Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond.

Front Immunol. 2018;9:636

Authors: de Valles-Ibáñez G, Esteve-Solé A, Piquer M, González-Navarro EA, Hernandez-Rodriguez J, Laayouni H, González-Roca E, Plaza-Martin AM, Deyà-Martínez Á, Martín-Nalda A, Martínez-Gallo M, García-Prat M, Del Pino-Molina L, Cuscó I, Codina-Solà M, Batlle-Masó L, Solís-Moruno M, Marquès-Bonet T, Bosch E, López-Granados E, Aróstegui JI, Soler-Palacín P, Colobran R, Yagüe J, Alsina L, Juan M, Casals F

Abstract
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15-24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls.

PMID: 29867916 [PubMed]

Whole-Exome Sequencing in Searching for New Variants Associated With the Development of Parkinson's Disease.

Front Aging Neurosci. 2018;10:136

Authors: Shulskaya MV, Alieva AK, Vlasov IN, Zyrin VV, Fedotova EY, Abramycheva NY, Usenko TS, Yakimovsky AF, Emelyanov AK, Pchelina SN, Illarioshkin SN, Slominsky PA, Shadrina MI

Abstract
Background: Parkinson's disease (PD) is a complex disease with its monogenic forms accounting for less than 10% of all cases. Whole-exome sequencing (WES) technology has been used successfully to find mutations in large families. However, because of the late onset of the disease, only small families and unrelated patients are usually available. WES conducted in such cases yields in a large number of candidate variants. There are currently a number of imperfect software tools that allow the pathogenicity of variants to be evaluated. Objectives: We analyzed 48 unrelated patients with an alleged autosomal dominant familial form of PD using WES and developed a strategy for selecting potential pathogenetically significant variants using almost all available bioinformatics resources for the analysis of exonic areas. Methods: DNA sequencing of 48 patients with excluded frequent mutations was performed using an Illumina HiSeq 2500 platform. The possible pathogenetic significance of identified variants and their involvement in the pathogenesis of PD was assessed using SNP and Variation Suite (SVS), Combined Annotation Dependent Depletion (CADD) and Rare Exome Variant Ensemble Learner (REVEL) software. Functional evaluation was performed using the Pathway Studio database. Results: A significant reduction in the search range from 7082 to 25 variants in 23 genes associated with PD or neuronal function was achieved. Eight (FXN, MFN2, MYOC, NPC1, PSEN1, RET, SCN3A and SPG7) were the most significant. Conclusions: The multistep approach developed made it possible to conduct an effective search for potential pathogenetically significant variants, presumably involved in the pathogenesis of PD. The data obtained need to be further verified experimentally.

PMID: 29867446 [PubMed]

Clinical Report: Warsaw Breakage Syndrome with small radii and fibulae.

Am J Med Genet A. 2017 Nov;173(11):3075-3081

Authors: Eppley S, Hopkin RJ, Mendelsohn B, Slavotinek AM

Abstract
We present two new cases of Warsaw Breakage Syndrome (WABS), an autosomal recessive cohesinopathy, in sisters aged 13 and 11 years who both had compound heterozygous mutations in DDX11. After exclusion of Fanconi anemia, Bloom syndrome and Nijmegen breakage syndrome, whole exome sequencing revealed two novel variants-c.1523T>G, predicting (p.Leu508Arg) and c.1949-1G>A (IVS19-1G>A), that were confirmed with Sanger sequencing in both affected individuals. DDX11 encodes an iron-sulfur-containing DNA helicase, and mutations in this gene have been reported in the five WABS cases previously identified to date. The sisters reported here display the distinguishing clinical features of WABS: pre- and post-natal growth restriction, microcephaly, intellectual disability, sensorineural hearing loss with cochlear abnormalities, and facial dysmorphic features. In addition, our cases had early menarche at 8 and 10 years of age, bilateral small thumbs, and the younger, more severely affected sister had small fibulae. These findings broaden the WABS phenotype and the limb malformations demonstrate further clinical overlap with Fanconi anemia and other cohesinopathies, such as Roberts Syndrome.

PMID: 28960803 [PubMed - indexed for MEDLINE]

Coexistence of mutations in keratin 10 (KRT10) and the mitochondrial genome in a patient with ichthyosis with confetti and Leber's hereditary optic neuropathy.

Am J Med Genet A. 2017 Nov;173(11):3093-3097

Authors: Kalinska-Bienias A, Pollak A, Kowalewski C, Lechowicz U, Stawinski P, Gergont A, Kosinska J, Pronicka E, Kowalski P, Wozniak K, Ploski R

Abstract
Ichthyosis with confetti (IWC) is a severe congenital genodermatosis characterized by ichthyosiform erythroderma since birth and confetti-like spots of normal skin appearing in childhood as a results of revertant mosaicism. This disorder is caused by mutations in KRT10 or KRT1 genes. We report a 16-year-old boy who presented ichthyosiform erythroderma with severe desquamation since birth and gradually worsening psycho-neurological symptoms (mental retardation, ataxia, dystonia, hypoacusis). The patient conspicuously lacked typical confetti-like spots at the age of 16. The molecular diagnostics by the whole exome sequencing showed a novel de novo (c.1374-2A>C) mutation in the KRT10 gene responsible for the development of IWC (KRT10 defect was confirmed by immunofluorescent study). Concurrently, the m.14484T>C mutation in mitochondrial MTND6 gene (characteristic for Leber's hereditary optic neuropathy or LHON) was detected in patient, his mother and brother. LHON causes frequent inherited blindness typically appearing during young adult life whose expression can be triggered by additional factors such as smoking or alcohol exposure. We speculate the effects of KRT10 and LHON mutations influence each other-skin inflammatory reaction due to severe ichthyosis might trigger the development of psychoneurological abnormalities whereas the mitochondrial mutation may reduce revertant mosaicism phenomenon resulting in the lack of confetti-like spots characteristic for IWC. However, based on a single case we should be cautious about attributing phenotypes to digenic mechanisms without functional data.

PMID: 28944608 [PubMed - indexed for MEDLINE]

De novo mutations in HNRNPU result in a neurodevelopmental syndrome.

Am J Med Genet A. 2017 Nov;173(11):3003-3012

Authors: Yates TM, Vasudevan PC, Chandler KE, Donnelly DE, Stark Z, Sadedin S, Willoughby J, Broad Center for Mendelian Genomics, DDD study, Balasubramanian M

Abstract
Exome sequencing in the context of developmental disorders is a useful technique, but variants found need to be interpreted in the context of detailed phenotypic information. Whole gene deletions and loss-of-function-mutations in the HNRNPU gene have been associated with intellectual disability and seizures in some patients. However, a unifying syndromic phenotype has not been previously elucidated. Here, we report a total of seven patients (six patients identified through the Wellcome Trust Deciphering Developmental Disorders study, with one additional patient), who have heterozygous de novo mutations in HNRNPU. These were found via trio-based exome sequencing. All but one of the mutations is predicted to cause loss-of-function. These patients have dysmorphic features in common, including prominent eyebrows, long palpebral fissures, overhanging columella, and thin upper lip. All patients have developmental delay and intellectual disability (ID), ranging from moderate to severe. Seizures are common from early childhood. These initially occur in the context of febrile episodes. This series demonstrates common phenotypic features, including emerging dysmorphism, associated with heterozygous HNRNPU mutations. This allows us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency.

PMID: 28944577 [PubMed - indexed for MEDLINE]

The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies.

Am J Med Genet A. 2017 Nov;173(11):3022-3028

Authors: Shen W, Heeley JM, Carlston CM, Acuna-Hidalgo R, Nillesen WM, Dent KM, Douglas GV, Levine KL, Bayrak-Toydemir P, Marcelis CL, Shinawi M, Carey JC

Abstract
De novo, germline variants in DNMT3A cause Tatton-Brown-Rahman syndrome (TBRS). This condition is characterized by overgrowth, distinctive facial appearance, and intellectual disability. Somatic DNMT3A variants frequently occur in hematologic malignances, particularly acute myeloid leukemia. The Arg882 residue is the most common site of somatic DNMT3A variants, and has also been altered in patients with TBRS. Here we present three additional patients with this disorder attributed to DNMT3A germline variants that disrupt the Arg882 codon, suggesting that this codon may be a germline mutation hotspot in this disorder. Furthermore, based on the investigation of previously reported variants in patients with TBRS, we found overlap in the spectrum of DNMT3A variants observed in this disorder and somatic variants in hematological malignancies.

PMID: 28941052 [PubMed - indexed for MEDLINE]

HLX is a candidate gene for a pattern of anomalies associated with congenital diaphragmatic hernia, short bowel, and asplenia.

Am J Med Genet A. 2017 Nov;173(11):3070-3074

Authors: Farrell SA, Sodhi S, Marshall CR, Guerin A, Slavotinek A, Paton T, Chong K, Sirkin WL, Scherer SW, Bérubé-Simard FA, Pilon N

Abstract
Isolated congenital diaphragmatic hernia is often a sporadic event with a low recurrence risk. However, underlying genetic etiologies, such as chromosome anomalies or single gene disorders, are identified in a small number of individuals. We describe two fetuses with a unique pattern of multiple congenital anomalies, including diaphragmatic hernia, short bowel and asplenia, born to first-cousin parents. Whole exome sequencing showed that both were homozygous for a missense variant, c.950A>C, predicting p.Asp317Ala, in the H.20-Like Homeobox 1 (HLX1) gene. HLX is a homeobox transcription factor gene which is relatively conserved across species. Hlx homozygous null mice have a short bowel and reduced muscle cells in the diaphragm, closely resembling the anomalies in the two fetuses and we therefore suggest that the HLX mutation in this family could explain the fetal findings.

PMID: 28898547 [PubMed - indexed for MEDLINE]

Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Evaluations Following Single Oral Doses of GSK2330672 in Healthy Japanese Volunteers.

Clin Pharmacol Drug Dev. 2018 Jun 05;:

Authors: Ino H, Endo A, Wakamatsu A, Ogura H, Numachi Y, Kendrick S

Abstract
GSK2330672 is an inhibitor of the ileal bile acid transporter, designed to have minimal systemic exposure, and is under development as a potential therapeutic for pruritus associated with primary biliary cholangitis and other cholestatic liver diseases. A phase 1, double-blind, placebo-controlled, 4-period crossover study was conducted to evaluate the safety, tolerability, and pharmacokinetic/pharmacodynamic characteristics of GSK2330672 in healthy Japanese participants. Sixteen healthy male participants received single oral doses of GSK2330672 (10-180 mg) or placebo in each period. No serious adverse events and no adverse events leading to study discontinuation or withdrawal were reported. Drug-related adverse events reported included gastrointestinal symptoms (mostly diarrhea) and positive fecal occult blood tests, and were all mild and resolved without any interventions. GSK2330672 was undetectable in the majority of participants' plasma. Pharmacodynamic observations included a tendency for total serum bile acids to reduce and for serum 7α-hydroxy-4-cholesten-3-one, a key intermediate of bile acid synthesis, to increase with increasing doses of GSK2330672. In the context of recently published indications of potential efficacy for cholestatic pruritus in non-Japanese populations, these data support further evaluations of GSK2330672 in Japanese patients.

PMID: 29870578 [PubMed - as supplied by publisher]

Glycaemic adverse drug reactions from anti-neoplastics used in treating pancreatic cancer.

Niger J Clin Pract. 2017 Nov;20(11):1422-1427

Authors: Yang J, Jia B, Yan J, He J

Abstract
PURPOSE: Pancreatic carcinoma is the most lethal cancer, with a 5-year survival rate of <5%. Hyperglycemia is one of the severe adverse drug reactions (ADRs) in cancer treatment. The aim was to analyze the blood glucose-related ADR of antineoplastics in treating pancreatic cancer.
MATERIALS AND METHODS: Antineoplastic drugs were selected from Martindale-The Complete Drug Reference (36th edition). ADR data were extracted from VigiBase, the WHO Uppsala Monitoring Centre, and the WHO's specialist center for drug safety.
RESULTS: Nineteen antineoplastic drugs were selected; VigiBase provided their ADR records including total 235,625 records and 27 heading ADR items, 1348 records of glucose metabolism disorders (GMDs), and 807 records of hyperglycemia. Based on the emphasized nine antineoplastic drugs with high hyperglycemic ADR incidence, we found: fluorouracil, sorafenib and pemetrexed with high ADR record of metabolism and nutrition disorders; fludarabine and flutamide with high ADR of GMD ratio. All the hyperglycemia ratios of the 9 antineoplastics were more than 50.0%, except pemetrexed and sorafenib. Thoroughly, doxorubicin carried high absolute records and ratios in hyperglycemic conditions.
CONCLUSIONS: Pancreatic carcinoma is an aggressive malignancy typically associated with severe hyperglycemia. Furthermore, hyperglycemia is one of the severe ADRs from antineoplastics, which must be paid special attention to when treating in pancreatic carcinoma, especially doxorubicin, fluorouracil, and gemcitabine. Such real-time monitoring or pretreatment gene test can be suggested.

PMID: 29303126 [PubMed - indexed for MEDLINE]

Mining Adverse Events of Dietary Supplements from Product Labels by Topic Modeling.

Stud Health Technol Inform. 2017;245:614-618

Authors: Wang Y, Gunashekar DR, Adam TJ, Zhang R

Abstract
The adverse events of the dietary supplements should be subject to scrutiny due to their growing clinical application and consumption among U.S. adults. An effective method for mining and grouping the adverse events of the dietary supplements is to evaluate product labeling for the rapidly increasing number of new products available in the market. In this study, the adverse events information was extracted from the product labels stored in the Dietary Supplement Label Data-base (DSLD) and analyzed by topic modeling techniques, specifically Latent Dirichlet Allocation (LDA). Among the 50 topics generated by LDA, eight topics were manually evaluated, with topic relatedness ranging from 58.8% to 100% on the product level, and 57.1% to 100% on the ingredient level. Five out of these eight topics were coherent groupings of the dietary supplements based on their adverse events. The results demonstrated that LDA is able to group supplements with similar adverse events based on the dietary supplement labels. Such information can be potentially used by consumers to more safely use dietary supplements.

PMID: 29295169 [PubMed - indexed for MEDLINE]

Automating the Identification of Patient Safety Incident Reports Using Multi-Label Classification.

Stud Health Technol Inform. 2017;245:609-613

Authors: Wang Y, Coiera E, Runciman W, Magrabi F

Abstract
Automated identification provides an efficient way to categorize patient safety incidents. Previous studies have focused on identifying single incident types relating to a specific patient safety problem, e.g., clinical handover. In reality, there are multiple types of incidents reflecting the breadth of patient safety problems and a single report may describe multiple problems, i.e., it can be assigned multiple type labels. This study evaluated the abilty of multi-label classification methods to identify multiple incident types in single reports. Three multi-label methods were evaluated: binary relevance, classifier chains and ensemble of classifier chains. We found that an ensemble of classifier chains was the most effective method using binary Support Vector Machines with radial basis function kernel and bag-of-words feature extraction, performing equally well on balanced and stratified datasets, (F-score: 73.7% vs. 74.7%). Classifiers were able to identify six common incident types: falls, medications, pressure injury, aggression, documentation problems and others.

PMID: 29295168 [PubMed - indexed for MEDLINE]

Phenotyping and Visualizing Infusion-Related Reactions for Breast Cancer Patients.

Stud Health Technol Inform. 2017;245:599-603

Authors: Sun D, Sarda G, Skube SJ, Blaes AH, Khairat S, Melton GB, Zhang R

Abstract
Infusion-related reactions (IRRs) are typical adverse events for breast cancer patients. Detecting IRRs and visualizing their occurance associated with the drug treatment would potentially assist clinicians to improve patient safety and help researchers model IRRs and analyze their risk factors. We developed and evaluated a phenotyping algorithm to detect IRRs for breast cancer patients. We also designed a visualization prototype to render IRR patients' medications, lab tests and vital signs over time. By comparing with the 42 randomly selected doses that are manually labeled by a domain expert, the sensitivity, positive predictive value, specificity, and negative predictive value of the algorithms are 69%, 60%, 79%, and 85%, respectively. Using the algorithm, an incidence of 6.4% of patients and 1.8% of doses for docetaxel, 8.7% and 3.2% for doxorubicin, 10.4% and 1.2% for paclitaxel, 16.1% and 1.1% for trastuzumab were identified retrospectively. The incidences estimated are consistent with related studies.

PMID: 29295166 [PubMed - indexed for MEDLINE]

Mining Adverse Drug Reactions in Social Media with Named Entity Recognition and Semantic Methods.

Stud Health Technol Inform. 2017;245:322-326

Authors: Chen X, Deldossi M, Aboukhamis R, Faviez C, Dahamna B, Karapetiantz P, Guenegou-Arnoux A, Girardeau Y, Guillemin-Lanne S, Lillo-Le-Louët A, Texier N, Burgun A, Katsahian S

Abstract
Suspected adverse drug reactions (ADR) reported by patients through social media can be a complementary source to current pharmacovigilance systems. However, the performance of text mining tools applied to social media text data to discover ADRs needs to be evaluated. In this paper, we introduce the approach developed to mine ADR from French social media. A protocol of evaluation is highlighted, which includes a detailed sample size determination and evaluation corpus constitution. Our text mining approach provided very encouraging preliminary results with F-measures of 0.94 and 0.81 for recognition of drugs and symptoms respectively, and with F-measure of 0.70 for ADR detection. Therefore, this approach is promising for downstream pharmacovigilance analysis.

PMID: 29295108 [PubMed - indexed for MEDLINE]

Unblinded ASCOT study results do not rule out that muscle symptoms are an adverse effect of statins.

Evid Based Med. 2017 12;22(6):210

Authors: Adhyaru BB, Jacobson TA

PMID: 29056606 [PubMed - indexed for MEDLINE]

Incidence of early anxiety aggravation in trials of selective serotonin reuptake inhibitors in depression.

Acta Psychiatr Scand. 2017 10;136(4):343-351

Authors: Näslund J, Hieronymus F, Emilsson JF, Lisinski A, Nilsson S, Eriksson E

Abstract
OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) may aggravate anxiety and agitation during the first days of treatment but the frequency of such reactions remains unknown.
METHOD: We analysed patient-level data from placebo-controlled trials of sertraline, paroxetine or citalopram in depressed adults. Somatic anxiety, psychic anxiety and psychomotor agitation as assessed using the Hamilton Depression Rating Scale (HDRS) were analysed in all trials (n = 8262); anxiety-related adverse events were analysed in trials investigating paroxetine and citalopram (n = 5712).
RESULTS: After one but not two weeks, patients on an SSRI were more likely than those on placebo to report enhanced somatic anxiety (adjusted risk 9.3% vs. 6.7%); likewise, mean rating of somatic anxiety was higher in the SSRI group. In contrast, patients receiving an SSRI were less likely to report aggravation of psychic anxiety (adjusted risk: 7.0% vs. 8.5%) with mean rating of psychic anxiety and agitation being lower in the SSRI group. The adverse event 'nervousness' was more common in patients given an SSRI (5.5% vs. 2.5%). Neither aggravation of HDRS-rated anxiety nor anxiety-related adverse events predicted poor antidepressant response.
CONCLUSION: Whereas an anxiety-reducing effect of SSRIs is notable already during the first week of treatment, these drugs may also elicit an early increase in anxiety in susceptible subjects that however does not predict a poor subsequent response to treatment.

PMID: 28859218 [PubMed - indexed for MEDLINE]

Safety of the 2D/3D direct-acting antiviral regimen in HCV-induced Child-Pugh A cirrhosis - A pooled analysis.

J Hepatol. 2017 Oct;67(4):700-707

Authors: Poordad F, Nelson DR, Feld JJ, Fried MW, Wedemeyer H, Larsen L, Cohen DE, Cohen E, Mobashery N, Tatsch F, Foster GR

Abstract
BACKGROUND & AIMS: Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit-risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r±DSV) in patients with Child-Pugh A cirrhosis, we undertook a comprehensive review of AbbVie-sponsored clinical trials enrolling patients with Child-Pugh A cirrhosis.
METHODS: Twelve phase II or III clinical trials of the 2-DAA regimen of OBV/PTV/r±ribavirin (RBV) or the 3-DAA regimen of OBV/PTV/r+DSV±RBV that included patients with Child-Pugh A cirrhosis were reviewed; patients who completed treatment by November 16, 2015 were included in a pooled, post hoc safety assessment. The number and percentage of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs consistent with hepatic decompensation were reported.
RESULTS: In 1,066 patients with Child-Pugh A cirrhosis, rates of serious TEAEs and TEAEs leading to study drug discontinuation were 5.3% (95% confidence interval [CI]: 4.1-6.8) and 2.2% (95% CI: 1.4-3.2), respectively. Thirteen patients (1.2%; 95% CI: 0.7-2.1) had a TEAE that was consistent with hepatic decompensation. The most frequent TEAEs consistent with hepatic decompensation were ascites (n=8), esophageal variceal hemorrhage (n=4), and hepatic encephalopathy (n=2).
CONCLUSIONS: This pooled analysis in 1,066 HCV-infected patients with Child-Pugh A cirrhosis confirms the safety of OBV/PTV/r±DSV±RBV in this population. These results support the use of OBV/PTV/r±DSV±RBV in this high-priority population. Lay summary: This pooled safety analysis in 1,066 HCV-infected patients with compensated cirrhosis, receiving treatment with ombitasvir, paritaprevir, and ritonavir with or without dasabuvir, with or without ribavirin, shows that the rate of hepatic decompensation events was similar to previously reported rates in untreated patients.

PMID: 28645740 [PubMed - indexed for MEDLINE]

Impact of an Integrated Antibiotic Allergy Testing Program on Antimicrobial Stewardship: A Multicenter Evaluation.

Clin Infect Dis. 2017 Jul 01;65(1):166-174

Authors: Trubiano JA, Thursky KA, Stewardson AJ, Urbancic K, Worth LJ, Jackson C, Stevenson W, Sutherland M, Slavin MA, Grayson ML, Phillips EJ

Abstract
Background: Despite the high prevalence of patient-reported antibiotic allergy (so-called antibiotic allergy labels [AALs]) and their impact on antibiotic prescribing, incorporation of antibiotic allergy testing (AAT) into antimicrobial stewardship (AMS) programs (AAT-AMS) is not widespread. We aimed to evaluate the impact of an AAT-AMS program on AAL prevalence, antibiotic usage, and appropriateness of prescribing.
Methods: AAT-AMS was implemented at two large Australian hospitals during a 14-month period beginning May 2015. Baseline demographics, AAL history, age-adjusted Charlson comorbidity index, infection history, and antibiotic usage for 12 months prior to testing (pre-AAT-AMS) and 3 months following testing (post-AAT-AMS) were recorded for each participant. Study outcomes included the proportion of patients who were "de-labeled" of their AAL, spectrum of antibiotic courses pre- and post-AAT-AMS, and antibiotic appropriateness (using standard definitions).
Results: From the 118 antibiotic allergy-tested patients, 226 AALs were reported (mean, 1.91/patient), with 53.6% involving 1 or more penicillin class drug. AAT-AMS allowed AAL de-labeling in 98 (83%) patients-56% (55/98) with all AALs removed. Post-AAT, prescribing of narrow-spectrum penicillins was more likely (adjusted odds ratio [aOR], 2.81, 95% confidence interval [CI], 1.45-5.42), as was narrow-spectrum β-lactams (aOR, 3.54; 95% CI, 1.98-6.33), and appropriate antibiotics (aOR, 12.27; 95% CI, 5.00-30.09); and less likely for restricted antibiotics (aOR, 0.16; 95% CI, .09-.29), after adjusting for indication, Charlson comorbidity index, and care setting.
Conclusions: An integrated AAT-AMS program was effective in both de-labeling of AALs and promotion of improved antibiotic usage and appropriateness, supporting the routine incorporation of AAT into AMS programs.

PMID: 28520865 [PubMed - indexed for MEDLINE]

Trends, causes and timing of 30-day readmissions after hospitalization for heart failure: 11-year population-based analysis with linked data.

Int J Cardiol. 2017 Dec 01;248:246-251

Authors: Fernandez-Gasso L, Hernando-Arizaleta L, Palomar-Rodríguez JA, Abellán-Pérez MV, Pascual-Figal DA

Abstract
BACKGROUND: Reliable data are necessary if the burden of early readmissions following hospitalization for heart failure (HF) is to be addressed. We studied unplanned 30-day readmissions, their causes and timing over an 11-year period, using population-based linked data.
METHODS: All hospitalizations from 2003 to 2013 were analyzed by using administrative linked data based on the Minimum Basic Set discharge registry of the Department of Health (Region of Murcia, Spain). Index hospitalizations with HF as principal diagnosis (n=27,581) were identified. Transfers between centers were merged into one discharge. Readmissions were defined as unplanned admissions to any hospital within 30-days after discharge.
RESULTS: In the 2003-2013 period, 30-day readmission rates had a relative mean annual growth of +1.36%, increasing from 17.6% to 22.1%, with similar trends for cardiovascular and non-cardiovascular causes. The figure of 22.1% decreased to 19.8% when only same-hospital readmissions were considered. Most readmissions were due to cardiovascular causes (60%), HF being the most common single cause (34%). The timing of readmission shows an early peak on the fourth day post discharge (+13.29%) due to causes other than HF, followed by a gradual decline (-3.32%); readmission for HF decreased steadily from the first day (-2.22%). Readmission for HF (12.7%) or non-cardiovascular causes (13.3%) had higher in-hospital mortality rates than the index hospitalization (9.2%, p<0.001). Age and comorbidity burden were the main predictors of any readmission, but the performance of a predictive model was poor.
CONCLUSION: These findings support the need for population-based strategies to reduce the burden of early-unplanned readmissions.

PMID: 28801153 [PubMed - indexed for MEDLINE]

The First Free Africans in America: HLA Study in San Basilio de Palenque (Colombia).

Hum Immunol. 2018 Jun 01;:

Authors: Arnaiz-Villena A, Juarez I, Palacio-Gruber J, Muñiz E, Campos C, Martinez-Laso J, Nieto J, Lopez-Nares A, Martin-Villa JM, Silvera C

Abstract
Original San Basilio de Palenque population (North Colombia) fled from Spanish traders that carried them as slaves and they funded in nearby Maria mountains a fortified town (Palenque). They started helping new Africans brought as slaves to flee and join them. Most of them spoke a Bantu-Congo language and nowadays they speak the only one extant Bantu-Spanish Creole language. Spanish Crown were forced to issue a decree declaring them free (1691 AD), more than 100 years before than Haiti Republic existed. HLA-A, -B, -DRB1 and -DQB1 alleles were studied and further computer procedures were performed with Arlequin 3.5 software. No Amerindian or Europeans gene flow to this population was found. However, three specific HLA extended haplotypes are found in this population, which may reflect an isolation from other Africans or Afro-Americans also. This may be due to the maintenance of their own African culture, and even their unique Creole language.

PMID: 29864459 [PubMed - as supplied by publisher]

Under explored epigenetic modulators: role in glioma chemotherapy.

Eur J Pharmacol. 2018 Jun 01;:

Authors: Chen YH, Zeng WJ, Wen ZP, Chen Q, Chen XP

Abstract
Patients with somatic mutations of epigenetic regulators are characterized by aberrant chromatin modification patterns. Recent mechanistic studies pairing chemical tool compounds and deep-sequencing technology have greatly broadened our understanding of epigenetic regulation in glioma progression and underpinned alternative treatment of epigenetic inhibitors. However, the effect of most inhibitors is condition-dependent, and the overall results of clinical trials still have not been applied to patients. There is an intense need to develop more potent and specific compounds as well as identify the population who may achieve clinical benefits. Besides, combination therapy with conventional therapeutics is another alternative strategy. In this review, we summarize well-characterized chemical probes in glioma research and clinical translation. We also discuss the target population and combination of therapy regimens of various agents. In a holistic sense, we try to provide guidance for selecting targeted chemical probes and pave the way for personalized rational therapy.

PMID: 29864410 [PubMed - as supplied by publisher]