Modification Of Treatment Regimen Research Articles

Rheumatology to hepatology cross talk: An evidence based update on the treat to target strategy in hepatitis-C related extrahepatic autoimmune syndromes

Hepatitis C virus (HCV) is a universally identified major epidemiological health problem with an estimated reservoir of almost 200 million or 3% of the global population. In the year 2013, the WHO declared viral hepatitis as “a leading cause of death worldwide 1.46 million deaths, a toll higher than that from HIV, tuberculosis or malaria, and on the increase since 1990” with more than 90% of these deaths being related to the sequelae of the infection with either forms of hepatitis viruses (HBV-HCV). HCV is classically a hepatotropic virus with the liver cells providing the primary bed for viral replication with clinical evidences supporting an additionally significant viral lymphotropism. HCV is a linear single stranded RNA retrovirus, member of the genus hepacivirus of the flaviviridae family. It is a small virus comprised of a positive-sense 9.6 Kb single-stranded RNA genome embodied in a double layered glycosylated protein envelope, the viral genome protein is basically made up of structural and non-structural proteins. The viral enzymes- NS2-3 and NS3-4A proteases, NS3 helicase and NS5BRdRp— are essential contributors for HCV replication, the HCV serine protease NS3, and its cofactor NS4A, constitute a complex that directs polyprotein cleavage. HCV infected individuals are capable of producing 10-13 trillion virions/day with the majority coming primarily from viral replication within the hepatocytes with an unpredictable yet significant extrahepatic contributions that may lead to the development and modulation of systemic extrahepatic disease. The use of conventional antiviral therapy PEGylated interferon (Peg-IFN) and ribavirin (RBV) practically contributed to the disease burden with less than a 50% sustained viral response rates. A major challenge for interferon therapy comes from the Hepatitis C viral genome itself. The challenging draw backs to interferon based regimen in patients with autoimmune extrahepatic disease EHD demanded an evidence based revisit to the classic recommendations on the use of conventional antivirals with immunomodulatory drugs in this indication. It wasn’t until spring of 2011 when the FDA approved the first two directly acting antiviral drugs that the hepatologists experienced a revolutionary shift in Hepatitis C virus (HCV) treatment paradigm. Directly acting antiviral drugs (DAAs are drugs that target some of the main molecular components of HCV, including NS3/4A protease (first and second generation protease inhibitors), NS5B polymerase (nucleoside and non-nucleoside analogs) and NS5A protein. The recent era of DAAs established an additional need to modify treatment regimens in extrahepatic disease. In the year 2017 the international study group of HCV extrahepatic disease published evidence based recommendations on the use of antivirals for control of EHD. The treatment armamentarium in chronic HCV viremia with and without extrahepatic disease has experienced a revolution with the establishment of directly acting antiviral drugs. Interferon free directly acting antiviral drug regimens are currently considered as standard of care in patients with extrahepatic disease. Longitudinal studies are further requested to assess the unmet needs including drugs addressing other potential targets in the viral genome and life cycle.

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after CD19 CAR-T Cell Immunotherapy

CD19 chimeric antigen receptor (CAR)-modified T cell therapy has produced impressive results in patients (pts) with CD19+B cell malignancies; however, treatment can be complicated by neurologic adverse events (AEs). The presentation and pathogenesis of neurotoxicity (NT) are incompletely understood.We report a clinical and pathologic study evaluating NT in 133 B-ALL, NHL and CLL pts treated with lymphodepletion chemotherapy and CD19 CAR-T cells (NCT01865617). Neurologic AEs were observed in 53 of 133 pts (40%; 19% grade [gr] 1-2; 16% gr 3; 2% gr 4; 3% gr 5). Most neurologic AEs were reversible. Delirium, headache, and language disturbances were the most frequently observed neurologic AEs, presenting in 66%, 55%, and 34% of pts with NT, respectively. Multivariable analysis showed that higher burden of malignant B cells in marrow, lymphodepletion with cyclophosphamide and fludarabine, and higher infused CAR-T cell dose were associated with increased risk of NT and cytokine release syndrome (CRS).The severity of NT correlated with higher peak concentrations of cytokines that may activate endothelial cells (EC), such as IL-6, IFN-γ, and TNF-α. Pts who developed gr ≥3 NT had more severe CRS with higher CAR-T cell counts in blood and evidence of vascular dysfunction. In severe NT, hypofibrinogenemia with elevated PT, aPTT, and d-dimer were consistent with EC activation. We confirmed in vivo EC activation during NT by demonstrating high concentrations of serum angiopoietin-2 (Ang-2) and von Willebrand Factor (VWF), which are released from Weibel-Palade bodies on EC activation. In vitro, serum from pts with NT induced activation and VWF release from human umbilical vein ECs (HUVECs), which suggests that the finding of a reduced fraction of high molecular weight VWF multimers in vivo during gr ≥4 NT results from consumption on platelets and sequestration on activated EC. Consistent with this explanation, we found reduced activity of the VWF-cleaving protease ADAMTS13 relative to VWF levels and more severe thrombocytopenia in pts with gr ≥4 NT.We considered that cytokine-induced EC activation might alter the integrity of the blood-brain barrier (BBB) during NT. During severe NT, CSF analyses demonstrated increased permeability of the BBB to protein and leukocytes, including CAR-T cells. The gradient between serum and CSF cytokines observed before lymphodepletion was lost during acute NT, consistent with inability of the BBB to shield the CNS from high concentrations of plasma cytokines. Brain vascular pericytes (BVP) play a critical role in vascular and BBB support, and when exposed to high TNF-α or IFN-γ concentrations BVP exhibited stress (increased cleaved caspase-3 and reduced PDGFRβ) and secreted IL-6 and VEGF, further promoting EC activation and BBB permeability.Neuropathologic examination of the brain of a patient with fatal NT demonstrated disrupted endothelium by CD31 immunohistochemistry and EC activation was confirmed by intravascular VWF binding and CD61+ platelet microthrombi. Further evidence of breach of the BBB included red blood cell extravasation from multiple vessels, vascular lesions with karyorrhexis, perivascular CD8+ T cell infiltration, and fibrinoid vessel wall necrosis. CAR-T cells were detected in the CNS.We investigated strategies to reduce the risks of severe NT. Logistic probability curves demonstrated that reduction in CAR-T cell dose to reduce the peak in vivo CAR-T cell blood count was associated with reduced risk of NT, but that the narrow therapeutic index of this approach would lead to loss of anti-tumor efficacy. To maintain CAR-T cell peak counts in blood, we developed a strategy to identify pts early after CAR-T cell infusion who might be at risk of subsequent severe NT and could be candidates for early intervention. Classification tree modeling demonstrated that in the first 36 hours after CAR-T cell infusion pts with fever ≥38.9°C, serum IL-6 ≥16 pg/mL, and MCP-1 ≥1343.5 pg/mL were at high risk of subsequent gr ≥4 NT (sensitivity 100%; specificity 94%). We also investigated whether pts with pre-existing endothelial activation were at higher risk of NT. Before lymphodepletion, pts who developed gr ≥4 NT had higher Ang-2:Ang-1 ratios than those with gr ≤3 NT, indicating that endothelial activation before lymphodepletion or CAR-T cell infusion may be a risk factor for NT that identifies pts who would benefit from a modified treatment regimen. DisclosuresTurtle:Adaptive Biotechnologies: Other: Advisory board; Bluebird Bio: Other: Advisory board; Gilead Sciences: Other: Advisory board; Precision Biosciences: Other: Advisory board; Celgene: Other: Advisory board; Juno Therapeutics: Other: Advisory board, Patents & Royalties, Research Funding. Liles:Juno Therapeutics: Consultancy, Other: Advisory board. Li:Juno Therapeutics: Employment, Equity Ownership. Yeung:Gilead: Research Funding. Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding. Maloney:Celgene: Other: Advisory board; Kite Pharmaceuticals: Other: Advisory board; Juno Theraapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Roche/Genetech: Other: Advisory board.

Hematologic Toxicities During Treatment Allow for Improved Prediction of Recurrences in Pediatric Medulloblastoma

Long-Term survival rates for pediatric medulloblastoma patients are encouraging, though treatment-related late sequelae are common and adversely impact quality of life. However, due to non-negligible rates of recurrence, ∼20-30% at 5 years, a general de-escalation of treatment is not warranted. Currently there are few markers to predict outcome in this patient group, impeding efforts to personalize therapy further. We hypothesize that hematologic toxicities during therapy can significantly improve predictions and help identify patients at very high/low risk of recurrence. We analyzed data for 59 medulloblastoma patients aged 3-21 years treated with combined modality therapy including proton therapy in a clinical trial at our institution. Median CSI dose and total dose were 23.4Gy and 54Gy respectively. The following standard variables were extracted for each patient and included in the model building process: age, risk stratification (standard or high/intermediate), histology, radiation dose and cumulative cisplatin dose. In addition, the following acute toxicities, scored according to CTCv3.0, were added: Lymphopenia, Anaemia, Neutrophil and Leukocyte counts. Based on these features we employed 4 commonly used classification techniques (k nearest neighbours, support vector machines (SVM), decision trees and random forests) to predict recurrence within 5 years after treatment (binary classification). 5-fold cross validation was used to protect against overfitting and area under the receiving operator characteristic curve (AUC) and specificity were used to score the models. 11 out of 59 patients had relapsed within 5 years post treatment. None of the clinical predictors was able to significantly separate the PFS curves (all log-rank p>0.2). Taking all 5 variables together did not result in any useful predictions, with AUC for all models between 0.48-0.6. However, analyzing the acute hematological toxicities yielded numerous significant correlations, especially high grade Neutrophils (log rank p<0.001) and Leukocytes (log rank p=0.003) clearly separated the PFS curves. Including these variables into the predictive models boosted their performance to an AUC of ∼0.73. The best models were SVM and tree-based approaches, with the latter showing the highest specificity: they can classify a significant part of the patients recurring within 5 years with a 95% confidence, avoiding inclusion of patients with good prognosis into the high-risk group. This study suggests hematological toxicities can predict outcomes in pediatric medulloblastoma. Several acute toxicities correlate with PFS, and their inclusion may allow for timely modification of treatment regimen before the end of therapy. Similar models could be used to guide clinical trials that aim at personalizing treatment regimen, improving outcomes for high-risk patients while maintaining a high quality of life for long term survivors.

Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning.

Paracetamol overdose is common and is treated with acetylcysteine to prevent the development of hepatotoxicity. N-acetyl-p-benzoquinone imine (NAPQI) is the toxic metabolite of paracetamol overdose. We aimed to assess the expected acetylcysteine concentration time profiles following delivery of modified acetylcysteine regimens proposed for those at high and low risk of hepatotoxicity. In addition, we will determine acetylcysteine concentrations post-cessation of abbreviated infusions. We performed pharmacokinetic simulations using Berkeley Madonna (version 8.3.23.0) comparing the time course of acetylcysteine concentration during and after the cessation of an abbreviated 12-h regimen (250mg/kg) using a two-bag infusion and compared this to the standard 21-h three-bag (300mg/kg) regimen. We also simulated extended duration acetylcysteine regimens and other increased dosing strategies that have been recommended in specific paracetamol poisoning scenarios. A more sustained serum concentration is achieved when the acetylcysteine loading dose is delivered over 4h using the two-bag compared to the 1-h loading dose of the three-bag regimen. When administering an abbreviated 12-h acetylcysteine regimen, circulating acetylcysteine is detectable for 8h after cessation of the infusion. This may provide a continued hepatoprotective effect if NAPQI is still being generated after the infusion is ceased. This pharmacokinetic simulation study is an important step in determining plasma acetylcysteine concentrations that are likely to be achieved using various modified treatment regimens. Importantly, for patients at low risk of liver injury after acute overdose, acetylcysteine is likely to be detectable many hours post-cessation of a 12-h regimen. This should provide a safety factor against development of hepatotoxicity for any ongoing paracetamol metabolism after cessation of the acetylcysteine infusion.

Proteomic profiling reveals DNA damage, nucleolar and ribosomal stress are the main responses to oxaliplatin treatment in cancer cells

Oxaliplatin is widely used to treat colorectal cancer in both palliative and adjuvant settings. It is also being tested for use in treating hematological, esophageal, biliary tract, pancreatic, gastric, and hepatocellular cancers. Despite its routine clinical use, little is known about the responses it induces in cancer cells. Therefore the whole-cell proteomics study was conducted to characterize the cellular response induced by oxaliplatin. Chemosensitive CCRF-CEM cells were treated with oxaliplatin at 29.3μM (5×IC50) for 240min (half-time to caspase activation). The proteomes of un−/treated cells were then compared by high-resolution mass spectrometry, revealing 4049 proteins expressed over 3 biological replicates. Among these proteins, 76 were significantly downregulated and 31 significantly upregulated in at least two replicates. In agreement with the DNA-damaging effects of platinum drugs, proteins involved in DNA damage responses were present in both the upregulated and downregulated groups. The downregulated proteins were divided into three subgroups; i) centrosomal proteins, ii) RNA processing and iii) ribosomal proteins, which indicates nucleolar and ribosomal stress. In conclusion, our data supported by further validation experiments indicate the initial cellular response to oxaliplatin is the activation of DNA damage response, which in turn or in parallel triggers nucleolar and ribosomal stress. Biological significanceWe have performed a whole-cell proteomic study of cellular response to oxaliplatin treatment, which is the drug predominantly used in the treatment of colorectal cancer. Compared to its predecessors, cisplatin and carboplatin, there is only a small fraction of studies dedicated to oxaliplatin. From those studies, most of them are focused on modification of treatment regimens or study of oxaliplatin in new cancer diagnoses. Cellular response hasn't been studied deeply and to our best knowledge, this is the first whole-cell proteomics study focused exclusively to this important topic, which can help to understand molecular mechanisms of action.

Clonality, virulence determinants, and profiles of resistance of clinical Acinetobacter baumannii isolates obtained from a Spanish hospital.

IntroductionAcinetobacter baumannii is a nosocomial pathogen that is showing increasing rates of carbapenem resistance. Multi-Drug Resistant (MDR) International Clones (ICs), associated with certain oxacillinases, are being reported globally. This organism also harbors numerous virulence determinants. In this study, we aim at characterizing A. baumannii isolated from a Spanish hospital in terms of antimicrobial susceptibility, clonality, carbapenemase genes harbored, and virulence determinants expressed.Materials and methodsFifty nine clinical bloodstream isolates were obtained from 2009 until 2013. Antimicrobial Susceptibility Testing was performed according to the CLSI guidelines. PFGE and tri-locus PCR typing were then performed in order to determine local and international clonality. PCRs for the detection of common carbapenemases were also performed. Production of hemolysis, biofilms, siderophores, surface motility, and proteolysis were determined phenotypically. Doubling times for selected strains were also calculated. Finally, statistical analysis for detecting associations between these factors was conducted.Results and discussionCarbapenem non-susceptibility was 84.75%, suggesting the immediate need for intervention. PFGE showed the distribution of the majority of the isolates among 7 clusters. Although all three ICs were detected, IC II was predominant at 71.19%. blaOXA-24-like was the most prevalent carbapenemase (62.71%), followed by blaOXA-58-like (13.56%), and blaOXA-23-like (11.86%). Strains pertaining to IC II, and those harboring blaOXA-24-like, were positively associated with α-hemolysis, production of strong biofilms, and siderophore production. Harboring blaOXA-23-like and blaOXA-58-like was associated with attenuated virulence. These associations suggest that an interplay exists between these factors that could be locally exploited.ConclusionsAn alarmingly high rate of carbapenem non-susceptibility has been detected in this study. There was a predominance of IC II and blaOXA-24-like, and those factors were associated with heightened expression of virulence determinants. This association could be exploited for modifying treatment regimens and for improving on infection control protocols in this hospital.

Contrasting roles of the ABCG2 Q141K variant in prostate cancer

ABCG2 is a membrane transport protein that effluxes growth-promoting molecules, such as folates and dihydrotestosterone, as well as chemotherapeutic agents. Therefore it is important to determine how variants of ABCG2 affect the transporter function in order to determine whether modified treatment regimens may be necessary for patients harboring ABCG2 variants. Previous studies have demonstrated an association between the ABCG2 Q141K variant and overall survival after a prostate cancer diagnosis. We report here that in patients with recurrent prostate cancer, those who carry the ABCG2 Q141K variant had a significantly shorter time to PSA recurrence post-prostatectomy than patients homozygous for wild-type ABCG2 (P=0.01). Transport studies showed that wild-type ABCG2 was able to efflux more folic acid than the Q141K variant (P<0.002), suggesting that retained tumoral folate contributes to the decreased time to PSA recurrence in the Q141K variant patients. In a seemingly conflicting study, it was previously reported that docetaxel-treated Q141K variant prostate cancer patients have a longer survival time. We found this may be due to less efficient docetaxel efflux in cells with the Q141K variant versus wild-type ABCG2. In human prostate cancer tissues, confocal microscopy revealed that all genotypes had a mixture of cytoplasmic and plasma membrane staining, with noticeably less staining in the two homozygous KK patients. In conclusion, the Q141K variant plays contrasting roles in prostate cancer: 1) by decreasing folate efflux, increased intracellular folate levels result in enhanced tumor cell proliferation and therefore time to recurrence decreases; and 2) in patients treated with docetaxel, by decreasing its efflux, intratumoral docetaxel levels and tumor cell drug sensitivity increase and therefore patient survival time increases. Taken together, these data suggest that a patient's ABCG2 genotype may be important when determining a personalized treatment plan.

Abstract TP393: Information Technology to Measure and Drive Outcomes for Acute Ischemic Stroke Patients

Background: The stroke program did not have a formal system to gather data elements needed for driving processes and measuring outcomes. Abstracting data was done by manually auditing every stroke electronic medical record. Purpose: The purpose was to use technology: To collect data for baseline and benchmarking patient demographics and outcomes. To communicate and educate healthcare professionals and improve processes. Methods: Based on the AHA/ASA Get with the Guidelines (GWTG). We identified and abstracted data from discrete fields in the electronic medical record (EMR). Using Clarity the Information Technology (IT) department built discrete fields in EMR to capture 23 missing fields for GWTG. Manual concurrent review and monthly clarity reports were completed. This data was used retrospectively for benchmarking and prospectively for telemedicine and transition of care follow-up. Results: To keep in alignment with AHA/ASA guidelines for GWTG data collection on the 48 GWTG discrete fields 43 are now automated. Random chart review is completed to validate data abstraction. We now have completed demographic and outcomes data on over 600 patients. Conclusions: In conclusion, the use of IT is a reliable and valid way of abstracting GWTG AIS data to provide benchmarking and process improvement. This IT process facilitates clinical data collection, transmission and communication between providers, enabling modification of treatment regimens and transitions of care.

Adverse drug reactions and treatment outcome analysis of DOTS-plus therapy of MDR-TB patients at district tuberculosis centre: A four year retrospective study.

Background:Treatment of multidrug-resistant tuberculosis (MDR-TB) requires the use of expensive and toxic second-line anti-tubercular drugs which are given for a longer duration. Adverse drug reactions (ADRs) of second-line antitubercular drugs affect compliance and thereby treatment outcome. We set out to analyze ADRs and treatment outcome of MDR-TB patients receiving directly observed treatments plus therapy.Materials and Methods:A retrospective study of registered MDR-TB cases at district tuberculosis center during 2010–2014 was performed. Data regarding sociodemographic profile, diagnosis, and treatment as well as ADRs were recorded and evaluated. ADRs were evaluated for causality, severity assessment, management aspects, and impact on treatment outcome.Results:In total 147 ADRs were reported among 72 cases. Most commonly observed ADRs were gastrointestinal (24.5%) followed by self reported weakness (21.23%), psychological (14.38%), joint pain (14.38%), and respiratory symptoms. Discontinuation of the drugs due to ADRs was required in 36 (24.48%) events. ADRs were significantly associated with nontreatment adherence and defaulter outcome. Cure rate was higher in MDR-TB cases with ADRs (59.72%) than MDR-TB cases without ADRs (30.18%).Conclusion:Attention needs to be paid for timely recognition and treatment of ADR with minimum modification of treatment regimen. Equal attention should be paid to MDR-TB without ADR cases to raise over all cure rate.

Treatment outcomes of drug-resistant pulmonary tuberculosis under programmatic management of multidrug-resistant tuberculosis, at tertiary care center in Mumbai

Background: This study was undertaken to analyze the clinical profile and treatment outcome in pulmonary drug-resistant tuberculosis (TB) patients under programmatic management of multidrug-resistant tuberculosis (PMDT) at a tertiary care center in Mumbai. Methodology: A retrospective study was conducted at PMDT site of a tertiary care hospital. The data of 194 pulmonary multidrug-resistant (MDR) TB patients diagnosed at our hospital or prediagnosed patients referred to our hospital were meticulously reviewed to study demography, baseline drug susceptibility to first- and second-line drugs, treatment outcomes, comorbidities, and adverse drug reactions (ADRs). Results: Out of 194 patients, 48.4% (68 cured + 26 treatment completed) were successfully treated, 22 (11.3%) failed on therapy, 39 (20.15%) patients died, 23 (11.8%) defaulted, 26 (13.4%) completed treatment with outcomes unknown, 13 (6.7%) were transferred out and in 3 patients (1.5%) treatment was stopped due to ADRs. Most common ADRs were gastrointestinal 32 (16.4%) and psychiatric 37 (19%). However, there was no statistical significance between the prevalence of ADRs and unfavorable outcomes. Most common comorbidities were GERD 27 (40.2%) and diabetes mellitus 22 (32.8%). Conclusion: Baseline drug susceptibility testing (DST) with rapid diagnostic tests, performing DST for second-line drugs, i.e., fluoroquinolones and aminoglycoside and modification of treatment regimen based on the same at start of MDR treatment has prime importance. Early detection of ADR's and comorbidities and their prompt treatment are also equally important.

Ovarian cancer in the older woman.

Ovarian cancer is the seventh most common cancer in women worldwide and accounts for nearly 4% of all new cases of cancer in women. Almost half of all patients with ovarian cancer are over the age of 65 at diagnosis, and over 70% of deaths from ovarian cancer occur in this same age group. As the population ages, the number of older women with ovarian cancer is increasing. Compared to younger women, older women with ovarian cancer receive less surgery and chemotherapy, develop worse toxicity, and have poorer outcomes. They are also significantly under-represented in clinical trials and thus application of standard treatment regimens can be challenging. Performance status alone has been shown to be an inadequate tool to predict toxicity of older patients from chemotherapy. Use of formal geriatric assessment tools is a promising direction for stratifying older patients on trials. Elderly-specific trials, adjustments to the eligibility criteria, modified treatment regimens, and interventions to decrease morbidities in the vulnerable older population should be encouraged.

Defining risk groups of patients with cancer of unknown primary site and cervical nodal metastases by F-18 fluorodeoxyglucose positron emission tomography and computed tomography imaging

We sought to investigate the clinical utility of F-18 fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) in Taiwanese patients with cancer of unknown primary site (CUP) and cervical nodal metastases. We also aimed to study the impact of F-18 FDG PET/CT on clinical treatment priority in this patient group. Between September 2006 and May 2014, patients with CUP and cervical nodal metastases who underwent F-18 FDG PET/CT imaging study were retrospectively identified. The clinicopathological risk factors and PET parameters were analyzed in relation to 2-year overall survival (OS) rates using univariate and multivariate analyses. Two-year OS curves were plotted with the Kaplan–Meier method. Of the eligible patients (n = 54), 12 (22.2%) had distant metastases (DM) at presentation. A total of 13 (24.1%) and 15 (27.8%) primary tumors were identified by FDG PET/CT imaging and an additional triple biopsy, respectively. The results of multivariate analysis identified smoking [p = 0.033, 95% confidence interval (CI) = 1.197−40.342], a maximum standardized uptake value (SUVmax) of cervical nodes ≥ 14.2 (p = 0.035, 95% CI = 1.134−28.029), and DM at presentation (p = 0.031, 95% CI = 1.257−114.854) as independent predictors of 2-year OS. Specifically, patients who carried ≥ 2 risk factors showed poorer outcomes (70.3% vs. 11.8%, p < 0.001). Fifteen study patients (27.8%) had their treatment modified by FDG PET/CT findings. We conclude that FDG PET/CT is clinically useful in CUP patients not only for tumor staging, but also for modifying treatment regimens.

Review of Select Practice Parameters, Evidence-Based Treatment Algorithms, and International Guidelines for Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare bradykinin-mediated disease that is characterized by recurrent attacks of subcutaneous or submucosal edema, which can be life threatening. HAE affects all ethnic groups equally and does not differentiate between age, sex, or race. However, the availability of therapies varies amongst countries resulting in a lack of uniformity of care. Not only is there a disparity of medication availability, but since HAE is a rare disease, it is frequently overlooked and the diagnosis is missed. Even with diagnosis, treatment and management is often less than optimal. For these reasons, it is essential to have practice parameters and guidelines. In this chapter, we focus on recent guidelines. These guidelines deal with recognition, diagnosis, medical care, patient management, and assessment, all which are essential to provide optimal care to people with a rare and orphan disease. The intent of the guidelines, and thus this chapter, is to reduce morbidity and mortality, and restore a normal quality of life for the patient with HAE. We will review the guidelines from various regions of the world as well as international group recommendations. In addition, specific patient populations such as the pregnant, elderly, and juvenile require modified treatment regimens, and for this reason, we have included these data as well. The intent of this chapter is to aid the practitioner in holistic care of the patient with HAE in order to ultimately provide the best standard of care possible.

Abstract NS1: Access and Use of Information Technologies Among Hypertensive Older Adults to Reduce Stroke Risk

Introduction: Information technology could play a crucial role in enhancing hypertension self-care and reduction of stroke risk, but, little is known of the role and impact of access and use of information technology on blood pressure (BP) control in older adults. Hypothesis: Access and use of information technologies will be associated with increased adherence to self-care activities and BP control in hypertensive older adults? Methods: In this cross-sectional, descriptive study, a total of 151 participants completed a survey to assess hypertension self-care activities, technology utilization, and BP knowledge. Clinical measures were obtained by trained assistants (height, weight and BP). Three BP measurements were obtained at 60-second intervals after resting for 5 minutes. A Pearson product-moment correlation coefficient was used to assess the relationship between information technologies and self-care activities. Results: The mean age of participants was 75 years. Participants were predominantly women (61.7%), retired (78.1%), owned cellphones (76.5%), but most did not have internet access at home (59.7%). In bivariate analyses, having a cellphone was positively associated with Diastolic BP (DBP) (r = .20, p &lt; .05), and a preference for receiving text or email reminders (r = .22, p &lt; .05). Computer use was significantly associated with DBP (r = .17, p &lt; .05), BP knowledge (r = .17, p &lt; .05), seeking health information online (r =.49, p &lt; .01), and belief that internet can be helpful to manage BP (r =.45, p &lt; .01). Internet use was significantly associated with DBP (r = .17, p &lt; .05) and BP knowledge (r = .16, p &lt; .05). Conclusion: The use of electronic technology was significantly correlated with lower BP and better BP knowledge. Internet-based hypertension self-care interventions could promote patient involvement and patient centered-care leading to better adherence and BP control to reduce the risk for stroke. Electronic technologies may facilitate clinical data transmission and communication between patients and providers so providers can modify treatment regimens between visits. However, our results suggest that the lack of internet access could limit the feasibility of internet-based interventions to reduce blood pressure in this population.

Changing Trends in the Susceptibility Pattern of Mycobacterium tuberculosis Over a Decade from a Tertiary Care DOTS Centre Delhi

Study Background: Drug resistance in Mycobacterium tuberculosis is a serious problem all over the world. One of the major factors contributing to drug resistance is delayed detection of drug-resistant isolates, which ultimately leads to delay in initiation of effective chemotherapy. An appropriate modification of treatment regimens, depending upon the susceptibility pattern of Mycobacterium isolates is the keystone for successful treatment of drug-resistant tuberculosis. Material and methods: The study was done to check the susceptibility pattern of both pulmonary and extrapulmonary isolates of Mycobacterium tuberculosis during Aug 2009 - Jun 2012, Phase II (35 month period) and compared it with our previous data of same duration (Aug 2002-Jun 2005, Phase I), to determine the burden of drug resistance in the current situation and to look for the change in resistance pattern over a decade. A total of 154 culture-confirmed Mycobacterium tuberculosis isolates (pulmonary-36, extra-pulmonary-118) were screened for their susceptibility pattern. Drug susceptibility testing was performed by an automated Bac T-Alert 3D, using ‘SIRE’ kit’ provided with Bact Alert 3D system (Biomereiux Pvt Ltd). Result: Current study demonstrated increased drug resistance for streptomycin, isoniazid, rifampicin and ethambutol as 8/36 (22.2%), 23/36 (63.8%), 6/36 (16.6%) and 21/36 (33.3%) respectively in the pulmonary isolates and 39/118 (33%), 71/118 (60.1%), 16/118 (13.5%) and 60/118 (50.8%) among the extra-pulmonary isolates. A significant increase in resistance (p value=0.0001) was observed for streptomycin in current phase as compared with the earlier phase of study while resistance to rifampicin was decreased in pulmonary isolates. However, resistance to streptomycin, isoniazid and ethambutol were significantly increased (p value=0.0001) among extrapulmonary isolates. Conclusion: Resistance to streptomycin has increased at an alarming rate in pulmonary tuberculosis (TB). However, resistance to isoniazid and rifampicin has stabilized over time, this could possibly imply adequacy of DOTS coverage in cases of pulmonary TB. This situation in patients with extra-pulmonary TB is more alarming as this data reveals a dramatic increase of resistance to isoniazid and other first-line agents. The “hidden reservoir” of resistance in extra-pulmonary patients may downgrade the efficacy of the DOTS program in the future.

Drug resistance characteristics and cluster analysis of M. tuberculosis in Chinese patients with multiple episodes of anti-tuberculosis treatment.

BackgroundTuberculosis (TB) patients with multiple episodes of anti-TB treatment represent an important source of TB transmission, as well as a serious threat to the control of drug resistant TB, due to the high risk of multidrug and extensively drug resistance (MDR/XDR) and elongating infectiousness of this patient group. In this study we analyzed the possible risk of development and transmission of MDR and XDR in TB patients with multiple episodes of previous treatment history.MethodsThe study subjects were pulmonary TB patients who had at least two episodes of previous anti-TB treatment. A total of 166 eligible patients were identified from 10 counties/districts distributed in east, west, north, south and central China. Drug susceptibility test (DST) was performed by proportion method on LJ-media for the 1st line anti-TB drugs and a line probe assay was used to detect mutations related to resistance of the key 2nd-line drugs. Genotyping of M. tuberculosis (Mtb) was performed with MIRU-VNTR and Spoligotyping.ResultsResistances to 1st-line drugs was observed in 122 (73.5 %) of the 166 Mtb isolates with 97 (58.4 %) being MDR-TB. Mutations relevant to 2nd-line drug resistance was seen in 63 isolates, including 35 MDR-TB isolates (30 pre-XDR, 5 XDR-TB). The Spoligotyping revealed 83.1 % Mtb isolates belonged to the Beijing family. The MIRU-VNTR based genotyping revealed 32 (19.3 %) of patients were infected with more than one strain. The number of previous TB treatment episode was found being significantly associated with the risk of MDR-TB and XDR-TB. Among the remaining 134 patients infected with a single Mtb strain, MIRU-VNTR revealed a high homogeneity of strain especially within Beijing family despite the polymorphic variations along with geographic locations.ConclusionsThe high genetic relatedness and risk of MDR-TB and subsequent pre-XDR and XDR-TB among repeatedly treated patients suggest the establishment of M/XDR Mtb in this specific patient population. It highlights the urgent needs of providing DST of both 1st- and 2nd-line drugs before and during the medication in China’s MDR-TB control program. Furthermore, the possibility of infection with multiple strains should also be considered to be associated with the drug resistance, which calls for the modification of treatment regimen.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-1331-z) contains supplementary material, which is available to authorized users.

Dynamic Changes in Phenotypic Groups in Patients with Stable Angina Pectoris after Treatment with Xinxuekang Capsule: A Randomized Controlled Trial.

To reveal the cutoff point and influencing factors in the dynamic change in phenotypic group in patients with stable angina pectoris (SAP) after Xinxuekang capsule treatment. Five hundred and seventy-six SAP patients were randomly assigned to receive Xinxuekang (XXK) capsules or Compound Danshen (CDS) tablets for 8 weeks. Global similarity degree analysis and nonlinear mixed effects modeling (NONMEM) were employed to reveal the cutoff points and influencing factors in dynamic changes in the SAP phenotypic group. The phenotypic group was defined as the six phenotypes in SAP, including angina, choking sensation in the chest, palpitations, dark purple lips, ecchymosis on the tongue, and fine-choppy pulse, which were quantitatively evaluated on Days 0, 14, 28, 42, and 56. Variation in the six individual phenotypes and distribution of the SAP phenotypic profile were similar between the two experimental groups, but cutoff points for changes in the SAP phenotypic group were 7.28 and 10.73 weeks in XXK and CDS groups, respectively. Degree of severity of SAP as well as study site significantly affected the tendency for change in the SAP Xueyu Zheng in both XXK and CDS treatment groups. Different Chinese patent drugs affected the tendency for change in phenotypic group in patients with SAP. XXK was superior to CDS in controlling a clinical phenotypic group. Based on global similarity degree analysis and NONMEM, the cutoff point and influencing factors in phenomic variation of SAP may be determined, to improve the development and modification of treatment regimens.

The Clinical Relevance of Gastrointestinal Endoscopy in Pediatric Patients with Suspected Gastrointestinal Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation

Background and aim: Graft-versus-host disease (GVHD) affecting visceral organs is a severe complication of hematopoietic stem cell transplantation (HSCT). GVHD in the gastrointestinal tract (GI-GVHD) is primarily a clinical-based diagnosis, but due to non-specific symptoms histopathology verification is recommended. Data in children concerning the efficacy of endoscopic examination performed due to clinically suspected GI-GVHD is scarce. The aim of this study was to investigate the modification of the pharmacological treatment regimen based on the gastrointestinal histopathology report.Material and Methods: A retrospective clinical study from 3 out of 4 transplantation(s) centers in Sweden including 62 children (40 boys, 22 girls) were enrolled. The patients underwent HSCT during 2000-2012. Endoscopy with biopsies, were performed due to clinically suspected GI-GVHD, <1 year after HSCT. Median age at the time of endoscopy was 4.2 years (0.3-18.6 years).Results: In total, 76 endoscopies were performed. Out of these, 62 % of them were done ≤100 days post-HSCT. A combined upper gastroscopy and lower endoscopy (ileocolon-, colon- or rectosigmoidoscopy) was performed in 59 %, whereas solely lower or upper endoscopy was performed in 37 % and 4 %, respectively. Symptoms at the time of endoscopy consisted of 64 cases with diarrhea, 35 with nausea or vomiting, 31 with abdominal pain and in 10 cases, failure to thrive.GVHD at any biopsy site was confirmed by histopathology in 54%. In 5 of these cases, concomitant viral enteritis was reported (4 CMV, 1 Adenovirus). The proportion of GVHD per number of endoscopy occasions before and after 100 days post-HSCT was 64 % (30/47) and 38% (11/29), respectively. CMV enteritis was detected in one case and posttransplant lymphoproliferative disease (PTLD) in 2 cases. Seven out of the 8 cases with verified viral GI infection were observed < 100 days post-HSCT.53 children had an ongoing additional anti-GVHD treatment at the time of endoscopy, of whom 62 % had histopathology confirmed GVHD, whereas 38 % had normal findings. Among the 23 cases, not treated with additional anti-GVHD treatment pre-endoscopy, 8 (35 %) had histopathological findings consistent with GVHD. Modification of the pharmacological treatment regimen, based on the histopathology reports was done in 38 %. Among the 29 cases with modified treatment regimen, 52% received an initiation or a more intensive anti-GVHD treatment, 28 % a withdrawal of additional anti-GVHD treatment, 7% were subjected to withdrawal of additional anti-GVHD treatment and initiation of anti-viral treatment, and in one patient anti-viral treatment was initiated.Discussion: The clinical usefulness of endoscopy, leading to pharmacological intervention has not previously been investigated in the pediatric HSCT patients with clinically suspected GI-GVHD. Clinicians may hesitate to perform endoscopy in this population due to risks related to general anesthesia/deep sedation and complications such as bleeding, perforations, or septicemia. Conversely, heavy immunosuppressive treatment in patients with viral GI infection might be fatal. We demonstrated that modification of treatment occurred in 38% of the patients, based on the histopathology report. Interestingly, the highest frequency of positive histopathology reports was observed when endoscopy was performed <100 days post-HSCT. During this time period 7 out of 8 cases with viral GI infection, including the 2 cases with severe PTLD, were diagnosed. Furthermore, we also noted that clinical-based diagnosis of GI-GVHD, where additional anti-GVHD treatment was started pre-endoscopy, was incorrect in approximately every third case.Conclusion: Our results provide evidence that there is a clinical relevance in performing endoscopy in children with clinically suspected GI-GVHD and should be performed in all of these children. Endoscopy in these cases will allow the clinician to target treatment, by confirming or rule out two clinically indistinguishable diseases, GVHD and viral GI infection, but also to avoid unnecessary immunosuppressive drugs. DisclosuresNo relevant conflicts of interest to declare.

Population pharmacokinetics and clinical response for artemether-lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Tanzania.

Artemether-lumefantrine (AL) is the first-line treatment for uncomplicated malaria in the second and third trimesters of pregnancy. Its efficacy during pregnancy has recently been challenged due to altered pharmacokinetic (PK) properties in this vulnerable group. The aim of this study was to determine the PK profile of AL in pregnant and nonpregnant women and assess their therapeutic outcome. Thirty-three pregnant women and 22 nonpregnant women with malaria were treated with AL (80/480 mg) twice daily for 3 days. All patients provided five venous plasma samples for drug quantification at random times over 7 days. Inter- and intraindividual variability was assessed, and the effects of covariates were quantified using a nonlinear mixed-effects modeling approach (NONMEM). A one-compartment model with first-order absorption and elimination with linear metabolism from drug to metabolite fitted the data best for both arthemether (AM) and lumefantrine (LF) and their metabolites. Pregnancy status and diarrhea showed a significant influence on LF PK. The relative bioavailability of lumefantrine and its metabolism rate into desmethyl-lumefantrine were, respectively, 34% lower and 78% higher in pregnant women than in nonpregnant patients. The overall PCR-uncorrected treatment failure rates were 18% in pregnant women and 5% in nonpregnant women (odds ratio [OR] = 4.04; P value of 0.22). A high median day 7 lumefantrine concentration was significantly associated with adequate clinical and parasitological response (P = 0.03). The observed reduction in the relative bioavailability of lumefantrine in pregnant women may explain the higher treatment failure in this group, mostly due to lower posttreatment prophylaxis. Hence, a modified treatment regimen of malaria in pregnancy should be considered.

Body Composition of Adults Living with HIV in Two Cities in Ghana

Background: Human immunodeficiency virus (HIV) infection affects nutrition through increases in resting energy expenditure, reduction in food intake, nutrient malabsorption and loss, and complex metabolic alterations that culminates in weight loss and wasting common in acquired immune deficiency syndrome. This study sought to assess body composition of adults living with HIV. Methods: This cross-sectional study involved 63 adults living with HIV in two cities in Ghana. Socio-demographic information was obtained with a questionnaire. Body composition was measured with the deuterium dilution method and with anthropometry. Data analysis was done by SPSS version 16.0. Descriptive statistics and frequencies and percentages were calculated. The independent sample t-test was used for comparisons between groups. Differences were considered significant at p < 0.05. Results: Median (interquartile range) body mass index was within normal for both males (20.6, (18.9, 21.6 kg/m 2 )) and females (21.6; (19.8, 24.9 kg/m 2 )). Underweight (7.9%) and overweight (19.0%) were however prevalent. Males have significantly higher median fat free mass than females (52.7 kg versus 40.1 kg; p<0.0001) kg whereas females have a significantly higher fat mass (27.5% versus 12.2%; p<0.0001), and high abdominal obesity (49.0%). Almost 21% and 8% of participants have depleted fat free mass and fat mass respectively. Conclusion: The study demonstrates some level of malnutrition among the study participants. This underscores the importance of monitoring body composition in people living with HIV. Measurements of waist and hip circumferences should form part of the assessment tools. This will help in identifying those on antiretroviral treatment that are at risk of developing abdominal obesity and thereby supporting the need for modifying treatment regimens when necessary. In addition, regular screening for hypertension, diabetes and other indicators of metabolic abnormalities is recommended.