Unsupervised Clustering of Membranoproliferative Glomerulonephritis and C3 Glomerulopathy Patients Discovers Distinct Patient Groups unlike the Current Classification.

INTRODUCTION: Membranoproliferative glomerulonephritis is currently divided into immunoglobulin-mediated glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G); however, the patients often overlap with histology, complement, clinical and prognostic factors. Our aim was to investigate if an unsupervised clustering method finds different patient groups in 44 IC-MPGN/C3G patients using only histological and clinical data available in everyday clinical work. METHODS: Primary IC-MPGN/C3G adult patients were included whose diagnostic (baseline) native biopsy was obtained in 2006-2017. The biopsies were reassessed and the clinical data at baseline and during follow-up were obtained from the medical records. There were 39 baseline histological and clinical variables included in the unsupervised clustering. Follow-up information was combined with the clustering results. RESULTS: The clustering resulted in two clusters (n = 24 and n = 20 patients for clusters 1-2, respectively), where cluster 1 had a significantly higher baseline plasma creatinine (mean 213 vs. 104, respectively, p value <0.001) and a lower baseline eGFR than cluster 2 (mean 37 vs. 70, respectively, p value <0.001). Regarding histology, chronic changes such as lobulated glomeruli, mesangial matrix expansion, and glomeruli double contours were more prevalent in cluster 1 (p value <0.001). Biopsy morphology was more often crescentic and membranoproliferative in cluster 1 (p value <0.001). Although the differences were insignificant, cluster 1 patients were in dialysis in the last follow-up or had a progressive disease more often than cluster 2 patients (21% vs. 5%, 38% vs. 10%). CONCLUSIONS: Our results indicate that these patients share greater similarity than the current classification IC-MPGN versus C3G indicates.

Very Low Frequency of Pathological Findings in One-year Protocol Biopsies of Uneventful Standard Risk Kidney Transplant Recipients: Results From the Nordic Protocol Biopsy Study.

Background: The clinical significance of kidney transplant protocol biopsies has been debated. We studied the frequency of borderline changes and T cell-mediated rejection (TCMR) in 1-y protocol biopsies in standard risk kidney transplant recipients. Methods: Consecutive non-HLA-sensitized recipients of kidney transplants between 2006 and 2017, who underwent a protocol biopsy at 1 y in 2 national transplant centers were studied retrospectively (N = 1546). Donor-specific HLA antibodies (DSAs), graft function (plasma creatinine), and proteinuria were measured at the time of 1-y protocol biopsy. The occurrence of subclinical acute TCMR (i2t2v0 or higher) or borderline changes suspicious of TCMR (i1t1v0 or higher) in the protocol biopsy was studied, together with frequency of findings causing changes in the composite score iBox. Results: Subclinical acute TCMR was detected in 30 of 1546 (1.9%) of the protocol biopsies, and borderline or TCMR in 179 of 1546 (12%). Among patients with no history of acute rejection, and no proteinuria or DSA, TCMR was detected in only 1 of 974 (0.1%) and borderline or TCMR in only 48 of 974 (4.9%) patients at 1 y. In the absence of proteinuria (<30 mg/g, or equivalent as measured with a negative dipstick proteinuria) or DSA, or history of acute rejection, only 50 of 974 (5.1%) biopsies showed any lesions significant for the iBox score. Conclusions: The likelihood of pathological findings in 1-y protocol biopsies in non-HLA-sensitized patients without previous immunological events is low. Clinical usefulness of protocol biopsies seems limited in these patients.

Expected impact of MRI-targeted biopsy interreader variability among uropathologists on ProScreen prostate cancer screening trial: a pre-trial validation study.

PURPOSE: Prostate cancer (PCa) histology, particularly the Gleason score, is an independent prognostic predictor in PCa. Little is known about the inter-reader variability in grading of targeted prostate biopsy based on magnetic resonance imaging (MRI). The aim of this study was to assess inter-reader variability in Gleason grading of MRI-targeted biopsy among uropathologists and its potential impact on a population-based randomized PCa screening trial (ProScreen). METHODS: From June 2014 to May 2018, 100 men with clinically suspected PCa were retrospectively selected. All men underwent prostate MRI and 86 underwent targeted prostate of the prostate. Six pathologists individually reviewed the pathology slides of the prostate biopsies. The five-tier ISUP (The International Society of Urological Pathology) grade grouping (GG) system was used. Fleiss' weighted kappa (κ) and Model-based kappa for associations were computed to estimate the combined agreement between individual pathologists. RESULTS: GG reporting of targeted prostate was highly consistent among the trial pathologists. Inter-reader agreement for cancer (GG1-5) vs. benign was excellent (Model-based kappa 0.90, Fleiss' kappa κ = 0.90) and for clinically significant prostate cancer (csPCa) (GG2-5 vs. GG0 vs. GG1), it was good (Model-based kappa 0.70, Fleiss' kappa κ 0.67). CONCLUSIONS: Inter-reader agreement in grading of MRI-targeted biopsy was good to excellent, while it was fair to moderate for MRI in the same cohort, as previously shown. Importantly, there was wide consensus by pathologists in assigning the contemporary GG on MRI-targeted biopsy suggesting high reproducibility of pathology reporting in the ProScreen trial.

The effect of a single closed-circuit rebreather decompression dive in extremely cold water to cardiac function.

PURPOSE: Dive-induced cardiac and hemodynamic changes are caused by various mechanisms, and they are aggravated by cold water. Therefore, aging divers with pre-existing cardiovascular conditions may be at risk of acute myocardial infarction, heart failure, or arrhythmias while diving. The aim of this study was to assess the effect of a single decompression CCR dive in arctic cold water on cardiac function in Finnish technical divers. METHODS: Thirty-nine divers performed one identical 45 mfw CCR dive in 2-4 °C water. Hydration and cardiac functions were assessed before and after the dive. Detection of venous gas embolization was performed within 120 min after the dive. RESULTS: The divers were affected by both cold-water-induced hemodynamic changes and immersion-related fluid loss. Both systolic and diastolic functions were impaired after the dive although the changes in cardiac functions were subtle. Venous inert gas bubbles were detected in all divers except for one. Venous gas embolism did not affect systolic or diastolic function. CONCLUSION: A single trimix CCR dive in arctic cold water seemed to debilitate both systolic and diastolic function. Although the changes were subtle, they appeared parallel over several parameters. This indicates a real post-dive deterioration in cardiac function instead of only volume-dependent changes. These changes are without a clinical significance in healthy divers. However, in a population with pre-existing or underlying heart problems, such changes may provoke symptomatic problems during or after the dive.

Better late than never: Diagnosis of recurrent atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) comprising microangiopathic hemolytic anemia, consumptive thrombocytopenia, and end-organ damage. Risk of end-stage renal disease is increased as HUS usually manifests in native and transplanted kidneys. In transplants, while de novo disease can be seen, recurrent disease is more common. The etiology is variable, being either primary or secondary. aHUS often constitutes a diagnostic and therapeutic challenge, which may lead to a considerable delay in the diagnosis and treatment. During the last decades, great progress has been made in understanding the mechanisms and therapeutic options of this devastating condition. We present a case of a 50-year-old female who received her first kidney transplant from her mother at the age of 9 years. She experienced recurrent losses of transplants, and only after the loss of her fourth transplant did the diagnosis of aHUS become evident.

Elevations of Extracellular Vesicles and Inflammatory Biomarkers in Closed Circuit SCUBA Divers.

Blood-borne extracellular vesicles and inflammatory mediators were evaluated in divers using a closed circuit rebreathing apparatus and custom-mixed gases to diminish some diving risks. "Deep" divers (n = 8) dove once to mean (±SD) 102.5 ± 1.2 m of sea water (msw) for 167.3 ± 11.5 min. "Shallow" divers (n = 6) dove 3 times on day 1, and then repetitively over 7 days to 16.4 ± 3.7 msw, for 49.9 ± 11.9 min. There were statistically significant elevations of microparticles (MPs) in deep divers (day 1) and shallow divers at day 7 that expressed proteins specific to microglia, neutrophils, platelets, and endothelial cells, as well as thrombospondin (TSP)-1 and filamentous (F-) actin. Intra-MP IL-1ß increased by 7.5-fold (p < 0.001) after day 1 and 41-fold (p = 0.003) at day 7. Intra-MP nitric oxide synthase-2 (NOS2) increased 17-fold (p < 0.001) after day 1 and 19-fold (p = 0.002) at day 7. Plasma gelsolin (pGSN) levels decreased by 73% (p < 0.001) in deep divers (day 1) and 37% in shallow divers by day 7. Plasma samples containing exosomes and other lipophilic particles increased from 186% to 490% among the divers but contained no IL-1ß or NOS2. We conclude that diving triggers inflammatory events, even when controlling for hyperoxia, and many are not proportional to the depth of diving.

Diagnostic and Prognostic Comparison of Immune-Complex-Mediated Membranoproliferative Glomerulonephritis and C3 Glomerulopathy.

Membranoproliferative glomerulonephritis (MPGN) is subdivided into immune-complex-mediated glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G). Classically, MPGN has a membranoproliferative-type pattern, but other morphologies have also been described depending on the time course and phase of the disease. Our aim was to explore whether the two diseases are truly different, or merely represent the same disease process. All 60 eligible adult MPGN patients diagnosed between 2006 and 2017 in the Helsinki University Hospital district, Finland, were reviewed retrospectively and asked for a follow-up outpatient visit for extensive laboratory analyses. Thirty-seven (62%) had IC-MPGN and 23 (38%) C3G (including one patient with dense deposit disease, DDD). EGFR was below normal (≤60 mL/min/1.73 m2) in 67% of the entire study population, 58% had nephrotic range proteinuria, and a significant proportion had paraproteins in their serum or urine. A classical MPGN-type pattern was seen in only 34% of the whole study population and histological features were similarly distributed. Treatments at baseline or during follow-up did not differ between the groups, nor were there significant differences observed in complement activity or component levels at the follow-up visit. The risk of end-stage kidney disease and survival probability were similar in the groups. IC-MPGN and C3G have surprisingly similar characteristics, kidney and overall survival, which suggests that the current subdivision of MPGN does not add substantial clinical value to the assessment of renal prognosis. The high proportion of paraproteins in patient sera or in urine suggests their involvement in disease development.

Delayed treatment for decompression illness: factors associated with long treatment delays and treatment outcome.

INTRODUCTION: Effectiveness of delayed hyperbaric oxygen treatment (HBOT) for decompression illness (DCI) and factors affecting treatment delays have not been studied in large groups of patients. METHODS: This retrospective study included 546 DCI patients treated in Finland in the years 1999-2018 and investigated factors associated with recompression delay and outcome. Treatment outcome was defined as fully recovered or presence of residual symptoms on completion of HBOT. The symptoms, use of first aid oxygen, number of recompression treatments needed and characteristics of the study cohort were also addressed. RESULTS: Delayed HBOT (> 48 h) remained effective with final outcomes similar to those treated within 48 h. Cardio-pulmonary symptoms were associated with a shorter treatment delay (median 15 h vs 28 h without cardiopulmonary symptoms, P < 0.001), whereas mild sensory symptoms were associated with a longer delay (48 vs 24 h, P < 0.001). A shorter delay was also associated with only one required HBOT treatment (median 24 h vs 34 h for those requiring multiple recompressions) ( P = 0.002). Tinnitus and hearing impairment were associated with a higher proportion of incomplete recoveries (78 and 73% respectively, P < 0.001), whereas a smaller proportion of cases with tingling/itching (15%, P = 0.03), nausea (27%, P = 0.03), motor weakness (33%, P = 0.05) and visual disturbances (36%, P = 0.04) exhibited residual symptoms. Patients with severe symptoms had a significantly shorter delay than those with mild symptoms (median 24 h vs 36 h respectively, P < 0.001), and a lower incidence of complete recovery. CONCLUSIONS: Delayed HBOT remains an effective and useful intervention. A shorter delay to recompression is associated with fewer recompressions required to achieve recovery or recovery plateau.

Decompression illness in Finnish technical divers: a follow-up study on incidence and self-treatment.

INTRODUCTION: Technical diving is increasing in popularity in Finland, and therefore the number of decompression illness (DCI) cases is also increasing among technical divers. Although hyperbaric oxygen treatment (HBOT) remains the standard of care, there are anecdotal reports of technical divers treating mild DCI symptoms themselves and not seeking a medical evaluation and possible recompression therapy. This study aimed to make an epidemiologic inventory of technical diving-related DCI symptoms, to establish the incidence of self-treatment and to determine the apparent effectiveness of different treatment methods. METHODS: A one-year prospective survey with online questionnaires was conducted. Fifty-five experienced and highly trained Finnish technical divers answered the survey and reported their diving activity, DCI symptoms, symptom treatment, and treatment outcome. RESULTS: Of the reported 2,983 dives, 27 resulted in symptoms of DCI, which yielded an incidence of 91 per 10,000 dives in this study. All of the reported DCI symptoms were mild, and only one diver received HBOT. The most common self-treatments were oral hydration and rest. First aid oxygen (FAO2) was used in 21% of cases. Eventually, none of the divers had residual symptoms. CONCLUSIONS: The incidence of self-treated DCI cases was 27 times higher than that of HBO-treated DCI cases. There is a need to improve divers' awareness of the importance of FAO2 and other recommended first aid procedures and to encourage divers to seek medical attention in case of suspected DCI.

Vascular Occlusion in Kidney Biopsy Is Characteristic of Clinically Manifesting Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) can sometimes manifest only histologically. Our aim was to retrospectively compare biopsy-proven adult TMA patients showing only histological (h-TMA) or both histological and clinical (c-TMA) TMA in 2006-2017. All native kidney biopsies with TMA were included. Biopsies were re-evaluated by light and electron microscopy, and immunofluorescence. Clinical characteristics, laboratory variables, and treatments were recorded from the electronic medical database. Patients were categorized into h-TMA and c-TMA and these groups were compared. In total, 30 biopsy-proven cases among 7943 kidney biopsies were identified and, of these, 15 had h-TMA and 15 c-TMA. Mean follow-up was 6.3 y, and 73.3% had secondary hemolytic uremic syndrome (HUS) and the rest were atypical HUS. Patient characteristics, treatments, and kidney, and patient survival in the groups were similar. Statistically significant differences were found in histological variables. Vascular myxoid swelling and vascular onion-skinning were almost exclusively detected in c-TMA and, thus, vascular occlusive changes indicate clinically apparent rather than merely histological TMA. In addition, regardless of clinical presentation, kidney and patient survival times were similar in the patient groups highlighting the importance of a kidney biopsy in the case of any kidney-related symptoms.

Inner ear barotrauma and inner ear decompression sickness: a systematic review on differential diagnostics.

INTRODUCTION: Inner ear barotrauma (IEBt) and inner ear decompression sickness (IEDCS) are the two dysbaric inner ear injuries associated with diving. Both conditions manifest as cochleovestibular symptoms, causing difficulties in differential diagnosis and possibly delaying (or leading to inappropriate) treatment. METHODS: This was a systematic review of IEBt and IEDCS cases aiming to define diving and clinical variables that help differentiate these conditions. The search strategy consisted of a preliminary search, followed by a systematic search covering three databases (PubMed, Medline, Scopus). Studies were included when published in English and adequately reporting one or more IEBt or IEDCS patients in diving. Concerns regarding missing and duplicate data were minimised by contacting original authors when necessary. RESULTS: In total, 25 studies with IEBt patients (n = 183) and 18 studies with IEDCS patients (n = 397) were included. Variables most useful in differentiating between IEBt and IEDCS were dive type (free diving versus scuba diving), dive gas (compressed air versus mixed gas), dive profile (mean depth 13 versus 43 metres of seawater), symptom onset (when descending versus when ascending or surfacing), distribution of cochleovestibular symptoms (vestibular versus cochlear) and absence or presence of other DCS symptoms. Symptoms of difficult middle ear equalisation or findings consistent with middle ear barotrauma could not be reliably assessed in this context, being insufficiently reported in the IEDCS literature. CONCLUSIONS: There are multiple useful variables to help distinguish IEBt from IEDCS. Symptoms of difficult middle ear equalisation or findings consistent with middle ear barotrauma require further study as means of distinguishing IEBt and IEDCS.

Inner ear decompression sickness in Finland: a retrospective 20-year multicenter study.

Introduction: Inner ear decompression sickness (IEDCS) is a condition from which only a minority of patients recover completely, the majority ending up with mild to moderate residual symptoms. IEDCS has been reported after deep technical dives using mixed breathing gases, and moderate recreational dives with compressed air as the breathing gas. Considering this and the high proportion of technical diving in Finland, a comparison between IEDCS cases resulting from technical and recreational dives is warranted. Methods: This is a retrospective examination of IEDCS patients treated at Hyperbaric Center Medioxygen or National Hyperbaric Centre of Turku University Hospital from 1999 to 2018. Patients were included if presenting with hearing loss, tinnitus, or vertigo and excluded if presenting only with symptoms of middle ear or cerebellar involvement. Patients were divided into technical and recreational divers, based on incident dive. Results: A total of 89 (15.6%) of all DCS patients presented with IEDCS, two-thirds treated during the latter decade. The most common predisposing factors were consecutive days of diving (47.2%), multiple dives per day (53.9%), and factors related to an increase in intrathoracic pressure (27.0%). The symptoms were cochlear in 19.1% and vestibular in 93.3% of cases, symptoms being more common and severe in technical divers. Complete recovery was achieved in 64.5% of technical and 71.4% of recreational divers. Conclusion: The incidence of IEDCS in Finland is increasing, most likely due to changing diving practices. A comprehensive examination should be carried out after an incident of IEDCS in all cases, irrespective of clinical recovery.

Assessment of Alertness and Cognitive Performance of Closed Circuit Rebreather Divers With the Critical Flicker Fusion Frequency Test in Arctic Diving Conditions.

Introduction: Cold water imposes many risks to the diver. These risks include decompression illness, physical and cognitive impairment, and hypothermia. Cognitive impairment can be estimated using a critical flicker fusion frequency (CFFF) test, but this method has only been used in a few studies conducted in an open water environment. We studied the effect of the cold and a helium-containing mixed breathing gas on the cognition of closed circuit rebreather (CCR) divers. Materials and Methods: Twenty-three divers performed an identical dive with controlled trimix gas with a CCR device in an ice-covered quarry. They assessed their thermal comfort at four time points during the dive. In addition, their skin temperature was measured at 5-min intervals throughout the dive. The divers performed the CFFF test before the dive, at target depth, and after the dive. Results: A statistically significant increase of 111.7% in CFFF values was recorded during the dive compared to the pre-dive values (p < 0.0001). The values returned to the baseline after surfacing. There was a significant drop in the divers' skin temperature of 0.48°C every 10 min during the dive (p < 0.001). The divers' subjectively assessed thermal comfort also decreased during the dive (p = 0.01). Conclusion: Our findings showed that neither extreme cold water nor helium-containing mixed breathing gas had any influence on the general CFFF profile described in the previous studies from warmer water and where divers used other breathing gases. We hypothesize that cold-water diving and helium-containing breathing gases do not in these diving conditions cause clinically relevant cerebral impairment. Therefore, we conclude that CCR diving in these conditions is safe from the perspective of alertness and cognitive performance.

Correction: Monocyte subset redistribution from blood to kidneys in patients with Puumala virus caused hemorrhagic fever with renal syndrome.

[This corrects the article DOI: 10.1371/journal.ppat.1009400.].

Sinus barotrauma in diving.

INTRODUCTION: Sinus barotrauma is a common occurrence in diving and subaquatic medicine, potentially compromising dive safety. To gain a more thorough understanding of the condition, an in-depth investigation is justified. METHODS: This was a survey study. An anonymous, electronic questionnaire was distributed to 7,060 recipients: professional divers of the Finnish Border Guard, the Finnish Rescue Services, and the Finnish Heritage agency, as well as recreational divers registered as members of the Finnish Divers' Association reachable by email (roughly two-thirds of all members and recreational divers in Finland). Primary outcomes were self-reported prevalence, clinical characteristics, and health effects of sinus barotrauma while diving. Secondary outcomes were adjusted odds ratios (OR) for frequency of sinus barotrauma with respect to possible risk factors. RESULTS: In total, 1,881 respondents participated in the study (response rate 27%). A total of 49% of the respondents had experienced sinus barotrauma while diving and of those affected, 32% had used medications to alleviate their symptoms. The factors associated with sinus barotrauma were pollen allergies (OR 1.59; 95% CI 1.10-2.29), regular smoking (OR 2.04; 95% CI 1.07-3.91) and a high number of upper respiratory tract infections per year (≥ 3 vs. < 3 infections per year: OR 2.76; 95% CI 1.79-4.24). CONCLUSIONS: Sinus barotrauma is the second most common condition encountered in diving medicine, having affected 49% of the respondents. Possible risk factors include allergies to pollen, regular smoking, and a high number of URTIs per year.

Prolonged syncope with multifactorial pulmonary oedema related to dry apnoea training: Safety concerns in unsupervised dry static apnoea.

Many competitive breath-hold divers use dry apnoea routines to improve their tolerance to hypoxia and hypercapnia, varying the amount of prior hyperventilation and lung volume. When hyperventilating and exhaling to residual volume prior to starting a breath-hold, hypoxia is reached quickly and without too much discomfort from respiratory drive. Cerebral hypoxia with loss of consciousness (LOC) can easily result. Here, we report on a case where an unsupervised diver used a nose clip that is thought to have interfered with his resumption of breathing after LOC. Consequently, he suffered an extended period of severe hypoxia, with poor ventilation and recovery. He also held his breath on empty lungs; thus, trying to inhale created an intrathoracic sub-atmospheric pressure. Upon imaging at the hospital, severe intralobular pulmonary oedema was noted, with similarities to images presented in divers suffering from pulmonary barotrauma of descent (squeeze, immersion pulmonary oedema). Describing the physiological phenomena observed in this case highlights the risks associated with unsupervised exhalatory breath-holding after hyperventilation as a training practice in competitive freediving.

Diving Responses in Experienced Rebreather Divers: Short-Term Heart Rate Variability in Cold Water Diving.

INTRODUCTION: Technical diving is very popular in Finland throughout the year despite diving conditions being challenging, especially due to arctic water and poor visibility. Cold water, immersion, submersion, hyperoxia, as well as psychological and physiological stress, all have an effect on the autonomic nervous system (ANS). MATERIALS AND METHODS: To evaluate divers' ANS responses, short-term (5 min) heart rate variability (HRV) during dives in 2-4°C water was measured. HRV resting values were evaluated from separate measurements before and after the dives. Twenty-six experienced closed circuit rebreather (CCR) divers performed an identical 45-meter decompression dive with a non-physical task requiring concentration at the bottom depth. RESULTS: Activity of the ANS branches was evaluated with the parasympathetic (PNS) and sympathetic (SNS) indexes of the Kubios HRV Standard program. Compared to resting values, PNS activity decreased significantly on immersion with face out of water. From immersion, it increased significantly with facial immersion, just before decompression and just before surfacing. Compared to resting values, SNS activity increased significantly on immersion with face out of water. Face in water and submersion measures did not differ from the immersion measure. After these measurements, SNS activity decreased significantly over time. CONCLUSION: Our study indicates that the trigeminocardiac part of the diving reflex causes the strong initial PNS activation at the beginning of the dive but the reaction seems to decrease quickly. After this initial activation, cold seemed to be the most prominent promoter of PNS activity - not pressure. Also, our study showed a concurrent increase in both SNS and PNS branches, which has been associated with an elevated risk for arrhythmia. Therefore, we recommend a short adaptation phase at the beginning of cold-water diving before physical activity.

Manifestations and Outcome of Cardiac Sarcoidosis and Idiopathic Giant Cell Myocarditis by 25-Year Nationwide Cohorts.

Background Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) share many histopathologic and clinical features. Whether they are parts of a one-disease continuum has been discussed. Methods and Results We compared medical record data of 351 CS and 28 GCM cases diagnosed in Finland since the late 1980s and followed until February 2018 for a composite end point of cardiac death, aborted sudden death, and heart transplantation. Heart failure was the presenting manifestation in 50% versus 15% (P<0.001), and high-grade atrioventricular block in 21% versus 43% (P=0.044), of GCM and CS, respectively. At presentation, left ventricular ejection fraction was ≤50% in 81% of cases of GCM versus in 48% of CS (P=0.004). The median (interquartile range) of plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) was 5273 (2782-11309) ng/L on admission in GCM versus 859 (290-1950) ng/L in CS (P<0.001), and cardiac troponin T exceeded 50 ng/L in 17 of 19 cases of GCM versus in 48 of 239 cases of CS (P<0.001). The 5-year estimate of event-free survival was 77% (95% CI, 72%-82%) in CS versus 27% (95% CI, 10%-45%) in GCM (P<0.001). By Cox regression analysis, GCM predicted cardiac events with a hazard ratio of 5.16 (95% CI, 2.82-9.45), which, however, decreased to 1.58 (95% CI, 0.71-3.52) after inclusion of markers of myocardial injury and dysfunction in the model. Conclusions GCM differs from CS in presenting with more extensive myocardial injury and having worse long-term outcome. Yet the key determinant of prognosis appears to be the extent of myocardial injury rather than the histopathologic diagnosis.