patients with metastatic (stage IV) melanoma were prospectively followed between 1 January 2010 and 3 December 2017 with follow-up until 31 March 2019, at the Karolinska University Hospital, Sweden. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were analysed with Cox regression, and logistic regression was used to estimate odds ratios (ORs) for therapy response. RESULTS: Patients receiving ICIs (n = 138) experienced longer PFS compared to patients that received MAPKis (n = 114; median PFS for ICIs was 6.8 months, and median PFS for MAPKis was 5.3 months). In the multivariable analyses of clinical markers, increasing M-stage (OR 0.65; 95% CI 0.45-0.94; P = 0.022) and male sex (OR 0.41; 95% CI 0.19-0.90; P = 0.027) were significantly associated with lower response to ICIs. Lower baseline albumin levels (OR 0.90; 95% CI 0.83-0.98; P = 0.019) and male sex (OR 0.33; 95% CI 0.12-0.93; P = 0.036) were related with lower response to MAPKis. For ICIs, increasing M-stage (HR 1.34; 95% CI 1.07-1.68; P = 0.010), increasing LDH (HR 1.73; 95% CI 1.19-2.50; P = 0.004) and decreasing albumin (HR 1.06; 95% CI 1.01-1.10; P = 0.011) were significantly associated lower PFS in the adjusted model. The corresponding markers for MAPKis were increasing LDH (HR 1.44; 95% CI 1.08-1.92; P = 0.013) and decreasing albumin (HR 1.05; 95% CI 1.02-1.09; P = 0.005) for PFS. CONCLUSION: ICIs and MAPKis were effective in this real-world population, and we could confirm the importance of previously reported clinical prognostic markers. Albumin values may be associated with therapy outcome but need further validation.

Sex differences in repair rates and outcomes of patients with ruptured abdominal aortic aneurysm.

BACKGROUND: Data are conflicting on sex differences in ruptured abdominal aortic aneurysm (rAAA) repair rates and outcomes have rarely been addressed. The aim of this study was to investigate differences in the management and outcome of rAAA in men and women, and to describe time trends over a 15-year interval. METHODS: Data on patients with rAAA were extracted from the Swedish National Patient Registry and the Cause of Death Registry for the interval 2001-2015. The study included patients with rAAA whether or not they were admitted to any hospital in Sweden. A propensity score-matched model was used to determine sex differences in repair type and outcome after rupture. Time trends for rAAA events and mortality were investigated. RESULTS: Some 10 724 patients were identified. A higher percentage of men were admitted to hospital (79·8 versus 77·5 per cent; P = 0·011). Of those admitted, a higher percentage of men than women were treated (56·6 versus 40·4 per cent, P < 0·001). Women were less likely to be treated when diagnosed with rAAA (average treatment effect (ATE) in the model -0·080, 95 per cent c.i. -0·106 to -0·055; P < 0·001). Thirty-day mortality was also higher in women (ATE 0·094, 0·053 to 0·135; P < 0·001); this effect persisted to 1 year (ATE 0·095, 0·052 to 0·137; P < 0·001). Time trends indicated a decrease in rAAA incidence, mostly owing to a decrease among men. CONCLUSION: In this study, fewer women with rAAA received surgery and 30-day mortality was higher than in men. There was an overall decrease in rAAA incidence, principally in men.

ANTECEDENTES: Los datos sobre las diferencias de sexo en las tasas de reparación del aneurisma de la aorta abdominal roto (ruptured abdominal aortic aneurysm, rAAA) son contradictorios y existe poca información de los resultados. El objetivo de este estudio fue investigar las diferencias en el tratamiento y resultados en varones y mujeres con rAAA y describir las tendencias a lo largo del tiempo durante un periodo de 15 años. MÉTODOS: Los datos de los pacientes con rAAA se obtuvieron a partir del Registro Nacional Sueco de Pacientes y del Registro de Mortalidad en el periodo 2001-2015. El estudio incluye pacientes con rAAA, tanto si fueron ingresados o no en cualquier hospital de Suecia. Se utilizó un modelo de emparejamiento por puntaje de propensión para determinar las diferencias de sexo en el tipo de reparación y los resultados tras la rotura del aneurisma. Se describen las tendencias temporales para los eventos de rAAA y de mortalidad. RESULTADOS: Se identificaron un total de 10.724 pacientes. Un elevado porcentaje de pacientes varones fueron ingresados en el hospital (79,8% versus 77,5%, P < 0,001). De aquellos que ingresaron, un mayor porcentaje de varones fueron tratados (56,6%, versus 40,4% P < 0,001) en comparación con las mujeres. Las mujeres tuvieron menos probabilidades de ser tratadas cuando se les diagnosticó de un rAAA, con un efecto medio del tratamiento (average treatment effect, ATE) en el modelo de -0,08 (i.c. del 95% -0,106 a -0,055, P < 0,01). La mortalidad a los 30 días fue también más elevada en las mujeres, ATE 0,094 (i.c. del 95% 0,053-0,135, P < 0,001) que persistió hasta un año, ATE 0,095 (i.c. del 95% 0,052-0,137, P < 0,001). Las tendencias temporales indicaron una disminución en la incidencia de rAAA, a causa principalmente de una disminución en los varones. CONCLUSIÓN: En este estudio, el número de mujeres con rotura de AAA operadas fue menor que en los varones, pero la mortalidad a los 30 días fue mayor en las mujeres. Hubo una disminución global en la incidencia de rAAA, principalmente en los varones.

Adherence to oxygen saturation targets increased in preterm infants when a higher target range and tighter alarm limits were introduced.

AIM: European consensus guidelines published in May 2013 recommended a target peripheral capillary oxygen saturation (SpO2 ) range of 90-95% for preterm infants. These were incorporated into guidelines at the Karolinska University Hospital, Sweden, in November 2013. This study compared clinical practice before and after those local guidelines. METHODS: We included infants who were born between 23 + 0 and 30 + 6 weeks from January 1, 2013 to December, 31 2015 and received intensive care in two Karolinska units. The lower saturation target of 88-92% and alarm limits of 85-95% used before November 2013 were compared to the new higher saturation target of 90-95% and alarm limits of 89-96%. RESULTS: Data from 399 infants were analysed. The mean SpO2 was 92.4% with the higher target (n = 301) and 91.1% with the lower target (n = 98). Using the higher instead of lower target meant that the SpO2 was within the prescribed target range more frequently (51% versus 30%) and the proportion of time with SpO2 >95% was increased by 9% (95% confidence interval 7-11%, p < 0.001). CONCLUSION: The higher saturation target and tighter alarm limits led to higher mean oxygen saturation, increased adherence to the target and increased time with hyperoxaemia.

Impact of comorbidity on disease characteristics, treatment intent and outcome in diffuse large B-cell lymphoma: a Swedish lymphoma register study.

BACKGROUND: Comorbidity impacts overall survival amongst patients with diffuse large B-cell lymphoma (DLBCL). However, associations of comorbidity with lymphoma characteristics, treatment selection and lymphoma-specific mortality are less well known. OBJECTIVE: To examine the impact of comorbidity on DLBCL characteristics, treatment intent and cause of death. METHODS: We identified 3905 adult patients diagnosed with DLBCL 2007-2013 through the Swedish Lymphoma Register. We assessed comorbid disease history according to the Charlson comorbidity index (CCI). Comorbidity data and causes of death were collected through register linkage. Associations were estimated using multinomial regression and flexible parametric survival models. RESULTS: Overall, 45% of the patients (n = 1737) had a history of at least one comorbidity at DLBCL diagnosis (cardiovascular disease, diabetes and solid cancer were most frequent), and 997 (26%) had a CCI score of ≥2. The relative probability of presenting with poor performance status (PS > 2) was higher amongst comorbid patients [Relative Risk Ratio (RRR)PS>2 : 2.02, 95% CI: 1.63-2.51]. Comorbid patients had a substantially lower relative probability of receiving curative treatment (RRR: 0.48, 95% CI: 0.38-0.61). Amongst all patients, CCI ≥ 1 was associated with a significantly increased risk of all-cause and lymphoma-specific death after adjustments. Amongst patients selected for curative treatment, comorbidity was associated with an increased risk of all-cause death (HRCCI>1 : 1.54, 95% CI: 1.32-1.80), but not with lymphoma-specific death (HRCCI>1 : 1.05, 95% CI: 0.86-1.28). CONCLUSION: Comorbidity is associated with inferior DLBCL outcome, mainly due to a lower likelihood of receiving treatment with curative intent. Possibly, more comorbid DLBCL patients could be treated with curative intent if comorbid conditions were optimized in parallel.

Development of an ICU discharge instrument predicting psychological morbidity: a multinational study.

PURPOSE: To develop an instrument for use at ICU discharge for prediction of psychological problems in ICU survivors. METHODS: Multinational, prospective cohort study in ten general ICUs in secondary and tertiary care hospitals in Sweden, Denmark and the Netherlands. Adult patients with an ICU stay ≥ 12 h were eligible for inclusion. Patients in need of neurointensive care, with documented cognitive impairment, unable to communicate in the local language, without a home address or with more than one limitation of therapy were excluded. Primary outcome was psychological morbidity 3 months after ICU discharge, defined as Hospital Anxiety and Depression Scale (HADS) subscale score ≥ 11 or Post-traumatic Stress Symptoms Checklist-14 (PTSS-14) part B score > 45. RESULTS: A total of 572 patients were included and 78% of patients alive at follow-up responded to questionnaires. Twenty percent were classified as having psychological problems post-ICU. Of 18 potential risk factors, four were included in the final prediction model after multivariable logistic regression analysis: symptoms of depression [odds ratio (OR) 1.29, 95% confidence interval (CI) 1.10-1.50], traumatic memories (OR 1.44, 95% CI 1.13-1.82), lack of social support (OR 3.28, 95% CI 1.47-7.32) and age (age-dependent OR, peak risk at age 49-65 years). The area under the receiver operating characteristics curve (AUC) for the instrument was 0.76 (95% CI 0.70-0.81). CONCLUSIONS: We developed an instrument to predict individual patients' risk for psychological problems 3 months post-ICU, http://www.imm.ki.se/biostatistics/calculators/psychmorb/ . The instrument can be used for triage of patients for psychological ICU follow-up. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov, NCT02679157.

Quantitative chromogenic immunohistochemical image analysis in cellprofiler software.

Visual grading of chromogenically stained immunohistochemical (IHC) samples is subjective, time consuming, and predisposed to considerable inter- and intra-observer variations. The open-source digital analysis software, CellProfiler has been extensively used for fluorescently stained cells/tissues; however, chromogenic IHC staining is routinely used in both pathological and research diagnostics. The current investigation aimed to compare CellProfiler quantitative chromogenic IHC analyses against the gold standard manual counting. Oral mucosal biopsies from patients with chronic graft-versus-host disease were stained for CD4. Digitized images were manually counted and subjected to image analysis in CellProfiler. Inter-observer and inter-platform agreements were assessed by scatterplots with linear regression and Bland-Altman plots. Validation comparisons between the manual counters demonstrated strong intra-observer concordance (r2 = 0.979), particularly when cell numbers were less than 100. Scatterplots and Bland-Altman plots demonstrated strong agreement between the manual counters and CellProfiler, with the number of positively stained cells robustly correlating (r2 = 0.938). Furthermore, CellProfiler allowed the determination of multiple variables simultaneously, such as area stained and masking to remove any nonstained tissue and white gaps, which also demonstrated reliable agreement (r2 = >0.9). CellProfiler demonstrated versatility with the ability to assess large numbers of images and allowed additional parameters to be quantified. CellProfiler allowed rapid high processing capacity of chromogenically stained chronic inflammatory tissue that was reliable, accurate, and reproducible and highlights potential applications in research diagnostics.

Restorative surgery after colectomy for ulcerative colitis in England and Sweden: observations from a comparison of nationwide cohorts.

AIM: A longstanding disparity exists between the approaches to restorative surgery after colectomy for patients with ulcerative colitis (UC) in England and Sweden. This study aims to compare rates of colectomy and restorative surgery in comparable national cohorts. METHOD: The English Hospital Episode Statistics (HES) and Swedish National Patient Register (NPR) were interrogated between 2002 and April 2012. Patients with two diagnostic episodes for UC (age ≥ 15 years) were included. Patients were excluded if they had an episode of inflammatory bowel disease or colectomy before 2002. The cumulative incidences of colectomy and restorative surgery were calculated using the Kaplan-Meier method. RESULTS: A total of 98 691 patients were included in the study, 76 129 in England and 22 562 in Sweden. The 5-year cumulative incidence of all restorative surgery after colectomy in England was 33% vs 46% in Sweden (P-value < 0.001). Of the patients undergoing restorative surgery, 92.3% of English patients had a pouch vs 38.8% in Sweden and 7.7% vs 59.1% respectively had an ileorectal anastomosis (IRA). The 5-year cumulative incidence of colectomy in this study cohort was 13% in England and 6% in Sweden (P-value < 0.001). CONCLUSION: Following colectomy for UC only one-third of English patients and half of Swedish patients underwent restorative surgery. In England nearly all these patients underwent pouches, in Sweden a less significant majority underwent IRAs. It is surprising to demonstrate this discrepancy in a comparable cohort of patients from similar healthcare systems. The causes and consequences of this international variation in management are not fully understood and require further investigation.

Colectomy prior to diagnosis of primary sclerosing cholangitis is associated with improved prognosis in a nationwide cohort study of 2594 PSC-IBD patients.

BACKGROUND: Despite the close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), the association between colectomy and the prognosis of PSC remains controversial. AIM: To explore whether colectomy prior to PSC-diagnosis is associated with transplant-free survival. METHODS: A nationwide cohort study in Sweden including all patients aged 18 to 69 years in whom both PSC and IBD was diagnosed between 1987 and 2014 was undertaken. Each patient was followed from date of both PSC and IBD diagnoses until liver transplantation or death, or 31 December 2014. Patients with colon in situ, and colectomy prior to PSC-diagnosis were compared. Survival analyses were performed using the Kaplan-Meier method and multivariable Cox regression models. RESULTS: Of the 2594 PSC-IBD patients, 205 patients were treated with colectomy before PSC-diagnosis. During follow-up, liver transplantations were performed in 327 patients and 509 died. The risk of liver transplantation or death was lower in patients treated with colectomy prior to PSC-diagnosis (HR 0.71, 95% CI 0.53-0.95) than in patients with colon in situ. Male gender, longer time between IBD and PSC-diagnosis and older age were all associated with an increased risk of liver transplantation or death. Colectomy after PSC-diagnosis was however not associated with an increased risk of liver transplantation or death during long-term follow-up. CONCLUSIONS: In PSC-IBD patients, colectomy prior to PSC-diagnosis is associated with a decreased risk of liver transplantation or death.

Fitness adjusted racial disparities in central adiposity among women in the USA using quantile regression.

OBJECTIVE: This study comprehensively explores racial/ethnic disparities in waist circumference (WC) after adjusting for cardiorespiratory fitness (CRF), among both adult and adolescent women, across WC percentiles. METHODS: Analysis was conducted using data from the 1999 to 2004 National Health and Nutrition Examination Survey. Female participants (n = 3,977) aged 12-49 years with complete data on CRF, height, weight and WC were included. Quantile regression models, stratified by age groups (12-15, 16-19 and 20-49 years), were used to assess the association between WC and race/ethnicity adjusting for CRF, height and age across WC percentiles (10th, 25th, 50th, 75th, 90th and 95th). RESULTS: For non-Hispanic (NH) Black, in both the 16-19 and 20-49 years age groups, estimated WC was significantly greater than for NH White across percentiles above the median with estimates ranging from 5.2 to 11.5 cm. For Mexican Americans, in all age groups, estimated WC tended to be significantly greater than for NH White particularly for middle percentiles (50th and 75th) with point estimates ranging from 1.9 to 8.4 cm. CONCLUSIONS: Significant disparities in WC between NH Black and Mexican women, as compared to NH White, remain even after adjustment for CRF. The magnitude of the disparities associated with race/ethnicity differs across WC percentiles and age groups.

Age at adiposity rebound and body mass index trajectory from early childhood to adolescence; differences by breastfeeding and maternal immigration background.

OBJECTIVE: This paper aims to assess association between breastfeeding and maternal immigration background and body mass index development trajectories from age 2 to 16 years. METHODS: A cohort of children born in Stockholm during 1994 to 1996 was followed from age 2 to 16 years with repeated measurement of height and weight at eight time points (n = 2278). Children were categorized into groups by breastfeeding status during the first 6 months of life and maternal immigration background. Body mass index (BMI) trajectories and age at adiposity rebound were estimated using mixed-effects linear models. RESULTS: Body mass index trajectories were different by breastfeeding and maternal immigration status (P-value < 0.0001). Compared with exclusively breastfed counterparts, never/short breastfed children of Swedish mothers had a higher BMI trajectory, whereas never/short breastfed children of immigrant mothers followed a lower BMI trajectory. Ages at adiposity rebound were earlier for higher BMI trajectories regardless of maternal immigration background. CONCLUSION: Differences in BMI trajectories between offspring of immigrant and of Swedish mothers suggest a lack of beneficial association between breastfeeding and long-term BMI development among children of immigrant mothers. Given the relation between long-term BMI development and risk of overweight/obesity, these differences challenge the notion that exclusive breastfeeding is always beneficial for children's BMI development and subsequent risk of overweight/obesity.

Extracorporeal membrane oxygenation improves coagulopathy in an experimental traumatic hemorrhagic model.

PURPOSE: Hemorrhage is the most common cause of preventable death after trauma. Coagulopathy plays a central role in uncontrolled bleeding and is caused by multiple factors. Extracorporeal Membrane Oxygenation (ECMO) is an established treatment for patients with respiratory failure and has in recent years also been used in severely injured trauma patients with cardiopulmonary failure and coexisting bleeding shock. The aim of this study was to evaluate the effect of ECMO on hypothermia, acidosis, and coagulopathy in a traumatic hemorrhagic rabbit model. METHODS: After anesthesia and tracheostomy, ten New Zealand White rabbits sustained laparotomy, bilateral femur fractures and were hemorrhaged 45% of their estimated blood volume. After 90 min of hemorrhagic shock they were resuscitated with a standard transfusion protocol together with venoarterial ECMO (n = 5) or with a standard transfusion protocol only (n = 5) for 60 min. No systemic heparin was administered. RESULTS: ECMO during 60 min of resuscitation significantly increased heart rate (p = 0.01), mean arterial pressure (p = 0.01), body temperature (p = 0.01) and improved the metabolic acidosis, pH (p = 0.01), and lactate (p = 0.01). ECMO also improved the coagulation capacity measured in vitro by Rotational Thromboelastometry with a significant decrease in clot formation time (p < 0.01). This finding was confirmed in vivo with a significant reduction in the animals' ear bleeding time (p < 0.01) and cuticle bleeding time (p < 0.01); 5/5 animals survived in the ECMO group and 3/5 animals survived in the control group. CONCLUSIONS: Heparin-free ECMO stabilizes circulation, improves coagulation, and may impact short-time survival, during the first 60 min, in an experimental traumatic model with severe hemorrhagic shock.

Cohort study of growth patterns by gestational age in preterm infants developing morbidity.

OBJECTIVES: To examine differences in growth patterns in preterm infants developing major morbidities including retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC) and intraventricular haemorrhage (IVH). STUDY DESIGN: Cohort study of 2521 infants born at a gestational age (GA) of 23-30 weeks from 11 level III neonatal intensive care units in USA and Canada, and 3 Swedish population-based cohorts. OUTCOMES: Birth weight and postnatal weight gain were examined relative to birth GA and ROP, BPD, NEC and IVH development. RESULTS: Among infants with a birth GA of 25-30 weeks, birth weight SD score and postnatal weight were lower in those developing ROP and BPD. Infants developing ROP showed lower growth rates during postnatal weeks 7-9 in the 23-24 weeks GA group, during weeks 4-6 in the 25-26 weeks GA group and during weeks 1-5 in the 27-30 weeks GA group. Infants with BPD born at 27-30 weeks GA showed lower growth rates during postnatal weeks 3-5. Infants with NEC had lower growth rates after postnatal week 6 in all GA groups, with no significant differences in birth weight SD score. IVH was not associated with prenatal or postnatal growth. CONCLUSIONS: In this cohort study of extremely preterm infants, we found that the postnatal growth pattern was associated with morbidities such as ROP, BPD and NEC as well as with gestational age at birth.

Subthreshold and threshold attention deficit hyperactivity disorder symptoms in childhood: psychosocial outcomes in adolescence in boys and girls.

OBJECTIVE: To examine the association between different levels of childhood attention deficit hyperactivity disorder (ADHD) symptoms and sex differences in psychosocial outcomes during adolescence. METHOD: Swedish children (n = 4635) were screened for neuropsychiatric symptoms at age 9 or 12. ADHD symptoms were divided into three levels: screen-negative, screen-intermediate, and screen-positive. At follow-up (age 15), parents and teenagers filled out questionnaires regarding (i) hyperactivity/inattention, (ii) peer problems, (iii) school problems, (iv) internalizing problems, (v) antisocial behaviour, (vi) alcohol misuse, and (vii) drug misuse. All outcomes were controlled for symptoms of diagnostic categories other than ADHD. RESULTS: Increasing levels of ADHD symptoms in childhood were associated with higher proportions of adolescents who displayed negative psychosocial outcomes. More girls than boys reported internalizing problems (all levels) and risky drug use (screen-intermediate and screen-positive only). More boys reported antisocial behaviour at the screen-negative and screen-intermediate levels, but at the screen-positive level, similar proportions of girls and boys displayed antisocial behaviour. CONCLUSION: The findings support the view that ADHD symptoms, as well as their negative outcomes, are dimensionally distributed in the population and that adolescent girls and boys display different risk profiles. The findings confirm that ADHD symptoms are associated with higher risk of drug misuse in girls.

Pain rather than induced emotions and ICU sound increases skin conductance variability in healthy volunteers.

BACKGROUND: Assessing pain in critically ill patients is difficult. Skin conductance variability (SCV), induced by the sympathetic response to pain, has been suggested as a method to identify pain in poorly communicating patients. However, SCV, a derivate of conventional skin conductance, could potentially also be sensitive to emotional stress. The purpose of the study was to investigate if pain and emotional stress can be distinguished with SCV. METHODS: In a series of twelve 1-min sessions with SCV recording, 18 healthy volunteers were exposed to standardized electric pain stimulation during blocks of positive, negative, or neutral emotion, induced with pictures from the International Affective Picture System (IAPS). Additionally, authentic intensive care unit (ICU) sound was included in half of the sessions. All possible combinations of pain and sound occurred in each block of emotion, and blocks were presented in randomized order. RESULTS: Pain stimulation resulted in increases in the number of skin conductance fluctuations (NSCF) in all but one participant. During pain-free baseline sessions, the median NSCF was 0.068 (interquartile range 0.013-0.089) and during pain stimulation median NSCF increased to 0.225 (interquartile range 0.146-0.3175). Only small increases in NSCF were found during negative emotions. Pain, assessed with the numeric rating scale, during the sessions with pain stimulation was not altered significantly by other ongoing sensory input. CONCLUSION: In healthy volunteers, NSCF appears to reflect ongoing autonomous reactions mainly to pain and to a lesser extent, reactions to emotion induced with IAPS pictures or ICU sound.

Diagnosis and classification of idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of diseases, collectively termed myositis, sharing symptoms of muscle weakness, fatigue and inflammation. Other organs are frequently involved, supporting the notion that these are systemic inflammatory diseases. The IIMs can be subgrouped into dermatomyositis, polymyositis and inclusion body myositis. The myositis-specific autoantibodies (MSAs) identify other and often more distinct clinical phenotypes, such as the antisynthetase syndrome with antisynthetase autoantibodies and frequent interstitial lung disease and anti-SRP and anti-HMGCR autoantibodies that identify necrotizing myopathy. The MSAs are important both to support myositis diagnosis and to identify subgroups with different patterns of extramuscular organ involvement such as interstitial lung disease. Another cornerstone in the diagnostic procedure is muscle biopsy to identify inflammation and to exclude noninflammatory myopathies. Treatment effect and prognosis vary by subgroup. To develop new and better therapies, validated classification criteria that identify distinct subgroups of myositis are critical. The lack of such criteria was the main rationale for the development of new classification criteria for IIMs, which are summarized in this review; the historical background regarding previous diagnostic and classification criteria is also reviewed. As the IIMs are rare diseases with a prevalence of 10 in 100 000 individuals, an international collaboration was essential, as was the interdisciplinary effort including experts in adult and paediatric rheumatology, neurology, dermatology and epidemiology. The new criteria have been developed based on data from more than 1500 patients from 47 centres worldwide and are based on clinically easily available variables.