Intensive Clinical Management Research Articles

Preexisting Autoimmunity Is Associated With Increased Severity of Coronavirus Disease 2019: A Retrospective Cohort Study Using Data From the National COVID Cohort Collaborative (N3C).

Identifying individuals with a higher risk of developing severe coronavirus disease 2019 (COVID-19) outcomes will inform targeted and more intensive clinical monitoring and management. To date, there is mixed evidence regarding the impact of preexisting autoimmune disease (AID) diagnosis and/or immunosuppressant (IS) exposure on developing severe COVID-19 outcomes. A retrospective cohort of adults diagnosed with COVID-19 was created in the National COVID Cohort Collaborative enclave. Two outcomes, life-threatening disease and hospitalization, were evaluated by using logistic regression models with and without adjustment for demographics and comorbidities. Of the 2 453 799 adults diagnosed with COVID-19, 191 520 (7.81%) had a preexisting AID diagnosis and 278 095 (11.33%) had a preexisting IS exposure. Logistic regression models adjusted for demographics and comorbidities demonstrated that individuals with a preexisting AID (odds ratio [OR], 1.13; 95% confidence interval [CI]: 1.09-1.17; P < .001), IS exposure (OR, 1.27; 95% CI: 1.24-1.30; P < .001), or both (OR, 1.35; 95% CI: 1.29-1.40; P < .001) were more likely to have a life-threatening disease. These results were consistent when hospitalization was evaluated. A sensitivity analysis evaluating specific IS revealed that tumor necrosis factor inhibitors were protective against life-threatening disease (OR, 0.80; 95% CI: .66-.96; P = .017) and hospitalization (OR, 0.80; 95% CI: .73-.89; P < .001). Patients with preexisting AID, IS exposure, or both are more likely to have a life-threatening disease or hospitalization. These patients may thus require tailored monitoring and preventative measures to minimize negative consequences of COVID-19.

Incidence, risk factors, outcomes, and clinical management of BK viremia in the modern era of kidney transplantation.

BK viremia is endemic among kidney transplant recipients (KTRs). Incidence, risk factors, outcomes, and clinical management of detectable versus high BK viremia have not been considered previously in KTR in the modern era. This observational study examined KTR transplanted between January 1, 2009 and December 31, 2016. Any BK viral load in the serum constituted detectable BK viremia and ≥103 copies/ml constituted high viremia. Among 1193 KTRs, the cumulative probability of developing detectable and high BK viremia within 2 years posttransplant were 27.8% and 19.6%, respectively. Significant risk factors for detectable BK viremia included recipient age (HR 1.02 [95% CI: 1.01, 1.03]) and donor age (HR 1.01 [95% CI: 1.00, 1.02]). Recipient age also predicted high BK viremia (HR 1.02 [95% CI: 1.01, 1.03]), whereas White race (HR 0.70 [95% CI: 0.52, 0.95]), nondepleting induction therapy (HR 0.61 [95% CI: 0.42, 0.89]), and delayed graft function (HR 0.61 [95% CI: 0.42, 0.88]) were protective. Mean estimated glomerular filtration rates were 4.28 ml/min/1.72 m2 (95% CI: 2.71, 5.84) lower with detectable BK viremia. Although low viral load was usually not acted upon at first presentation, antiproliferative dose reductions were the most common initial management. BK viremia remains a common early complication in a modern cohort of KTRs. These findings highlight the benefit of early BKV monitoring in addition to intensive clinical management. Clinical responses beyond first positive BK viremia tests, and their implications for graft outcomes, merit further investigation.

Clinical characteristics in immune thrombocytopenia patients after COVID-19 vaccination

ABSTRACT It is well documented that COVID-19 vaccines greatly reduce the severity and complications of SARS-CoV-2 infection. However, it has been reported that COVID-19 related vaccines may induce or exacerbate autoimmune hematological disorders, for example, a decrease in platelet numbers characteristic of immune thrombocytopenia (ITP). To investigate this, we retrospectively reported, for the first time, the clinical characteristics of 42 ITP patients after COVID-19 vaccination in southwest China. Of the 42 patients, 28 patients were historically diagnosed ITP, and their platelet counts (PC) decrease mainly occurred after the first-dose vaccinations. The average PC after vaccination was 39.5 × 109/L and recovered to an average of 80.6 × 109/L after treatment. Efficacy of treatment was 90%, and only 10% maintained low PC at the third month of treatment. More interestingly, of the 42 patients, 14 were newly diagnosed ITP following vaccination. Of these 14 patients, 6 patients (43%) were found PC deterioration after the first vaccine dose, and 7 patients (50%) after the second dose. Fortunately, the peripheral PC of all 14 patients recovered significantly after treatment, and the average PC was 139.4 × 109/L, including 8 CRs (complete response) and 6 PRs (partial response). Notably, 9 of the 14 cases were found to have abnormal immune indices when thrombocytopenia diagnosed. No severe organ hemorrhage was found in either subgroup. These results are reassuring the vaccine safety for ITP patients, in that the risks of aggravating thrombocytopenia by COVID-19 vaccination do exist, but it was transient and can be effectively controlled through intensive clinical monitoring and management.

Clusters of risk factors in metabolic syndrome and their influence on central blood pressure in a global study

The effect of metabolic syndrome (MetS) and clusters of its components on central blood pressure (CBP) has not been well characterized. We aimed to describe the effect of MetS and clusters of its components on CBP in a large population and to identify whether this effect differs in men and women. We studied 15,609 volunteers (43% women) from 10 cohorts worldwide who participated in the Metabolic syndrome and Artery REsearch Consortium. MetS was defined according to the NCEP-ATP III criteria (GHTBW, glucose, high-density lipoprotein cholesterol, triglyceride, blood pressure, waist circumference). CBP was measured noninvasively and acquired from pulse wave analysis by applanation tonometry. MetS was associated with a 50% greater odds of having higher CSBP. After controlling for age, male sex, non HDL cholesterol, diabetes mellitus, and mean arterial pressure, only specific clusters of MetS components were associated with a higher CSBP; and some of them were significant in women but not in men. We identified “risky clusters” of MetS variables associated with high CSBP. Future studies are needed to confirm they identify subjects at high risk of accelerated arterial aging and, thus, need more intensive clinical management.

Mitchell-Riley Syndrome: Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations.

Aims/HypothesisCaused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell–Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function.MethodsClinical records were analyzed and described in detail. The functional impact of two RFX6R181W and RFX6V506G variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function.ResultsAll four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6V506G and RFX6R181W mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function.Conclusions/InterpretationMultidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.

Abstract 5773: A one-stop approach in diagnosing hereditary colorectal cancer: A prospective, proof-of-principle, single-center study

Abstract Background: Colorectal cancer (CRC) remains one of the most commonly diagnosed cancers and a leading cause of cancer-related deaths worldwide. Between 3 and 6% of all CRC cases are attributed to hereditary colorectal cancer (HCRC). It is important to distinguish CRCs that arise hereditarily from those that arise sporadically, because patients with HCRC and their relatives can benefit from intensive clinical management and surveillance. The detection of germline variants using tumor tissue and paired non-cancerous tissue/whole blood cells (WBC) (conventional method) is considered as the gold standard for germline confirmation, but which could introduce high cost and long turnaround time. In this work, we aimed to investigate the feasibility of diagnosing HCRC using only tumor next-generation sequencing data without normal tissue/WBC data. Methods: One-hundred patients with suspected HCRC were prospectively enrolled according to the clinical diagnosis. Both tumor tissue and paired WBC were collected from each patient. Capture-based targeted sequencing using a panel consisting of 41 cancer-related genes was performed on both tumor tissue and WBC sample. The germline variants were identified using conventional and ColonCore method, respectively. The sensitivity and positive predictive value (PPV) of ColonCore method in identifying germline alterations were calculated, when conventional method was used as a reference. Results: A total of 636 alterations were identified using ColonCore method, including 606 somatic alterations and 30 germline alterations. Among the somatic alterations detected from this panel, 599 single-nucleotide variants and 7 copy number variants were observed. The most frequently mutated genes were APC, TP53, and KRAS, occurring in 76%, 66%, and 46% of patients, respectively. For ColonCore analysis, 17, 9, 2, and 2 patients harbored germline pathogenic variants in DNA mismatch repair (MMR) genes, APC, MUTYH, and ATM, respectively. Compared to the conventional method, the sensitivity of ColonCore method in the diagnosis of HCRC achieved 88.5% with a PPV of 82.1%. Next, the diagnostic performance of ColonCore method in Lynch syndrome (LS) and familial adenomatous polyposis (FAP) was subsequently investigated. We found its sensitivity in the diagnosis of LS achieved 100% (with a PPV of 98.8%), which was obviously higher than that in the diagnosis of FAP (70.0% with a PPV of 63.6%). Twenty-three patients identified as having a microsatellite instability (MSI)-high tumor using ColonCore method were also identified as having an MMR-deficient (dMMR) tumor using immunohistochemistry staining analysis. Conclusions: Our study suggests that ColorCore method is a one-stop approach for detecting germline/somatic alterations and MSI/dMMR status for suspected HCRC. Furthermore, ColorCore method is a feasible and valid tool to diagnose HCRC, especially LS. Citation Format: Cong Li, Yun Xu, Fangqi Liu, Ye Xu. A one-stop approach in diagnosing hereditary colorectal cancer: A prospective, proof-of-principle, single-center study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5773.

Comparison of Risk Assessment Strategies for Patients with Diabetes Mellitus and Stable Chest Pain: A Coronary Computed Tomography Angiography Study.

Background To compare two risk assessment strategies to identify individuals likely to benefit from further imaging testing in patients with diabetes mellitus (DM) and stable chest pain (SCP) suspected of obstructive coronary artery disease (CAD). Methods 602 DM patients referred to coronary computed tomography angiography (CCTA) for SCP were included. They were divided into high- and low-risk groups according to the 2016 National Institute of Health and Care Excellence guideline-determined strategy (NICE strategy) which focused on symptom evaluation and 2019 European Society of Cardiology guideline-determined strategy (ESC strategy) which was based on pretest probability (PTP) sequentially determined by the ESC-PTP estimator and risk factor-weighted clinical likelihood (RF-CL) model, respectively. The associations of clinical outcomes with risk groups and net reclassification improvement (NRI) were evaluated. Results The NICE and ESC strategy classified 44% and 39% patients into the low-risk group, respectively. Compared to the NICE strategy, the ESC strategy indicated stronger associations between risk groups and events (hazard ratios: 4.24 versus 1.91), intensive clinical management, and a positive NRI (27.71%, p < 0.0001). The application of the RF-CL model ameliorated the underestimation of risk in patients with borderline ESC-PTP, which principally account for the improvement of the ESC strategy. Conclusion Compared to the NICE strategy, the ESC strategy seemed to be associated with greater efficiency in identifying high risk individuals in patients with DM and SCP.

Comparison of NICE and ESC strategy for risk assessment in women with stable chest pain: a coronary computed tomography angiography study.

For women presenting with stable chest pain (SCP), the appropriate risk assessment strategy to identify individuals unlikely to benefit from further cardiovascular imaging testing (CIT) is debatable. Thus, the present study intended to compare two risk assessment strategies in these individuals. 2592 women with SCP who underwent coronary computed tomography angiography (CCTA) were divided into low and high risk group according to 2016 National Institute of Health and Care Excellence guideline-determined strategy (NICE strategy) and 2019 European Society of Cardiology guideline-determined strategy (ESC strategy), respectively. The associations of coronary artery disease (CAD), major adverse cardiovascular event (MACE) and other subsequent clinical outcomes with risk groups and net reclassification improvement (NRI) were evaluated to compare different strategies. Both NICE strategy which focused on symptom evaluation and ESC strategy which was based on pretest probability (PTP) determined by ESC-PTP model and coronary artery calcium score-weighted clinical likelihood (CACS-CL) model classified a proportion (34.49% and 63.97%, respectively) of individuals into the low risk group. Compared to NICE strategy, ESC strategy indicated stronger associations between risk groups and obstructive CAD (odds ratio: 27.63 versus 3.57), MACE (hazard ratios: 4.24 versus 1.91), more intensive clinical management as well as a positive NRI (27.71%, p < 0.0001). Compared to NICE strategy, ESC strategy which sequentially incorporated ESC-PTP model with CACS-CL model seemed to be associated with greater effectiveness in identifying individuals who may derive maximum benefit from further CIT in women presenting with SCP.

Comparison of Different Investigation Strategies to Defer Cardiac Testing in Patients With Stable Chest Pain

ObjectivesThis study aimed to compare the current 5 investigation strategies to defer cardiac testing in patients with stable chest pain. BackgroundFor the clinical management of stable chest pain, the identification of patients unlikely to benefit from further cardiac testing is important, but the most appropriate investigation strategy is unknown. MethodsA total of 4,207 patients referred to coronary computed tomography angiography for stable chest pain were classified into low- and high-risk groups according to the 2016 National Institute of Health and Care Excellence (NICE) guideline-determined strategy; PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) minimal risk tool–based strategy; 2019 European Society of Cardiology (ESC) guideline–determined strategy; and coronary artery calcium score (CACS), either in isolation (the CACS strategy) or as part of a weighted clinical likelihood model–based strategy (the CACS-CL strategy). The associations of obstructive coronary artery disease on coronary computed tomography angiography, major adverse cardiovascular events, and subsequent clinical management with risk groups according to different strategies were evaluated and compared. ResultsThe NICE, PROMISE, ESC, CACS, and CACS-CL strategies classified a proportion (22.63%, 29.21%, 41.84%, 46.76%, and 51.41%, respectively) of patients into low-risk groups. Compared with the NICE, PROMISE, ESC, and CACS strategies, the CACS-CL strategy had a stronger association between risk groups and obstructive coronary artery disease (odd ratios: 16.00 vs 2.93, 5.53, 7.94, and 10.39, respectively), major adverse cardiovascular events (HRs: 6.83 vs 1.90, 2.94, 4.23, and 5.13, respectively) and intensive subsequent clinical management as well as better metrics of diagnostic accuracy and positive net reclassification improvement. ConclusionsAmong contemporary strategies used to identify patients with stable chest pain at low risk, the use of CACS, especially when combined with clinical risk features, showed the strongest potential to effectively defer cardiac testing.

Facteurs individuels et contextuels participant à l’apparition de comportements violents en cours d’hospitalisations psychiatriques

BackgroundThe prevention of Physical Violent Behavior (VB) toward others during psychiatric hospitalization is a major concern of clinicians. These VBs can have a deleterious impact on the victims, inpatients or caregivers, as well as on the therapeutic milieu. Such violence can also have negative consequences for the assailant patients, such as repeatedly being hospitalized under restraint, stigmatization, and difficulties reintegrating into the community. ObjectivesThis study explored individual (age, gender, marital status, living status, diagnostic) and institutional (type of admission, length of stay, number of previous hospitalizations) risk factors, and how their interactions could increase the risk of VB during psychiatric hospitalizations. MethodThe study was carried out over a period of four years in the psychiatry department of the Lausanne University Hospital, on the 15 wards (219 beds) specialized in acute psychiatric care for adults. All the patients admitted to one of these wards during this period (n=4518), aged between 18 and 65 years, were included in the study. The sample was divided in two groups: non-violent patients (NVPs) and violent patients (VPs). VBs, defined as physical aggressions against another person, were assessed by the Staff Observation Aggression Scale – Revised (SOAS – R). Only physical assaults, associated or not with other types of violence, involving hospitalized patients were analyzed. Personal and institutional factors were extracted from the hospital database. Chi2 independence tests were used to assess differences between groups. Logistic regression models were used to identify the links between each factor and the VB. Classification and regression trees were used to study the hierarchical effect of factors, and combinations of factors, on VBs. ResultsDuring the study period, 414 VBs were reported involving 199 patients (4.40 % of all patients). VPs were significantly younger, male, more likely to be unmarried and living in sheltered housing before hospitalization. In this group, the proportion of patients with diagnoses of schizophrenia, and/or schizophrenia with comorbid substance abuse and cognitive impairment, were higher compared to NVPs. VPs were more frequently admitted involuntarily, had a longer average length of stay and a greater number of previous hospitalizations. The logistic regression model performed on individual factors have shown a significant link between age (OR=0.99; CI: 0.97–1.00; P-value=0.024), living in sheltered housing before admission (OR=2.46; CI: 1.61–3.75; P-value<0.000), schizophrenic disorders (OR=2.18; CI: 1.35–3.57; P-value=0.001), schizophrenic disorders with substance abuse comorbidity (OR=2.00; CI: 1.16–3.37; P-value=0.016), cognitive impairment (OR=3.41; CI: 1,21–8.25; P-value=0.010), and VBs. The logistic regression model on institutional factors have shown a significant link between involuntary hospitalization (OR=4.38; CI: 3.20–6.08; P-value<0.000), length of previous stay (OR=1.01; CI: 1.00–1.01; P-value<0.000), number of previous hospitalizations (OR=1.06; CI: 1.00–1.12; P-value=0.031), and VBs. The logistic regression model on individual and institutional factors have shown a significant link between age (OR=0.99; CI: 0.97–1.00; P-value=0.008), living in sheltered housing before admission (OR=2.46: CI: 1.61–3.75; P-value=0.034), cognitive impairment (OR=3.41; CI: 1.21–8.25; P-value=0.074), involuntary hospitalization (OR=3.46; CI: 2.48–4.87; P-value<0.000), length of previous stay (OR=1.01; CI: 1.00–1.01; P-value<0.000), and VBs. The classification and regression trees have shown that the relationship between long length of stay and repeated hospitalizations mainly potentiate the risk of violence. ConclusionThe results of this study have shown the existence of a small group of vulnerable patients who accumulate constrained hospital stays during which violence occurs. Exploring the clinical profiles and institutional pathways of patients could help to better identify these patients and promote a more appropriate mode of support, such as intensive clinical case management. This model could facilitate the development of a clinical network and the links between the structures and partners caring for a patient. This would create a continuous support, avoiding or limiting the lack of continuity of care and care disruption.

Anti-cyclic-citrullinated-protein-antibodies in psoriatic arthritis patients: how autoimmune dysregulation could affect clinical characteristics, retention rate of methotrexate monotherapy and first line biotechnological drug survival. A single center retrospective study.

Aim:Occasional findings of anti-cyclic-citrullinated-protein-antibodies (anti-CCP) were rarely observed in psoriatic arthritis (PsA). The aim of our study is to evaluate whether the presence of anti-CCP can determine different clinical subsets and influence methotrexate monotherapy survival, and biotechnological drug retention rate.Methods:We conducted a retrospective study on PsA patients. All patients were required to fulfill the CASPAR criteria for PsA, and to present juxta-articular osteo-proliferative signs at X-ray. The exclusion criteria were age less than 18 years old, satisfaction of rheumatoid arthritis classification criteria, and seropositivity for rheumatoid factor. Clinical characteristics, anti-CCP titer, drug survival and comorbidities information were recorded for each patient. Statistical significance was set at p ⩽ 0.05.Results:Of 407 patients with PsA screened 113 were recruited. Twelve patients were anti-CCP positive. Methotrexate monotherapy survival was shorter in patients with anti-CCP (150 ± 48.3 weeks versus 535.3 ± 65.3 weeks; p = 0.026) [discontinuation risk hazard ratio (HR) = 2.389, 95% confidence interval (CI) 1.043, 5.473; p = 0.039] than those without. Significant shorter survival of first-line biotechnological drugs (b-DMARDs) was observed in the anti-CCP positive group than in that without (102.05 ± 24.4 weeks versus 271.6 ± 41.7 weeks; p = 0.005) with higher discontinuation risk (HR = 3.230, 95% CI 1.299, 8.028; p = 0.012). A significant higher rate of multi-failure (more than second-line b-DMARDs) was found in anti-CCP positive patients than in those without (50% versus 14%, p = 0.035).Conclusion:Anti-CCP in PsA could be suggestive of more severe disease, with worse drug survival of both methotrexate monotherapy and first-line b-DMARDs, and higher chance to be b-DMARDs multi-failure. So, they can be considered for more intensive clinical management of these patients.

Intensive care and anesthetic management of patients with Brugada syndrome and COVID-19 infection.

Coronavirus disease 2019 (COVID‐19) spreads across the world, and the intensive care unit (ICU) community must prepare for the challenges associated with this pandemic viral infection. Rapid diagnosis, isolation, and intensive clinical management are very important for all patients with COVID‐19, especially for those with cardiac diseases as Brugada syndrome (BrS). BrS is an arrhythmogenic disease reported to be one among the leading causes of sudden cardiac death. In these patients, episodes of lethal arrhythmias may be induced by several factors or situations, and for this reason management during ICU permanence or anesthesia must provide some precautions, avoiding factors that are known to have the potential to worsen the probability to induce arrhythmias. For ICU practitioners, management of acute respiratory failure, hemodynamics, and cardiovascular complications certainly are the key for the best treatment of these patients but to date specific data on supportive ICU care for these patients are lacking, and current recommendations are based on existing evidence from other viral infections and general intensive care management. We want to focus on some general rules, resulted from cases series and clinical practice, to be followed during the ICU management of patients with BrS and concomitant COVID‐19 infection.

When basal insulin is not enough: successful strategies for insulin intensification in patients with type 2 diabetes mellitus

Maintaining glycemic control through intensive clinical management of patients with type 2 diabetes mellitus (T2DM) is well recognized to reduce the risk of diabetes-associated complications. Patients in Russia have high rates of microvascular and macrovascular complications as a result of undiagnosed, untreated, or inadequately treated diabetes, emphasizing the need for better clinical management. The introduction of basal insulin therapy is often necessary for patients with T2DM when oral antihyperglycemic drugs and lifestyle management strategies are no longer effective inmaintaining glycemic targets. However, after initiation of insulin, patients often remain on basal insulin for long periods despite suboptimal glycemic control, and intensification of insulin therapy is frequently necessary. Here, we report on several different insulin intensification strategies available to clinicians and their patients to improve glycemic control and the advantages and disadvantages of each approach. These strategies include the use of short- and long-acting insulins administered either as bolus doses or as premixed insulins. When selecting the most appropriate intensification strategy, clinicians should consider the lifestyle and treatment goals of their patients to help ensure treatment success.

Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas.

Patients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making. To define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas. The tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome. We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.

Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial

Introduction of human papillomavirus-based screening is ongoing in many countries, given its higher sensitivity and longer-lasting protection compared with cytology-based screening. However, optimal clinical management of human papillomavirus-positive but cytology-negative women is unclear, and additional studies with clinical follow-up are warranted. The aim of the current study was to investigate the long-term outcomes of the clinical management used in a double-blind, randomized clinical trial of human papillomavirus screening conducted in the context of the routine, organized screening program in Sweden. Among 12,527 women aged 32-38 years enrolled in the trial, we followed up the 195 women who attended the colposcopy screening who were cytologically normal but persistently human papillomavirus positive (at least 12 months later; median, 19 months) in the human papillomavirus testing arm (n= 100) or were randomly selected from the control arm (n= 95). Women in the human papillomavirus testing arm were followed up with repeated human papillomavirus testing, cytologies, and colposcopies if persistently human papillomavirus-positive without cervical intraepithelial neoplasia grade 2 or worse. A similar number of random colposcopies and tests were carried out in the control arm. Women were followed up over 13 years for the main outcome measures: cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse and cervical intraepithelial neoplasia grade 3 or worse. Among women who continued to attend and had continuous human papillomavirus persistence, all (40 of 40, 100% [95% confidence interval, 91-100%]) developed cervical intraepithelial neoplasia grade 2 or worse. There were no cases among women who cleared their human papillomavirus persistence (0 of 35, 0% (95% confidence interval, 0-10%) (P < .001). Among women who had had human papillomavirus persistence but did not continue with repeated human papillomavirus tests (unknown persistence status), 56% (15 of 27 women) developed cervical intraepithelial neoplasia grade 2 or worse. Almost all cases occurred within 6 years. The intensive clinical management in the trial appeared to result in diagnoses of earlier cervical intraepithelial neoplasia grade 2 or worse but apparently did not prevent cervical intraepithelial neoplasia grade 2 or worse. Women with human papillomavirus persistence will, in general, either become human papillomavirus negative or develop cervical intraepithelial neoplasia grade 2 or worse within 6 years, even with intensive clinical follow-up.

The Impact of Socioeconomic Position on Severe Maternal Morbidity Outcomes Among Women in Australia: A National Case-control Study

(BJOG. 2015;122(12):1601–1609) Research conducted in Australia in 2000 determined that although there had been improvements in the health of the population over previous years, increased inequalities for socioeconomically related mortality had occurred for some conditions. Studies in other developed countries, such as the United Kingdom, have suggested that socioeconomic position may be a risk factor for poorer pregnancy outcomes. Identifying high-risk parturients is critical for the prevention of adverse pregnancy outcomes because it allows targeted interventions and intensive clinical management of specific groups of women. The Australasian Maternal Outcomes Surveillance System is based on the methodology of the UK Obstetric Surveillance System and enables research and surveillance for a range of pregnancy complications across Australia and New Zealand. This study aimed to explore the independent impact of socioeconomic position on selected severe maternal morbidities among women in Australia.

Practising evidence-based medicine in an era of high placebo response: number needed to treat reconsidered.

The number needed to treat (NNT) statistic was developed to facilitate the practice of evidence-based medicine. Placebo was assumed to be therapeutically inert when the NNT was originally conceived, but more recent data for conditions such as major depressive disorder (MDD) suggest that the placebo control condition can have considerable therapeutic effects. Complications arise because the NNT calculated from randomised controlled trials (RCTs) reflects a comparison between medication plus clinical management and placebo plus clinical management, whereas, in the clinical setting, physicians choose between prescribing open medication, observing a patient over time with a supportive approach, and doing nothing. Thus, NNTs derived from clinical trials are not directly relevant to clinical decision-making, because they are based on control conditions that do not exist in standard practice. Additional difficulties may arise when using NNTs to compare alternative treatments for MDD, such as medication and psychotherapy, since these comparisons require the control conditions upon which the respective NNTs are based to be similar.Whereas pill placebo conditions include intensive clinical management and elicit expectations of improvement, attention control conditions for psychotherapy research are less well developed. Often the effects of psychotherapy are gauged against a wait-list control condition, which has substantially fewer therapeutic components than a pill placebo control condition. To improve the clinical utility of NNTs for the treatment of MDD, we advocate effectiveness studies that include treatment conditions resembling actual clinical practice, rather than using placebo-controlled RCTs for this purpose. Until such studies are performed, the effect of bias in comparing NNTs across treatments can be controlled by ensuring that the RCT control conditions upon which the NNTs are based are comparable.

Telephone-administered psychotherapy in combination with antidepressant medication for the acute treatment of major depressive disorder

BackgroundTelephone-administered psychotherapies (T-P) provided as an adjunct to antidepressant medication may improve response rates in major depressive disorder (MDD). The goal of this study was to compare telephone-administered social rhythm therapy (T-SRT) and telephone-administered intensive clinical management (T-ICM) as adjuncts to antidepressant medication for MDD. A secondary goal was to compare T-P with Treatment as Usual (TAU) as adjunctive treatment to medication for MDD. Methods221 adult out-patients with MDD, currently depressed, were randomly assigned to 8 sessions of weekly T-SRT (n=110) or T-ICM (n=111), administered as an adjunct to agomelatine. Both psychotherapies were administered entirely by telephone, by trained psychologists who were blind to other aspects of treatment. The 221 patients were a posteriori matched with 221 depressed outpatients receiving TAU (controls). The primary outcome measure was the percentage of responders at 8 weeks post-treatment. ResultsNo significant differences were found between T-SRT and T-ICM. But T-P was associated with higher response rates (65.4% vs 54.8%, p=0.02) and a trend toward higher remission rates (33.2% vs 25.1%; p=0.06) compared to TAU. LimitationsShort term study. ConclusionsThis study is the first assessing the short-term effects of an add-on, brief, telephone-administered psychotherapy in depressed patients treated with antidepressant medication. Eight sessions of weekly telephone-delivered psychotherapy as an adjunct to antidepressant medication resulted in improved response rates relative to medication alone.

ABSTRACT 478

Background and aims: Systemic lupus erythematosus (SLE) is a chronic inflammatory, multisystem, of unknown cause autoimmune nature, characterized by the presence of autoantibodies. Evolves with polymorphic clinical manifestations with periods of exacerbations and remissions. Its etiology is not completely understood, the development of the disease is associated with genetic predisposition and environmental factors such as ultraviolet light and certain drugs. The pulmonary hemorrhagic syndromes are designated in the current medical literature as pulmonary hemorrhage, alveolar hemorrhage (AH), lung intraparenchymal hemorrhage, diffuse microvascular lung hemorrhage, etc. These terms are usually used to describe bleeding originating from the pulmonary microvasculature: arterioles, capillaries and venules, often resulting injury involving the alveolar-capillary membrane. Alveolar hemorrhage as a manifestation of SLE is an event not common, life threatening, whose pathophysiological mechanism is not fully understood, but appears to involve deposition of immune complexes in the walls of blood vessels by a disruption of the immune system. Aims: Report a rare case of initial presentation of SLE in childhood to increase diagnostic suspicion is facing a severe pulmonary haemorrhage. Methods: A case report emphasizing clinical presentation, management, diagnosis and follow up of a child admitted to the intensive care. Results: Child developed severe pulmonary haemorrhage as initial clinical manifestation of SLE and after vital control and diagnosis, recovered well and was discharged without sequelae. Conclusions: Alveolar hemorrhage is a rare manifestation in SLE, but life-threatening and requires an intensive clinical management with greater risk of mortality and rapid differential diagnosis.

Progression to the Persistent Form in Asymptomatic Paroxysmal Atrial Fibrillation

This study investigated the progression of paroxysmal atrial fibrillation (AF) to the persistent form in Japanese asymptomatic AF patients. Data were derived from a single hospital-based cohort in the Shinken Database 2004-2012 (n=19,994), in which 1,176 patients were diagnosed as having paroxysmal AF. AF progression occurred in 115 patients (6.0%/year) during the mean follow-up period (1,213±905 days). Although patients who were asymptomatic at the initial visit (n=468) had a low-risk profile compared with symptomatic patients, they had greater AF progression at follow-up (unadjusted hazard ratio, 1.611; 95% CI: 1.087-2.389; P=0.018). Absence of symptoms, male sex, and cardiomyopathy were independent predictors for AF progression in the multivariate model. It was noted that asymptomatic patients were less likely to undergo pulmonary vein isolation (PVI). In addition, the interaction term between asymptomatic AF and absence of PVI could be another independent predictor for AF progression. Prognosis was similar between asymptomatic and symptomatic patients with AF. Irrespective of low-risk profile, patients with asymptomatic paroxysmal AF had greater progression of AF compared with symptomatic patients. This paradoxical result appeared to be the result of less intensive clinical management, including invasive rhythm control.