Polyphenic risk score shows robust predictive ability for long-term future suicidality.

Suicides are preventable tragedies, if risk factors are tracked and mitigated. We had previously developed a new quantitative suicidality risk assessment instrument (Convergent Functional Information for Suicidality, CFI-S), which is in essence a simple polyphenic risk score, and deployed it in a busy urban hospital Emergency Department, in a naturalistic cohort of consecutive patients. We report a four years follow-up of that population (n = 482). Overall, the single administration of the CFI-S was significantly predictive of suicidality over the ensuing 4 years (occurrence- ROC AUC 80%, severity- Pearson correlation 0.44, imminence-Cox regression Hazard Ratio 1.33). The best predictive single phenes (phenotypic items) were feeling useless (not needed), a past history of suicidality, and social isolation. We next used machine learning approaches to enhance the predictive ability of CFI-S. We divided the population into a discovery cohort (n = 255) and testing cohort (n = 227), and developed a deep neural network algorithm that showed increased accuracy for predicting risk of future suicidality (increasing the ROC AUC from 80 to 90%), as well as a similarity network classifier for visualizing patient's risk. We propose that the widespread use of CFI-S for screening purposes, with or without machine learning enhancements, can boost suicidality prevention efforts. This study also identified as top risk factors for suicidality addressable social determinants. Supplementary Information: The online version contains supplementary material available at 10.1007/s44192-022-00016-z.

Ruling out pulmonary embolism across different subgroups of patients and healthcare settings: protocol for a systematic review and individual patient data meta-analysis (IPDMA).

BACKGROUND: Diagnosing pulmonary embolism in suspected patients is notoriously difficult as signs and symptoms are non-specific. Different diagnostic strategies have been developed, usually combining clinical probability assessment with D-dimer testing. However, their predictive performance differs across different healthcare settings, patient subgroups, and clinical presentation, which are currently not accounted for in the available diagnostic approaches. METHODS: This is a protocol for a large diagnostic individual patient data meta-analysis (IPDMA) of currently available diagnostic studies in the field of pulmonary embolism. We searched MEDLINE (search date January 1, 1995, till August 25, 2016) to retrieve all primary diagnostic studies that had evaluated diagnostic strategies for pulmonary embolism. Two authors independently screened titles, abstracts, and subsequently full-text articles for eligibility from 3145 individual studies. A total of 40 studies were deemed eligible for inclusion into our IPDMA set, and principal investigators from these studies were invited to participate in a meeting at the 2017 conference from the International Society on Thrombosis and Haemostasis. All authors agreed on data sharing and participation into this project. The process of data collection of available datasets as well as potential identification of additional new datasets based upon personal contacts and an updated search will be finalized early 2018. The aim is to evaluate diagnostic strategies across three research domains: (i) the optimal diagnostic approach for different healthcare settings, (ii) influence of comorbidity on the predictive performance of each diagnostic strategy, and (iii) optimize and tailor the efficiency and safety of ruling out PE across a broad spectrum of patients with a new, patient-tailored clinical decision model that combines clinical items with quantitative D-dimer testing. DISCUSSION: This pre-planned individual patient data meta-analysis aims to contribute in resolving remaining diagnostic challenges of time-efficient diagnosis of pulmonary embolism by tailoring available diagnostic strategies for different healthcare settings and comorbidity. SYSTEMATIC REVIEW REGISTRATION: Prospero trial registration: ID 89366.

Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial.

BACKGROUND: Acute pulmonary embolism (PE) can worsen quality of life due to persistent dyspnea or exercise intolerance. OBJECTIVE: Test if tenecteplase increases the probability of a favorable composite patient-oriented outcome after submassive PE. METHODS: Normotensive patients with PE and right ventricular (RV) strain (by echocardiography or biomarkers) were enrolled from eight hospitals. All patients received low-molecular-weight heparin followed by random assignment to either a single weight-based bolus of tenecteplase or placebo, administered in a double-blinded fashion. The primary composite outcome included: (i) death, circulatory shock, intubation or major bleeding within 5 days or (ii) recurrent PE, poor functional capacity (RV dysfunction with either dyspnea at rest or exercise intolerance) or an SF36(®) Physical Component Summary (PCS) score < 30 at 90-day follow-up. RESULTS: Eighty-three patients were randomized; 40 to tenecteplase and 43 to placebo. The trial was terminated prematurely. Within 5 days, adverse outcomes occurred in three placebo-treated patients (death in one and intubation in two) and one tenecteplase-treated patient (fatal intracranial hemorrhage). At 90 days, adverse outcomes occurred in 13 unique placebo-treated patients and five unique tenecteplase-treated patients Thus, 16 (37%) placebo-treated and six (15%) tenecteplase-treated patients had at least one adverse outcome (exact two-sided P = 0.017). CONCLUSIONS: Treatment of patients with submassive pulmonary embolism with tenecteplase was associated with increased probability of a favorable composite outcome.

Autoimmune signals in non-segmental vitiligo patients are associated with distinct clinical parameters and toxic exposures.

BACKGROUND: Although non-segmental vitiligo is commonly considered an autoimmune disease, the possible differences between non-segmental vitiligo patients with and without autoimmune signals have not been clearly established. OBJECTIVE: To perform a comparison of non-segmental vitiligo patients with autoimmune signals (AIS) vs. those without autoimmune signals (NAIS) in regards to clinical characteristics and toxic/drug exposure. METHODS: 112 vitiligo patients were selected for a sex and age matched (1 : 1) case control study at an university based dermatology outpatient hospital specialized in pigmentary disorders. Medical assessment was performed by dermatologists using the modified Vitiligo European Task Force form and serological and clinical signs of autoimmunity were evaluated. RESULTS: Disease duration, age of onset, patient history of cardiovascular disease, past smoking history, use of drugs, and consummation of goitrogenic foods were all significantly increased in the AIS group using McNemar's test for matched pairs. In our conditional regression model, the simultaneous presence of disease duration, use of prescription drugs, and consummation of goitrogenic foods were the best predictors of AIS vitiligo patients. CONCLUSION: The evaluation of non-segmental vitiligo patients according to the presence vs. the absence of autoimmune signals allows us to correlate patients exhibiting autoimmune phenomenon with certain clinical characteristics, namely long disease duration, use of prescription drugs, and consumption of goitrogenic substances. In the presence of the aforementioned clinical profile, we suggest an evaluation of autoimmune signals.

D-dimer threshold increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary computerized tomographic pulmonary angiography.

BACKGROUND: Increasing the threshold to define a positive D-dimer could reduce unnecessary computed tomographic pulmonary angiography (CTPA) for a suspected pulmonary embolism (PE) but might increase rates of a missed PE and missed pneumonia, the most common non-thromboembolic diagnosis seen on CTPA. OBJECTIVE: Measure the effect of doubling the standard D-dimer threshold for 'PE unlikely' Revised Geneva (RGS) or Wells' scores on the exclusion rate, frequency and size of a missed PE and missed pneumonia. METHODS: Patients evaluated for a suspected PE with 64-channel CTPA were prospectively enrolled from emergency departments (EDs) and inpatient units of four hospitals. Pretest probability data were collected in real time and the D-dimer was measured in a central laboratory. Criterion standard was CPTA interpretation by two independent radiologists combined with clinical outcome at 30 days. RESULTS: Of 678 patients enrolled, 126 (19%) were PE+ and 93 (14%) had pneumonia. Use of either Wells' ≤ 4 or RGS ≤ 6 produced similar results. For example, with RGS ≤ 6 and standard threshold (< 500 ng mL(-1)), D-dimer was negative in 110/678 (16%), and 4/110 were PE+ (posterior probability 3.8%) and 9/110 (8.2%) had pneumonia. With RGS ≤ 6 and a threshold < 1000 ng mL(-1) , D-dimer was negative in 208/678 (31%) and 11/208 (5.3%) were PE+, but 10/11 missed PEs were subsegmental and none had concomitant DVT. Pneumonia was found in 12/208 (5.4%) with RGS ≤ 6 and D-dimer < 1000 ng mL(-1). CONCLUSIONS: Doubling the threshold for a positive D-dimer with a PE unlikely pretest probability could reduce CTPA scanning with a slightly increased risk of missed isolated subsegmental PE, and no increase in rate of missed pneumonia.

Autoimmune markers in vitiligo patients appear correlated with obsession and phobia.

BACKGROUND: Current studies have treated a limited portion of the subjective aspects of vitiligo patients and have yet to elucidate possible psychological differences between those with autoimmune markers (AIM) with respect to those without autoimmune markers (NAIM). OBJECTIVE: To perform an age and gender-matched 1:1 case-control study through a comparison of non-segmental vitiligo patients with autoimmune features vs. those without autoimmune features in regards to psychiatric features, psychosomatic aspects and social parameters. METHODS: A total of 112 non-segmental vitiligo patients have been examined at the Florence University dermatology outpatient service (2nd dermatology unit). Vitiligo with an autoimmune background was defined by the presence of autoimmune antibodies and/or autoimmune diseases. Psychiatric screening was performed by dermatologists using the modified Middlesex Healthcare Questionnaire (MHQ); psychosomatic aspects and social impact were analysed with a standardized, Florentine questionnaire. RESULTS: Upon performing a conditional regression model, age, phobia and obsession were significantly predictive of the presence of AIM and a low total MHQ score was significantly predictive of NAIM in vitiligo patients. With univariate analysis, we found significant differences in: identifiable stress related to the onset of vitiligo, vitiligo triggered by stress, and modified interpersonal relationships related to vitiligo, which were associated with the subgroup containing autoimmunity markers. CONCLUSIONS: We found a higher prevalence of age, obsession and phobia among vitiligo patients AIM as compared to vitiligo patients NAIM. Thus, in the presence of demonstrated autoimmunity, screening for particular psychiatric aspects may be useful in the clinical practice of vitiligo.

Effects of angiotensin (1-7) upon right ventricular function in experimental rat pulmonary embolism.

Right ventricular (RV) dysfunction contributes to poor clinical prognosis after pulmonary embolism (PE). The present studies evaluate the effects of angiotensin (1-7) (ANG (1-7)) upon RV function during experimental PE in rats. Circulating ANG II increased 8-fold 6 hr after PE (47±13 PE vs. 6±3 pg/mL, control, p<0.05). ACE2 protein was uniformly localized in the RV myocardium of control rats, but showed a patchy distribution with some cells devoid of stain after 6 or 18 hr of PE. RV function decreased 18 hr after PE compared with control treated animals (19±4 vs. 41±1 mmHg, respectively, p<0.05; 669±98 vs. 1354±77 mmHg/sec, respectively, p<0.05), while left ventricular function (LV) was not significantly changed. Animals treated with ANG (1-7) during PE showed improved RV +dP/dt and peak systolic pressure development to values not significantly different from control animals. Protection of RV function by ANG (1-7) was associated with improved arterial blood sO2, base excess and pH. Supplemental delivery of ANG (1-7) reduced the development of RV dysfunction, suggesting a novel approach to protecting RV function in the setting of acute experimental PE.

Rapid clearance of circulating haptoglobin from plasma during acute pulmonary embolism in rats results in HMOX1 up-regulation in peripheral blood leukocytes.

BACKGROUND: Acute pulmonary embolism (PE) causes pulmonary hypertension (PH) via several mechanisms including pulmonary vasospasm. We hypothesize that PE with associated PH leads to alterations in plasma protein concentrations indicative of disease severity and prognosis. OBJECTIVE: To identify plasma proteins altered in abundance by PE in rats. METHODS: Plasma samples were obtained from rats at 2, 6 and 18 h after experimental PE produced with intrajugular injection of polystyrene beads at three different levels of severity (mild, moderate and severe). Total plasma protein was separated using two-dimensional sodium dodecylsulfate-polyacrylamide gel electrophoresis (2D SDS-PAGE) and candidate protein spots altered in expression by PE were identified by mass spectroscopy. Haptoglobin identity and amount was verified by western blot analysis. RESULTS: The PE model produced a dose-dependent increase in right ventricular systolic pressure (RVSP) (mmHg) at 2 h: mild 39+/-1.7, moderate 40+/-1.8 and severe 51+/-1.3 mmHg, coincident with significant increases in free plasma (hemoglobin). Combined 2D SDS-PAGE and Western blot analysis indicated time- and dose-dependant loss of plasma haptoglobin levels in response to acute PE. Haptoglobin (HP) was essentially absent from plasma within 2 h of severe PE. Clearance of HP from plasma was accompanied by increased expression of heme oxygenase-1 (hmox1) in peripheral blood leukocytes and in HMOX1 enzyme activity in the liver. CONCLUSIONS: PE that causes pulmonary hypertension is associated with haptoglobin depletion and up-regulation of HMOX1 enzyme.

Prospective multicenter assessment of interobserver agreement for radiologist interpretation of multidetector computerized tomographic angiography for pulmonary embolism.

BACKGROUND: Emergency physicians rely on the interpretation of radiologists to diagnose and exclude pulmonary embolism (PE) on the basis of computerized tomographic pulmonary angiography (CTPA). Few data exist regarding the interobserver reliability of this endpoint. OBJECTIVE: To quantify the degree of agreement in CTPA interpretation between four academic hospitals and an independent reference reading (IRR) laboratory. METHODS: Hospitalized and emergency department patients who had one predefined symptom and sign of PE and underwent 64-slice CTPA were enrolled from four academic hospitals. CTPA results as interpreted by board-certified radiologists from the hospitals were compared against those from the IRR laboratory. CTPAs were read as indeterminate, PE(-) or PE(+), and percentage obstruction was computed by the IRR laboratory, using a published method. Agreement was calculated with weighted Cohen's kappa. RESULTS: We enrolled 492 subjects (63% female, age 54 +/- 1 years, and 16.7% PE(+) at the site hospitals). Overall agreement was 429/492 (87.2%; 95% confidence interval 83.9-90.0). We observed 13 cases (2.6%) of complete discordance, where one reading was PE(+) and the other reading was PE(-). Weighted agreement was 92.3%, with kappa = 0.75. The median percentage obstruction for all patients was 9% (25th-75th percentile interquartile range: 5% to -30%). For CTPAs interpreted at the site hospitals as PE(-) or indeterminate but read as PE(+) by the IRR laboratory, the median of percentage obstruction was 6% (4-7%). CONCLUSION: We found in this sample a good level of agreement, with a weighted kappa of 0.75, but with 2.6% of patients having total discordance. Overall, a large proportion of clots were distal or minimally occlusive clots.

Prospective multicenter evaluation of the pulmonary embolism rule-out criteria.

BACKGROUND: Over-investigation of low-risk patients with suspected pulmonary embolism (PE) represents a growing problem. The combination of gestalt estimate of low suspicion for PE, together with the PE rule-out criteria [PERC(-): age < 50 years, pulse < 100 beats min(-1), SaO(2) >or= 95%, no hemoptysis, no estrogen use, no surgery/trauma requiring hospitalization within 4 weeks, no prior venous thromboembolism (VTE), and no unilateral leg swelling], may reduce speculative testing for PE. We hypothesized that low suspicion and PERC(-) would predict a post-test probability of VTE(+) or death below 2.0%. METHODS: We enrolled outpatients with suspected PE in 13 emergency departments. Clinicians completed a 72-field, web-based data form at the time of test order. Low suspicion required a gestalt pretest probability estimate of <15%. The main outcome was the composite of image-proven VTE(+) or death from any cause within 45 days. RESULTS: We enrolled 8138 patients, 85% of whom had a chief complaint of either dyspnea or chest pain. Clinicians reported a low suspicion for PE, together with PERC(-), in 1666 patients (20%). At initial testing and within 45 days, 561 patients (6.9%, 95% confidence interval 6.5-7.6) were VTE(+), and 56 others died. Among the low suspicion and PERC(-) patients, 15 were VTE(+) and one other patient died, yielding a false-negative rate of 16/1666 (1.0%, 0.6-1.6%). As a diagnostic test, low suspicion and PERC(-) had a sensitivity of 97.4% (95.8-98.5%) and a specificity of 21.9% (21.0-22.9%). CONCLUSIONS: The combination of gestalt estimate of low suspicion for PE and PERC(-) reduces the probability of VTE to below 2% in about 20% of outpatients with suspected PE.

Comparison of the Simplify D-dimer assay performed at the bedside with a laboratory-based quantitative D-dimer assay for the diagnosis of pulmonary embolism in a low prevalence emergency department population.

BACKGROUND: The immunofiltration D-dimer assay could allow point-of-care testing for pulmonary embolism (PE). A study was undertaken to compare a clinician-performed qualitative D-dimer assay with the automated quantitative D-dimer test. METHODS: A prospective observational study was conducted from January to October 2005 at an urban academic emergency department (ED). 1193 patients of mean (SD) age 47 (16) years (66% female) were enrolled. The study protocol combined pretest probability estimation, D-dimer testing by both a qualitative immunochromatographic assay (Simplify) performed at the point of care by 192 different clinicians and a quantitative D-dimer test performed in a CLIA-certified laboratory. The criterion standard was image-proven PE or deep venous thrombosis within 45 days after enrollment. To test interobserver agreement for the qualitative assay, two blinded observers independently read 841 Simplify cartridges. RESULTS: Of 1193 patients enrolled, 45 were PE+ (3.8%, 95% CI 2.8% to 5.0%). Qualitative results were available for 1169 (98%) and quantitative results were available for 1136 (95%). Comparison of the qualitative and quantitative D-dimer tests gave the following results: sensitivity 91% (95% CI 78% to 98%) vs 93% (95% CI 80% to 98%); specificity 57% (95% CI 54% to 60%) vs 57% (95% CI 54% to 60%); likelihood ratio negative 0.16 (95% CI 0.06 to 0.37) vs 0.13 (95% CI 0.05 to 0.35). The weighted Cohen's kappa for interpretation of the qualitative assay was 0.69 (95% CI 0.63 to 0.76). CONCLUSIONS: In this very low-risk ED population, a qualitative D-dimer assay performed at the point of care had similar diagnostic accuracy to the quantitative D-dimer test. Interobserver agreement for the qualitative test was good.

Contrast nephropathy following computed tomography angiography of the chest for pulmonary embolism in the emergency department.

OBJECTIVE: To estimate the frequency of contrast nephropathy after computed tomography angiography (CTA) to rule out pulmonary embolism (PE) in the emergency department (ED) setting. METHODS: We prospectively followed patients undergoing CTA for PE, while in the ED, for 45 days. Patients who refused follow-up or were receiving hemodialysis were excluded. Severe renal failure was defined as an increase in creatinine > or = 3.0 mg dL(-1) or a need for hemodialysis within the follow-up period. Patients were also followed for laboratory-defined contrast nephropathy, defined as an increase in creatinine of > 0.5 mg dL(-1) or > 25%, within seven days following CTA. RESULTS: A total of 1224 patients were followed, and 354 [29%, 95% confidence interval (CI): 26-32%] patients had paired (preCTA and post-CTA) creatinine measurements. None developed renal failure (0/1224; 0%, CI: 0-0.3%). 44 patients developed laboratory-defined contrast nephropathy, corresponding to an overall frequency of 4% (44/1224; CI: 3-5%) and 12% (44/354; 95% CI: 9-16%) among those with paired creatinine measurements. CONCLUSIONS: Following CTA for PE, the incidence of severe renal failure was very low, but the incidence of laboratory-defined contrast nephropathy (4% overall and 12% of those with paired measurements) was higher than expected.

Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.

Overuse of the d-dimer to screen for possible pulmonary embolism (PE) can have negative consequences. This study derives and tests clinical criteria to justify not ordering a d-dimer. The test threshold was estimated at 1.8% using the method of Pauker and Kassirer. The PE rule-out criteria were derived from logistic regression analysis with stepwise backward elimination of 21 variables collected on 3148 emergency department patients evaluated for PE at 10 US hospitals. Eight variables were included in a block rule: Age < 50 years, pulse < 100 bpm, SaO(2) > 94%, no unilateral leg swelling, no hemoptysis, no recent trauma or surgery, no prior PE or DVT, no hormone use. The rule was then prospectively tested in a low-risk group (1427 patients from two hospitals initially tested for PE with a d-dimer) and a very low-risk group (convenience sample of 382 patients with chief complaint of dyspnea, PE not suspected). The prevalence of PE was 8% (95% confidence interval: 7-9%) in the low-risk group and 2% (1-4%) in the very low-risk group on longitudinal follow-up. Application of the rule in the low-risk and very low-risk populations yielded sensitivities of 96% and 100% and specificities of 27% and 15%, respectively. The prevalence of PE in those who met the rule criteria was 1.4% (0.5-3.0%) and 0% (0-6.2%), respectively. The derived eight-factor block rule reduced the pretest probability below the test threshold for d-dimer in two validation populations, but the rule's utility was limited by low specificity.

Metabolic dysfunction and depletion of mitochondria in hearts of septic rats.

Our previous studies indicate that hearts from septic rats have decreased work with oxygen wasting. The present studies test if there is energy deficit, changes in cardiac mitochondrial content and caspase activation during sepsis. Anesthetized, male Sprague-Dawley rats received no surgical treatment (control), laparotomy (sham), or laparotomy with cecal ligation and puncture (CLP) to induce polymicrobial septic shock. Hearts were isolated 12-14 h later. Cardiac work, oxygen consumption, substrate oxidation and energy stores were measured in perfused hearts. Normalized density of mitochondria was determined in ventricles without perfusion by morphometric analysis with electron microscopy. Citrate synthase activity was assessed in homogenates and isolated mitochondria. Cardiac work decreased significantly in CLP (47%), while oxygen consumption and glucose oxidation were unchanged compared with control or sham hearts (oxygen and substrate wasting). Tissue adenosine triphosphate, creatine phosphate and glycogen were lower in CLP hearts (energy deficit). Mitochondrial grid intersects decreased significantly from 151 +/- 8 sham to 130 +/- 4 CLP out of 361 possible intersects and autophagy was observed in CLP hearts. Total activity of citrate synthase decreased in homogenates (99 +/- 8 micromol/min/g wet weight sham vs. 62 +/- 7 CLP, P < 0.05) and in the mitochondrial fraction (27 +/- 1 micromol/min/g wet weight sham to 22 +/- 1 CLP, P < 0.05). Calculated mitochondrial content decreased from 63 +/- 4 mg protein/g wet weight sham to 46 +/- 5 CLP, P < 0.05 (mitochondrial depletion). Caspase-3 activity doubled and tumor necrosis factor alpha content tripled in CLP hearts. CONCLUSIONS. - Oxygen and substrate wasting in CLP occurs with fewer mitochondria and energy deficit, processes that are coincident with caspase-3 activation.

Contribution of indirect computed tomography venography to computed tomography angiography of the chest for the diagnosis of thromboembolic disease in two United States emergency departments.

Recent reports suggest that physicians in non-ambulatory settings can use indirect CT venography (CTV) of the lower extremities immediately following spiral CT angiography (CTA) of the chest to identify patients with a negative CTA who have thromboembolic disease identified on CTV. We sought to determine the frequency of isolated deep venous thrombosis (DVT) discovered on CTV in emergency department (ED) patients with complaints suggestive of pulmonary embolism (PE) yet having a negative CTA. This study was conducted in a suburban and urban ED where patients with symptoms suspicious for PE were primarily evaluated with CTA and CTV. A total of 800 patients were studied, including 360 from the suburban ED and 440 from the urban ED. 88 (11%) patients were diagnosed with thromboembolic disease by CTA, or CTV, or both. Seventy-three patients had a CTA of the chest that was positive for PE, 42 (5.2%) of whom had evidence of both PE on CTA and DVT on CTV. Fifteen patients (2%, 95% CI = 1-3%) had a negative CTA and were subsequently found to have isolated DVT on CTV, all of whom received anticoagulation therapy. These data suggest that indirect CT venography of immediately following CT angiography of the chest significantly increased the frequency of diagnosed thromboembolic disease requiring anticoagulation in ED patients with suspected PE.