Individual Clinical Outcome Research Articles

A novel prediction score determining individual clinical outcome 3 months after juvenile stroke (PREDICT-score)

BackgroundJuvenile strokes (< 55 years) account for about 15% of all ischemic strokes. Structured data on clinical outcome in those patients are sparse. Here, we aimed to fill this gap by systematically collecting relevant data and modeling a juvenile stroke prediction score for the 3-month functional outcome.MethodsWe retrospectively integrated and analyzed clinical and outcome data of juvenile stroke and TIA patients treated at the LMU University Hospital, LMU Munich, Munich. Good outcome was defined as a modified Rankin Scale of 0–2 or return to baseline of function. We analyzed candidate predictors and developed a predictive model. Predictive abilities were inspected using Area Under the ROC curve (AUROC) and visual representation of the calibration. The model was validated internally.Results346 patients were included in the analysis. We observed a good outcome in n = 293 patients (84.7%). The prediction model for an unfavourable outcome had an AUROC of 89.1% (95% CI 83.3–93.1%). The model includes age NIHSS, ASPECTS, blood glucose and type of vessel occlusion as predictors for the individual patient outcome.ConclusionsHere, we introduce the highly accurate PREDICT-score for the 3-month outcome after juvenile stroke derived from clinical routine data. The PREDICT-score might be helpful in guiding individual patient decisions and designing future studies but needs further prospective validation which is already planned.Trial registration The study has been registered at https://drks.de (DRKS00024407) on March 31, 2022.

Managing malnutrition and multimorbidity in primary care: dietary approaches to reduce treatment burden.

There are many health and nutrition implications of suffering from multimorbidity, which is a huge challenge facing health and social services. This review focuses on malnutrition, one of the nutritional consequences of multimorbidity. Malnutrition can result from the impact of chronic conditions and their management (polypharmacy) on appetite and nutritional intake, leading to an inability to meet nutritional requirements from food. Malnutrition (undernutrition) is prevalent in primary care and costly, the main cause being disease, accentuated by multiple morbidities. Most of the costs arise from the deleterious effects of malnutrition on individual's function, clinical outcome and recovery leading to a substantially greater burden on treatment and health care resources, costing at least £19·6 billion in England. Routine identification of malnutrition with screening should be part of the management of multimorbidity together with practical, effective ways of treating malnutrition that overcome anorexia where relevant. Nutritional interventions that improve nutritional intake have been shown to significantly reduce mortality in individuals with multimorbidities. In addition to food-based interventions, a more 'medicalised' dietary approach using liquid oral nutritional supplements (ONS) can be effective. ONS typically have little impact on appetite, effectively improve energy, protein and micronutrient intakes and may significantly improve functional measures. Reduced treatment burden can result from effective nutritional intervention with improved clinical outcomes (fewer infections, wounds), reducing health care use and costs. With the right investment in nutrition and dietetic resources, appropriate nutritional management plans can be put in place to optimally support the multimorbid patient benefitting the individual and the wider society.

New Approach to Equitable Intervention Planning to Improve Engagement and Outcomes in a Digital Health Program: Simulation Study.

Digital health programs provide individualized support to patients with chronic diseases and their effectiveness is measured by the extent to which patients achieve target individual clinical outcomes and the program's ability to sustain patient engagement. However, patient dropout and inequitable intervention delivery strategies, which may unintentionally penalize certain patient subgroups, represent challenges to maximizing effectiveness. Therefore, methodologies that optimize the balance between success factors (achievement of target clinical outcomes and sustained engagement) equitably would be desirable, particularly when there are resource constraints. Our objectives were to propose a model for digital health program resource management that accounts jointly for the interaction between individual clinical outcomes and patient engagement, ensures equitable allocation as well as allows for capacity planning, and conducts extensive simulations using publicly available data on type 2 diabetes, a chronic disease. We propose a restless multiarmed bandit (RMAB) model to plan interventions that jointly optimize long-term engagement and individual clinical outcomes (in this case measured as the achievement of target healthy glucose levels). To mitigate the tendency of RMAB to achieve good aggregate performance by exacerbating disparities between groups, we propose new equitable objectives for RMAB and apply bilevel optimization algorithms to solve them. We formulated a model for the joint evolution of patient engagement and individual clinical outcome trajectory to capture the key dynamics of interest in digital chronic disease management programs. In simulation exercises, our optimized intervention policies lead to up to 10% more patients reaching healthy glucose levels after 12 months, with a 10% reduction in dropout compared to standard-of-care baselines. Further, our new equitable policies reduce the mean absolute difference of engagement and health outcomes across 6 demographic groups by up to 85% compared to the state-of-the-art. Planning digital health interventions with individual clinical outcome objectives and long-term engagement dynamics as considerations can be both feasible and effective. We propose using an RMAB sequential decision-making framework, which may offer additional capabilities in capacity planning as well. The integration of an equitable RMAB algorithm further enhances the potential for reaching equitable solutions. This approach provides program designers with the flexibility to switch between different priorities and balance trade-offs across various objectives according to their preferences.

P1204 Oral Streptococcus mutans isolates aggravated colitis in mice

Abstract Background The incidence of inflammatory bowel disease (IBD) is increasing year by year and the mechanism is unclear. A great number of studies have shown that the gut microbiota composition of IBD patients has changed and the diversity of gut microbiota decreases. The abundance of firmicutes decreases, and the abundance of Proteobacteria increases, which eventually leads to the immune disorders and intestinal inflammation. The mouth is the "gateway" of the digestive tract, which has various microbiota. The entry of extraneous microbiota from the mouth into the intestines play an important role in influencing the composition of the gut microbiota. The continuous disorder of the oral microenvironment (such as periodontitis and dental caries) are also closely related to intestinal inflammation. Methods A series of in vivo and in vitro experiments were conducted to investigate the effect and mechanism of S. mutans on colitis mice. Results S.mutans strain UA159 which is closely related to dental caries significantly aggravated colitis in DSS induced mice, as shown by body weight loss, shorter colon length, and increased inflammatory histological scores (Fig1A). UA159 up-regulated intestinal pro-inflammatory cytokines and inhibited the expression of barrier molecules in DSS mice (Fig1B). The proportion of adaptive immune cells (Th1, Th17) was up-regulated in intestinal lamina propria of UA159-administered mice (Fig1C-D).The fecal microbiota composition of UA159 mice was different from control group. The pro-inflammatory effects of UA159 on DSS mice disappeared when antibiotics were used to eliminate the intestinal microbiota. It is suggested that S.mutans may play a proinflammatory role by influencing the intestinal microbiota of mice (Fig1E). We followed 55 IBD patients for more than 1 year and found that IBD patients with poor control had a higher proportion of S.mutans in saliva (Fig1F). S.mutans strains were isolated from IBD saliva samples and were found to cluster in different branches in the phylogenetic tree (Fig1G). S.mutans isolates have different pro-inflammatory effects on colitis mice and intestinal epithelial cells (Fig1H-I). Subsequent experiments are under way to further explore the mechanism leading to the differences of the pro-inflammatory effects. Conclusion Our study were the first to find that oral S.mutans has aggravated intestinal inflammation. S.mutans UA159 aggravated colitis in mice through damaging intestinal mucosal barrier function, enhancing immune response and disrupting intestinal microbiota (Fig1J). The difference in pro-inflammatory effect of S.mutans derived from different IBD patients saliva may be related to the individual clinical outcome.

EEG Individual Alpha Frequencies May Predict Clinical Outcome in TMS Treatment

EEG Individual Alpha Frequencies May Predict Clinical Outcome in TMS Treatment

Individual net clinical outcome with oral anticoagulation in atrial fibrillation using the ABC‐AF risk scores

BackgroundDecisions on stroke prevention strategies in patients with atrial fibrillation (AF) depend on the perceived risks of stroke and bleeding with different antithrombotic treatment strategies. The study objectives were to evaluate net clinical outcome with oral anticoagulation (OAC) for the individual patient with AF and to identify clinically relevant thresholds for OAC treatment. MethodsPatients with AF receiving OAC treatment in the randomized ARISTOTLE and RE-LY trials, with available biomarkers for calculation of ABC-AF scores at baseline, were included (n = 23,121). Observed 1-year risk on OAC was compared with predicted 1-year risk if the same patients would not have received OAC using the ABC-AF scores calibrated for aspirin. Net clinical outcome was defined as the sum of stroke and major bleeding risks. ResultsThe ratio between the 1-year incidence of major bleeding and stroke/systemic embolism events ranged from 1.4 to 10.6 according to different ABC-AF risk profiles. Net clinical outcome analyses showed that in patients with an ABC-AF-stroke risk >1% per year on OAC (>3% without OAC), treatment with OAC consistently provides larger net clinical benefit than no-OAC treatment. In patients with an ABC-AF-stroke risk <1.0% per year on OAC (<3% without OAC) an individualized balancing of risks regarding OAC or no-OAC treatment is needed. ConclusionsIn patients with AF, the ABC-AF risk scores allow an individual and continuous estimate of the balance between benefits and risks with OAC treatment. This precision medicine tool therefore seems useful as decision support and visualizes the net clinical benefit or harm with OAC treatment (http://www.abc-score.com/abcaf/). Clinical Trial RegistrationClinicalTrials.gov identifier NCT00412984 (ARISTOTLE) and NCT00262600 (RE-LY).

PREDICT-juvenile-stroke: PRospective evaluation of a prediction score determining individual clinical outcome three months after ischemic stroke in young adults – a study protocol

BackgroundAlthough of high individual and socioeconomic relevance, a reliable prediction model for the prognosis of juvenile stroke (18–55 years) is missing. Therefore, the study presented in this protocol aims to prospectively validate the discriminatory power of a prediction score for the 3 months functional outcome after juvenile stroke or transient ischemic attack (TIA) that has been derived from an independent retrospective study using standard clinical workup data.MethodsPREDICT-Juvenile-Stroke is a multi-centre (n = 4) prospective observational cohort study collecting standard clinical workup data and data on treatment success at 3 months after acute ischemic stroke or TIA that aims to validate a new prediction score for juvenile stroke. The prediction score has been developed upon single center retrospective analysis of 340 juvenile stroke patients. The score determines the patient’s individual probability for treatment success defined by a modified Rankin Scale (mRS) 0–2 or return to pre-stroke baseline mRS 3 months after stroke or TIA. This probability will be compared to the observed clinical outcome at 3 months using the area under the receiver operating characteristic curve. The primary endpoint is to validate the clinical potential of the new prediction score for a favourable outcome 3 months after juvenile stroke or TIA. Secondary outcomes are to determine to what extent predictive factors in juvenile stroke or TIA patients differ from those in older patients and to determine the predictive accuracy of the juvenile stroke prediction score on other clinical and paraclinical endpoints. A minimum of 430 juvenile patients (< 55 years) with acute ischemic stroke or TIA, and the same number of older patients will be enrolled for the prospective validation study.DiscussionThe juvenile stroke prediction score has the potential to enable personalisation of counselling, provision of appropriate information regarding the prognosis and identification of patients who benefit from specific treatments.Trial registrationThe study has been registered at https://drks.de on March 31, 2022 (DRKS00024407).

Tumor Necrosis Factor-α, CD1A and CD1E Genetic Polymorphisms in Guillain-Barré Syndrome: A Study from India.

Guillain-Barré Syndrome (GBS) is an acute acquired autoimmune inflammatory disorder of peripheral nerves and roots. The pathogenesis is essentially an aberrant post-infectious immune response in a genetically susceptible host milieu. Single nucleotide polymorphisms (SNP) in genes encoding the inflammatory mediators like TNF-α, CD1A and CD1E can influence their expression and level and the susceptibility and clinical course of disease in GBS. We tried to study the susceptibility of single nucleotide polymorphisms of TNF-α and CD1 genes in Guillain-Barré Syndrome in Indian population and determine the association in terms of genotype, allele and haplotype distribution along with individual subtype, severity and clinical outcome. In this case-control study, we investigated the single nucleotide polymorphism pattern in the promoter region of TNF-α (-308 G/A), TNF-α (-863C/A), CD1A and CD1E genes using real-time polymerase chain reaction in 75 GBS patients and analysed in comparison with 75 age and sex-matched healthy controls. The findings revealed that the allelic distribution of TNF-α (-308 G/A) *A allele was associated with GBS (P value 0.04, Odds Ratio 2.03, 95% Confidence Interval 1.01-4.07). There was no association found with genotype, haplotype combination and other allele distribution for GBS in the study. CD1A and CD1E SNPs did not reveal any susceptibility for GBS. The subtype analysis did not reveal any statistical significance, except for CD1A *G allele with AMAN subtype (P value 0.026). The haplotypic combinations and mutant allele of TNF-α (-308 G/A), TNF-α (-863C/A), CD1A and CD1E were significantly associated with severe GBS in the study. However, there was no association of any SNP for mortality and survival of GBS in the study. TNF-α (-308 G/A)*A allele might confer genetic susceptibility for GBS in Indian population. CD1 genetic polymorphism could not be considered for susceptibility to GBS. TNF-α and CD1 genetic polymorphism did not affect mortality in GBS.

Subacromial Balloon Spacer versus Partial Repair for Massive Rotator Cuff Tears: A Prospective, Randomized, Multi-center Trial

Objectives:Despite various treatment options, the successful management of irreparable, massive rotator cuff tears (MRCTs) remains challenging. Implantation of a biodegradable subacromial balloon spacer (InSpaceTM system; OrthoSpace, Caesarea, Isreal) has gained considerable interest for the treatment of MCRTs due to its ability to effectively recenter the humeral head within the glenoid. Despite promising results, investigations examining outcomes following balloon spacer implantation are limited to small case series and short-term prospective trials without comparison to other surgical modalities. The purpose of the present investigation was to prospectively evaluate the safety and efficacy of the arthroscopically deployed, subacromial spacer balloon compared to partial rotator cuff repair in patients with MRCTs at 24 month follow up.Methods:A non-inferiority, prospective, single-blinded, multicenter, randomized, controlled, pivotal study was conducted to compare the outcomes of arthroscopic subacromial balloon spacer implantation to partial repair in the treatment of MRCTs. Patients ≥ 40 years of age with symptomatic full thickness MRCTs (tears ≥ 5 cm or ≥ 2 tendons) that had failed non-operative management were included. Clinical outcome data, derived from subjective questionnaires and physical examination, were collected at baseline and follow-up intervals at Day 10, Week 6, Month 3, 6, 12 and 24. Postoperative magnetic resonance imaging (MRI) scans were obtained at 6 weeks and 12 months. The primary composite effectiveness endpoint was defined as achievement of the minimal clinically important difference (MCID) for the Western Ontario Rotator Cuff (WORC) score (275 points) and American Shoulder and Elbow Society (ASES) score (6.4 points) by week 6 and maintenance at month 12 without subsequent secondary surgical intervention (SSSI) or serious adverse device effects (SADEs). Secondary effectiveness endpoints included changes in individual and composite clinical outcome scores relative to baseline in addition to MRI findings. Intention-to-treat (ITT), per-protocol (PP), and safety analyses were performed separately.Results:A total of 20 sites were enrolled in the investigation. One hundred, eighty-four patients were randomized into the clinical study (n= 93 balloon spacer; n= 91 partial repair) and included in the safety population, of which 183 patients were included in the ITT analysis (n=93 balloon spacer; n= 90 partial repair) and 176 in the PP analysis (n= 88 balloon spacer; n= 88 partial repair). No significant difference in demographic characteristics based on mean age, sex, race or body mass index were appreciated between groups. Mean procedure duration was 44.6 ± 16.9 minutes for the balloon spacer group and 71.2 ± 30.1 minutes for the partial repair group. Significant improvement over time relative to baseline was observed in all WORC (Fig. 1) and ASES (Fig. 2) scores in both groups. The magnitude of improvement for subjects in the balloon spacer group was the same or better than for subjects in the partial repair group at 12 and 24 month follow up. At 12 months, 51% (n=45 of 88) of patients in the balloon spacer group and 35 patients 40% (n= 35 of 88) in the partial repair group had reached and maintained the primary composite endpoint, meeting the noninferiority criteria (non-inferiority margin 10%; p = 0.0049) and corresponding to an 11.4% mean advantage for the spacer implant group. Non-inferiority was similarly confirmed in the ITT population (p=0.0089). SSSI occurred in 6 subjects (n=3 balloon spacer; n=3 partial repair), with two subjects in each group requiring reverse shoulder arthroplasty and one subject in each group undergoing shoulder arthroscopy.Conclusions:Use of the balloon spacer was found to produce non-inferior outcomes when compared to partial rotator cuff repair for patients with MRCTs at 24 month follow up. Outcomes following balloon spacer device placement met non-inferiority criteria when compared to the partial repair group based on primary composite endpoints.

RARE ORPHAN DISEASES IN PATIENTS ON HOME ARTIFICIAL NUTRITION.

Rare genetic and non-genetic diseases are often associated with high risk of malnutrition[1]. The purpose of the study is to evaluated rare diseases among patients on Home Artificial Nutrition (HAN) and prescriptions registered at Local Health Care Unit Naples 3, Italy. Data were collected from 231 patients (M=131; F=100) recorded in 2019 (1st January-31st December). Oral Nutritional Supplements (ONS), Enteral Nutrition (HEN), Parenteral Nutrition (HPN) were included; complications of pregnancy and childbirth were excluded. Adults were 182 (78.8%), Pediatrics 49 (21.2% ). Rare diseases of the nervous system were 177 (76.7%), congenital anomalies 25 (10.8%) and inborn errors of metabolism 8 (3%). Respiratory, hematologic, immunologic, and skin diseases, primitive glomerulopathies and intestinal disorders, rare tumors were found in fewer cases (9.1%). Amyotrophic Lateral Sclerosis was the most frequent diagnosis (43.3%; 94 ALS and 6 ALS-Juvenile). Spinal Muscolar Atrophy (SMA) was found in 23.8% of pediatrics, Progressive Supranuclear Palsy (PSP) and Duchenne Muscular Dystrophy (DMD) in 8.4% and 4.5% of adult patients. ONS were 123, mainly prescribed to adults (87%); HEN were 100, administered through Percutaneous Endoscopy Gastrostomy (86%) and nasogastric tube feeding (14%), HPN were only 9 prescriptions. Nutritional impairment in patient with rare neurologic diseases is frequent. HAN could improve clinical management of symptoms worsening quality of life of patients. Further research is needed to evaluate the impact of nutritional intervention on individual clinical outcome[1].

Radical Hemithoracic Radiotherapy Induces Systemic Metabolomics Changes That Are Associated with the Clinical Outcome of Malignant Pleural Mesothelioma Patients.

Simple SummaryRadical hemithoracic radiotherapy represents a promising new advance in the field of radiation oncology and encouraging results have been achieved in the treatment of malignant pleural mesothelioma patients. This study showed that this radiotherapy modality produces significant changes in serum metabolomics profile mainly affecting arginine and polyamine biosynthesis pathways. Interestingly, individual metabolomics alterations were found associated with the clinical overall survival outcome of the radiotherapy treatment. These results highlight metabolomics profile analysis as a powerful prognostic tool useful to better understand the mechanisms underlying the interpatients variability and to identify patients who may receive the best benefit from this specific radiotherapy treatment.Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual clinical outcome. Nineteen patients undergoing RHRT at the dose of 50 Gy in 25 fractions were enrolled. Serum targeted metabolomics profiles were investigated at baseline and the end of radiotherapy by liquid chromatography and tandem mass spectrometry. Univariate and multivariate OPLS-DA analyses were applied to study the serum metabolomics changes induced by RHRT while PLS regression analysis to evaluate the association between such changes and overall survival. RHRT was found to affect almost all investigated metabolites classes, in particular, the amino acids citrulline and taurine, the C14, C18:1 and C18:2 acyl-carnitines as well as the unsaturated long chain phosphatidylcholines PC ae 42:5, PC ae 44:5 and PC ae 44:6 were significantly decreased. The enrichment analysis showed arginine metabolism and the polyamine biosynthesis as the most perturbed pathways. Moreover, specific metabolic changes encompassing the amino acids and acyl-carnitines resulted in association with the clinical outcome accounting for about 60% of the interpatients overall survival variability. This study highlighted that RHRT can induce profound systemic metabolic effects some of which may have a significant prognostic value. The integration of metabolomics in the clinical assessment of the malignant pleural mesothelioma could be useful to better identify the patients who can achieve the best benefit from the RHRT treatment.

Evidence for a Serotonergic Subtype of Major Depressive Disorder

Background: First line pharmacological treatment of Major Depressive Disorder (MDD) is selective serotonin reuptake inhibitors (SSRIs), but only 1/3 of patients obtain remission. Cerebral serotonin 4 receptor (5-HT4R) binding measured with positron emission tomography (PET) is inversely related to serotonin levels and can serve as a proxy for brain serotonin levels. We here determine if a successful outcome of serotonergic treatment in MDD is linked to a serotonergic deficit. Methods: We [11C]-SB207145 PET-scanned 100 untreated patients with moderate to severe MDD and 91 healthy controls; 40 patients were re-scanned after 8 weeks treatment. All patients were started on SSRI and were followed up clinically after 1, 2, 4, 8 and 12 weeks. Treatment response was measured as change from baseline in Hamilton depression rating scale 6 score. Findings: Before treatment, patients with MDD had 8% lower global 5-HT4R binding than controls (95% confidence interval [-13·1%;-2·5%], p<0·001). Non-responders did not differ from controls ([-11·5%;4·0%], p=0.31), whereas remitters had 9% lower binding than controls at baseline ([-16·1%;-2·7%], p=0.004). The probability that a remitter had a lower baseline 5-HT4R neocortex binding compared to a non-responder was 0.63 [0.43;0.84] with p=0.20.Independent of treatment outcomes, patients reduced their neostriatal 5-HT4R binding (-9%, [-12·8%;-5·0%], p<0·001, N=40) after serotonergic intervention. Interpretation: Patients with MDD who remit to SSRIs have lower cerebral 5-HT4R levels than controls whereas non-responders do not differ, suggesting the presence of a serotonergic subtype of MDD. While SSRI intervention decreased neostriatal 5-HT4R, the change was not associated with the individual clinical outcome. Our data suggest that non-responders to SSRI’s constitute a subgroup with non-serotonergic depression. Trial Registration: Registered as a clinical trial before initiation (NCT02869035). Funding Statement: Key economic support was granted from the Innovation Fund Denmark, Research Fund of the Mental Health Services - Capital Region of Denmark, Independent Research Fund Denmark, G.J. Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savvaerksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation and the H. Lundbeck A/S. H. Declaration of Interests: GMK has received honoraria as expert advisor for Sage Therapeutics and as speaker for Jannsen. VGF has served as consultant for SAGE therapeutics. MBJ has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other authors declare no conflict of interest. Ethics Approval Statement: The study protocol was approved by all relevant authorities (the Health Research Ethics Committee of the Capital Region of Denmark (H15017713), the Danish Data Protection Agency (04711/RH-2016-163) and Danish Medicines Agency (EudraCT- 2016-001626-34)). All participants provided written informed consent prior to inclusion.

Outcomes and Laboratory and Clinical Findings of Asthma and Allergic Patients Admitted With Covid-19 in a Spanish University Hospital.

Individual susceptibility and clinical outcome of Covid-19 are variable and mortality is also very variable across countries, being particularly high in Spain. Comorbidities might increase the risk for less favourable outcomes, but it has been reported that patients with antecedents of asthma or allergic diseases were under-represented among hospitalized Covid-19 patients. Aiming to compare the clinical evolution of patients with antecedents of asthma or allergic diseases and patients without these antecedents, we analyzed a series of 113 consecutive patients with Covid-19 in a regional hospital in Spain. We collected and analyzed the putative effect of the 16 most common co-morbidities, previous treatment with 33 drug classes, symptoms, radiological, and laboratory findings at admission and drug therapy after admission. Predictors of long hospital stays were older age (P = 0.002), low oxygen saturation (P = 0.001) and bilateral radiological findings at admission (P = 0.023). Predictors of Intensive Care Unit (ICU) admission were the previous use of calcium-channel blockers (P = 0.005), proton pump inhibitors (P = 0.017), low oxygen saturation (P = 0.002), high leukocyte count (P = 0.011), and high D-dimer values (P = 0.005). Predictors of mortality were older age (P = 0.001), antecedents of cerebrovascular disorders (P = 0.034), previous use of oral anticoagulants (P = 0.009) or selective serotonin reuptake inhibitors (P = 0.003), and increased levels of interleukin-6 (P = 0.001). Patients with antecedents of allergic diseases were about ten years younger (P = 0.003) and had fewer comorbidities (P = 0.026) than the rest of the patients. In conclusion, antecedents of allergic diseases might influence hospitalization risk in relatively young patients.

Risk perception of antimicrobial resistance by infection control specialists in Europe: a case-vignette study

BackgroundUsing case-vignettes, we assessed the perception of European infection control (IC) specialists regarding the individual and collective risk associated with antimicrobial resistance (AMR) among inpatients.MethodsIn this study, sixteen case-vignettes were developed to simulate hospitalised patient scenarios in the field of AMR and IC. A total of 245 IC specialists working in different hospitals from 15 European countries were contacted, among which 149 agreed to participate in the study. Using an online database, each participant scored five randomly-assigned case-vignettes, regarding the perceived risk associated with six different multidrug resistant organisms (MDRO). The intra-class correlation coefficient (ICC), varying from 0 (poor) to 1 (perfect), was used to assess the agreement for the risk on a 7-point Likert scale. High risk and low/neutral risk scorers were compared regarding their national, organisational and individual characteristics.ResultsBetween January and May 2017, 149 participants scored 655 case-vignettes. The perceptions of the individual (clinical outcome) and collective (spread) risks were consistently lower than other MDRO for extended spectrum beta-lactamase producing Enterobacteriaceae cases and higher for carbapenemase producing Enterobacteriaceae (CPE) cases. Regarding CPE cases, answers were influenced more by the resistance pattern (93%) than for other MDRO. The risk associated with vancomycin resistant Enterococci cases was considered higher for the collective impact than for the individual outcome (63% vs 40%). The intra-country agreement regarding the individual risk was globally poor varying from 0.00 (ICC: 0–0.25) to 0.51 (0.18–0.85). The overall agreement across countries was poor at 0.20 (0.07–0.33). IC specialists working in hospitals preserved from MDROs perceived a higher individual (local, p = 0.01; national, p < 0.01) and collective risk (local and national p < 0.01) than those frequently exposed to bacteraemia. Conversely, IC specialists working in hospitals with a high MDRO clinical burden had a decreased risk perception.ConclusionsThe perception of the risk associated with AMR varied greatly across IC specialists and countries, relying on contextual factors including the epidemiology. IC specialists working in high prevalence areas may underestimate both the individual and collective risks, and might further negatively promote the MDRO spread. These finding highlight the need to shape local and national control strategies according to risk perceptions and contextual factors.

Malignant pheochromocytoma and paraganglioma: management options.

Although the majority of pheochromocytoma and paraganglioma are benign, 15-17% develop metastatic disease, being present at the initial diagnosis in about 11-31% of cases. The natural course of metastasized disease is highly heterogeneous, with an overall 5-year survival rate varying between 40% and 85%. For individual patients, overall survival, progression-free survival, and clinical outcome are difficult to predict. Management of metastasized pheochromocytoma and paraganglioma is challenging. Currently available therapeutic options are surgical debulking, treatment with radiopharmaceuticals (I-MIBG, Y and Lu-DOTATATE), chemotherapy and targeted therapy. The pathogenesis of pheochromocytoma and paraganglioma (PPGL) is largely driven by genomic alterations in PPGL susceptibility genes related to three different clusters: altered pseudo-hypoxic signaling (cluster-1), altered MAP-kinase signaling (cluster-2) and altered Wnt signaling (cluster-3). Novel targeted therapies (tyrosine kinase inhibitors) and potential future therapeutic options, guided by improved knowledge about the oncogenic cluster 1-3 signaling pathways, will be discussed. Treatment of metastasized pheochromocytoma and paraganglioma remains challenging. Profiling of gene expression and methylation can serve as a powerful tool for characterizing disease clusters and for guiding targeted therapy to improve selectivity and efficacy. Current knowledge of signatures involved in molecular signaling, metabolism, and resistance mechanisms of PPGLs suggests that therapeutic regimens can be optimized to each molecular subtype.

Feasibility Technique of Low-passage In Vitro Drug Sensitivity Testing of Malignant Pleural Effusion from Advanced-stage Non-small Cell Lung Cancer for Prediction of Clinical Outcome.

Individualized proper chemotherapy using in vitro drug sensitivity testing has been proposed as a novel therapeutic modality and shown to have better efficacy than empiric chemotherapy. However, issues around establishing a patient-derived cell culture or xenograft, the timing of the testing obtained, and the validity of testing represent major limitations to translating the use of such a technique to clinical practice. In this study, we assessed the feasibility of an in vitro drug sensitivity technique for testing malignant pleural effusion from advanced-stage non-small cell lung cancer. Our technique was able to produce a turnaround time for in vitro drug sensitivity testing of less than 1 week, with a success rate of more than 90% of cases. Correlated with the individual clinical outcome, using the area under the dose response curve (AUC) could define the level of in vitro drug sensitivity as: responsive (AUC>0.25), intermediate response (0.1≤AUC≤0.25), or resistance (AUC<0.1). Data obtained from this method of drug testing were correlated with the clinical outcome. The present drug sensitivity evaluation may benefit the development of individual precision chemotherapy.

Exaggerated systolic hypertensive response to exercise predicts cardiovascular events: a systematic review and meta-analysis.

The pathophysiology of exaggerated systolic hypertensive response to exercise (SHRE) is not fully understood, with contradictory data on its role in predicting cardiovascular (CV) events. The aim of this review and meta‑analysis was to assess the association of SHRE with CV clinical outcomes in healthy normotensive individuals. We searched PubMed (MEDLINE), Cochrane Library, RefWorks, and Google Scholar to identify clinical studies that reported data on CV event rates and outcomes for patients with SHRE on exercise stress testing. Sensitivity and specificity analysis for assessing the diagnostic accuracy of the SHRE cutoff associated with CV events was estimated using hierarchical summary receiver operating characteristic analysis. We included 8 studies with 47 188 participants and a median follow‑up of 19.3 years. Exaggerated SHRE was found in patients with composite events (CV mortality and coronary artery disease; hazard ratio [HR], 1.363; 95% CI, 1.135-1.604; P <0.001), in those with coronary artery events (HR, 1.532; 95% CI, 1.240-1.893; P <0.001), and in those with CV mortality (HR, 1.286; 95% CI, 1.075-1.539; P =0.006), as compared with individuals with normal response. An exercise systolic blood pressure of 196 mm Hg predicted CV events with a sensitivity of 62% (54%-69%) and specificity of 75% (60%-86%), with a positive likelihood ratio of less than 3 and a strong correlation (r = -0.71). Our study supports the clinical relevance of exaggerated SHRE as a predictor of composite and individual CV clinical outcome. These findings should be considered as thought‑provoking evidence for better stratification and, consequently, for optimal management of this high‑risk population.

The relationship between individual alpha peak frequency and clinical outcome with repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD)

BackgroundThe individual α frequency (IAF) has been associated with the outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD), but the association has been inconsistent. HypothesisProximity of IAF to the stimulation frequency, rather than the value of IAF per se, is associated with outcome for patients receiving 10 Hz rTMS. MethodsWe examined the relationships between IAF, rTMS stimulation frequency, and treatment outcome in 147 patients. All patients initially received 10 Hz rTMS unilateral treatment delivered to left dorsolateral prefrontal cortex (DLPFC) (10UL), with subsets of patients changed to unilateral 5 Hz to left DLPFC (5UL) or sequential bilateral (SB) stimulation (10 Hz/1Hz) to left and right DLPFC based upon worsening symptoms with or intolerance of 10UL. Outcome was percent change in total score on the Inventory of Depressive Symptomatology – Self Report (IDS-SR) scale from pre-treatment baseline to the 30th treatment. IAF values and absolute difference between IAF and 10 Hz (|IAF-10Hz|) were examined in relation to outcome for the overall sample and for each stimulation group separately. ResultsThere was no correlation between IAF value, or |IAF-10Hz| and outcome in the overall sample. ANCOVA showed a significant interaction between IAF measures and treatment type. Post-hoc analyses revealed that IAF and |IAF-10Hz| were both significantly associated with degree of improvement (IDS-SR % change) for patients who received 10UL (P < 0.01) but not 5UL or SB stimulation. There was a trend-level difference in IAF between responders and non-responders only within the 10 Hz group, but not within the other treatment groups (n.s.). For the 10UL group, membership in the highest IAF quartile was associated with significantly greater clinical improvement than membership in the lowest IAF quartile (p = 0.0034). ConclusionsIAF measures were associated with clinical outcome of patients treated with 10UL but not 5UL or SB rTMS treatment. This suggests that interactions between endogenous frequencies and treatment outcome may be related to the selected stimulation parameters and/or physiologic and clinical characteristics of patients who benefit from those parameters.

Abstract 2273: A machine learning approach to identify a peripheral prognostic cytokine signature via nivolumab clearance in patients with advanced melanoma

Abstract Background: Data suggest that peripheral factors such as circulating cytokines could function as predictive indicators of clinical response to specific therapies or as general prognostic indicators of outcome in patients with cancer. Previous studies have focused on evaluating the association between individual cytokines and clinical outcome. There is no clear consensus on how or which of these cytokines should be selected for prediction of treatment outcome. Clearance of immunotherapeutic agents such as the anti-PD-1 nivolumab (NIVO) has been shown to be a predictor of best overall response and overall survival (OS) across multiple indications. Determination of clearance requires post-treatment pharmacokinetic (PK) samples which negates its utility as a baseline prognostic factor. We investigated a novel machine learning approach to identify a baseline composite cytokine signature that correlates with the established efficacy response relationship for NIVO clearance in advanced melanoma. This approach, which is capable of integrating multivariate factors into a composite feature, may provide a more accurate reflection of underlying biologic factors that contribute to outcome following treatment. Methods: Peripheral serum PK (NIVO clearance) and pharmacodynamic (Myriad Rules Based Medicine-customized inflammatory cytokine panel) data from 2 phase 3 studies (NCT01721772; NCT01844505) of NIVO monotherapy in patients with melanoma (n = 471) were used for machine learning model development (training data set). A third phase 3 study of NIVO in advanced melanoma (NCT01721746) was included in model application (test data set; n = 158). Random forest, a tree-based ensemble learning method, was used for feature selection and classification (low vs high) of NIVO clearance. Kaplan-Meier analyses and log-rank p values were used to assess statistical difference in long-term OS between predicted high- vs low-clearance groups. Results: A panel of ~20 baseline inflammatory cytokines related to immune cell modulation were selected by the machine learning model to predict clearance of NIVO monotherapy in patients with advanced melanoma (area under the curve of receiver operating characteristic: 0.79). The predicted clearance value from the cytokine signature was significantly associated with OS across all 3 studies, including patients treated with NIVO or dacarbazine (control) (p&amp;lt;0.01). Conclusions: We developed a machine learning approach to identify a serum prognostic cytokine signature based on the relationship between NIVO clearance and response. The strong association of the defined cytokine signature with OS from NIVO and dacarbazine suggests a prognostic role for drug clearance. This cytokine signature has the potential to be a prognostic biomarker in melanoma and may be used for balancing and randomization of patients in clinical studies. Citation Format: Rui Wang, Xiao Shao, Junying Zheng, Abdel Saci, Max Qian, Irene Pak, Amit Roy, Akintunde Bello, Jasmine Rizzo, Fareeda Hosein, Rebecca A. Moss, Megan Wind-Rotolo, Yan Feng. A machine learning approach to identify a peripheral prognostic cytokine signature via nivolumab clearance in patients with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2273.

Cochlear Implantation in Patients With Single-sided Deafness After the Translabyrinthine Resection of the Vestibular Schwannoma-Presented at the Annual Meeting of ADANO 2016 in Berlin.

To evaluate effectiveness of the cochlear implant (CI) to facilitate single-sided deafness (SSD) rehabilitation following translabyrinthine resection of the vestibular schwannoma. Retrospective patient review. Single center, University hospital. Patients with SSD who underwent translabyrinthine resection of a vestibular schwannoma with anatomical preservation of the cochlear nerve and subsequent CI on the same ear. CI at post-translabyrinthine resection of the acoustic neuroma to treat SSD, and evaluation by retrospective individual case review in a period from 2009 to 2016. Individual patients' clinical outcome and speech understanding. Thirteen patients were provided CI. In all cases, complete removal of the tumor was achieved and the cochlear nerve was preserved; in one case, the CI was implanted simultaneously. In most cases, the follow-up interval was 2 years. In 9 of 13 cases, the implanted ear achieved capability to understand and discriminate monosyllabic words at 65 dB. Level of speech understanding of over 50% at 65 dB was possible in 7 patients at 12 months after the first fitting of CI. Under certain conditions, CI was an effective solution to restore hearing in patients with SSD following translabyrinthine access to the skull base. Study with prospective design is required to provide more significant results.