Disease burden of bacteraemia with extended-spectrum beta-lactamase-producing and carbapenem-resistant Enterobacterales in Korea.

BACKGROUND: Despite the significant impact of multi-drug-resistant bacteraemia, especially extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) and carbapenem-resistant Enterobacterales (CRE), the burden of disease has not been investigated thoroughly. AIM: To evaluate the clinical outcomes and socio-economic burden of ESBL-E and CRE bacteraemia nationwide in the Republic of Korea. METHODS: A search was undertaken for all cases of ESBL-E and CRE bacteraemia and matched controls in 10 hospitals in the Republic of Korea over 6 months. Patients with ESBL-E or CRE bacteraemia were classified as the R group, and matched controls with antibiotic-susceptible bacteraemia and without infection were classified as the S and N groups, respectively. Patients' clinical data were collected, and the economic burden was estimated based on medical expenses, loss of productivity and total costs. FINDINGS: In total, 795 patients were identified, including 265 patients with ESBL-E or CRE bacteraemia and their matched controls. The mean total length of stay for patients with ESBL-E and CRE in the R group was 1.53 and 1.90 times that of patients in the S group, respectively. The 90-day mortality rates for ESBL-E in the R and S groups were 12.1% and 5.6%, respectively, and the corresponding figures for CRE were 28.6% and 12.0%. There were significant differences in the total costs between the R, S and N groups for both ESBL-E and CRE (ESBL-E: $11,151 vs $8712 vs $6063, P=0.004; CRE: $40,464 vs $8748 vs $7279, P=0.024). CONCLUSION: The clinical and economic burden imposed by ESBL-E or CRE bacteraemia was extremely high. These findings suggest that efforts to control resistant bacteraemia are necessary to reduce this burden.

Development of Allison scanner to measure transverse emittance at low energy beam transport of rare-isotope accelerator complex for ON-line experiments.

The Rare-isotope Accelerator complex for ON-line experiments is a heavy-ion accelerator facility that accelerates a stable or rare isotope beam up to 400 kW with an energy of 200 MeV/u. Various heavy-ion beams are generated from the Electron Cyclotron Resonance Ion Source, with an energy of 10 keV/u and separated according to A/Q at the first dipole magnet (DM). To measure beam transverse emittance at the Low Energy Beam Transport section, two Allison scanners are installed behind the DM for the X and Y directions. It consist of a servo motor for driving, a Faraday cup for current measurement, deflection plates, and electronic device. The measurable range of beam angle in of the Allison scanner is determined by the structure of the deflection plate and designed based on mathematical calculations. Experimental Physics and Industrial Control System (EPICS) is adopted to integrate and control a variety of devices. To control the complex measurement sequence of the Allison scanner, an EPICS sequencer module was used. Normalized emittance is calculated by python code with Pyepics module using phase space distribution data. In this paper, we present the detailed design of the Allison scanner, the configuration of the control system, and the experimental results using an Ar9+ 30 µA beam.

United we thrive: friendship and subsequent physical, behavioural and psychosocial health in older adults (an outcome-wide longitudinal approach).

AIMS: Three factors converge to underscore the heightened importance of evaluating the potential health/well-being effects of friendships in older adulthood. First, policymakers, scientists, and the public alike are recognizing the importance of social relationships for health/well-being and creating national policies to promote social connection. Second, many populations are rapidly aging throughout the world. Third, we currently face what some call a 'friendship recession'. Although, growing research documents associations between friendship with better health and well-being, friendship can also have a 'dark side' and can potentially promote negative outcomes. To better capture friendship's potential heterogeneous effects, we took an outcome-wide analytic approach. METHODS: We analysed data from 12,998 participants in the Health and Retirement Study (HRS) - a prospective and nationally representative cohort of U.S. adults aged >50, and, evaluated if increases in friendship strength (between t0; 2006/2008 and t1; 2010/2012) were associated with better health/well-being across 35 outcomes (in t2; 2014/2016). To assess friendship strength, we leveraged all available friendship items in HRS and created a composite 'friendship score' that assessed the following three domains: (1) friendship network size, (2) friendship network contact frequency and (3) friendship network quality. RESULTS: Stronger friendships were associated with better outcomes on some indicators of physical health (e.g. reduced risk of mortality), health behaviours (e.g. increased physical activity) and nearly all psychosocial indicators (e.g. higher positive affect and mastery, as well as lower negative affect and risk of depression). Friendship was also associated with increased likelihood of smoking and heavy drinking (although the latter association with heavy drinking did not reach conventional levels of statistical significance). CONCLUSIONS: Our findings indicate that stronger friendships can have a dual impact on health and well-being. While stronger friendships appear to mainly promote a range of health and well-being outcomes, stronger friendships might also promote negative outcomes. Additional research is needed, and any future friendship interventions and policies that aim to enhance outcomes should focus on how to amplify positive outcomes while mitigating harmful ones.

Appropriateness of antibiotic use for patients with asymptomatic bacteriuria or urinary tract infection with positive urine culture: a retrospective observational multi-centre study in Korea.

BACKGROUND: Antibiotic resistance threatens public health worldwide, and inappropriate use of antibiotics is one of the main causes. AIM: To evaluate qualitative use of antibiotics in asymptomatic bacteriuria (ABU) and urinary tract infection (UTI). METHODS: Cases of positive urine culture (≥105 colony-forning units/mL) performed in inpatient, outpatient and emergency departments in April 2021 were screened in 26 hospitals in the Republic of Korea. The cases were classified as ABU, lower UTI and upper UTI. The appropriateness of antibiotic use was evaluated retrospectively by infectious disease specialists using quality indicators based on clinical guidelines for ABU and UTI. RESULTS: This study included a total of 2697 patients with ABU or UTI. The appropriateness of antibiotic use was assessed in 1157 patients with ABU, and in 677 and 863 patients with lower and upper UTI, respectively. Among the 1157 patients with ABU, 251 (22%) were prescribed antibiotics without appropriate indications. In 66 patients with ABU in which antibiotics were prescribed with appropriate indications, the duration was adequate in only 23 (34.8%) patients. The appropriateness of empirical and definite antibiotics was noted in 527 (77.8%) and 353 (68.0%) patients with lower UTI, and 745 (86.3%) and 583 (78.2%) patients with upper UTI, respectively. The duration of antibiotics was adequate in 321 (61.8%) patients with lower UTI and 576 (78.7%) patients with upper UTI. CONCLUSIONS: This nationwide qualitative assessment of antibiotic use in ABU and UTI revealed that antibiotics were often prescribed inappropriately, and the duration of antibiotics was unnecessarily prolonged.

Applicability and limitations of quality indicator-based assessment of appropriateness in antimicrobial use: a comparison with expert opinion.

BACKGROUND: The effective implementation of antimicrobial stewardship requires an a-priori assessment of the appropriateness of antimicrobial prescriptions. AIM: To evaluate the effectiveness of quality indicators (QIs) in determining the appropriateness of antimicrobial prescriptions compared to that of expert opinions. METHODS: The study assessed antimicrobial use in 20 hospitals in Korea, with infectious disease specialists rating the appropriateness based on QIs and expert opinions. The selected QIs were (1) taking two blood cultures, (2) taking cultures from suspected sites of infection, (3) prescribing empirical antimicrobials according to guidelines, and (4) changing from empirical to pathogen-directed therapy for hospitalized patients and (2, 3, and 4) for ambulatory patients. Applicability, compliance with QIs, and agreement between QIs and expert opinions were investigated. FINDINGS: Overall, 7999 therapeutic uses of antimicrobials were investigated at the study hospitals. The experts rated 20.5% (1636/7999) as inappropriate use. For hospitalized patients, antimicrobial use was assessed based on all four QIs in 28.8% (1798/6234) of the cases. For ambulatory care patients, only 7.5% (102/1351) of the antimicrobial use cases were assessed using all three QIs. The agreement between expert opinions and all four QIs for hospitalized patients was minimal (κ = 0.332), whereas that between expert opinions and all three QIs for ambulatory patients was weak (κ = 0.598). CONCLUSION: QIs have limitations in determining the appropriateness of antimicrobial use, and the degree of agreement with expert opinions was low. Therefore, these QI limitations should be considered when determining the appropriateness of antimicrobial use.

Differences in strategies for prevention of COVID-19 transmission in hospitals: nationwide survey results from the Republic of Korea.

BACKGROUND: Hospital infection control measures against coronavirus disease 2019 (COVID-19) are often based on expert discretion due to the lack of detailed guidelines. AIM: To survey the current strategies for preventing the transmission of COVID-19 in medical institutions. METHODS: Thirteen key issues related to the prevention of COVID-19 transmission within medical institutions were selected via discussion among infectious diseases specialists, and related critical questions were obtained following a review of national-level guidelines in government databases. Six hospitals had an open survey between 11th and 25th August 2020 to provide responses to these topics. An online questionnaire developed from these data was sent to infection control teams at 46 hospitals in South Korea between 31st January 2021 and 20th February 2021. FINDINGS: All 46 hospitals responded to the survey. All operated screening clinics, but 89.1% (41/46) allowed symptomatic patients without COVID-19-associated symptoms to visit general outpatient clinics. Most hospitals (87.2%, 34/39) conducted polymerase chain reaction (PCR) tests for all hospitalized patients. Of 35/46 (76.1%) hospitals with pre-emptive isolation policies for hospitalized patients, 31 (88.6%) released patients from isolation after a single negative PCR test, while most (76.9%, 20/26) allowed shared-room accommodation for patients meeting the national criteria for release from isolation despite positive PCR results with above cycle threshold values (34.6%, 9/26), or after a certain period that satisfied the national criteria (26.9%, 7/26). CONCLUSION: Individual hospitals in South Korea are currently relying on experience to frame relevant guidelines, and responded differently to some infection control issues on hospital settings during the COVID-19 pandemic.

High-throughput organ-on-chip platform with integrated programmable fluid flow and real-time sensing for complex tissue models in drug development workflows.

Drug development suffers from a lack of predictive and human-relevant in vitro models. Organ-on-chip (OOC) technology provides advanced culture capabilities to generate physiologically appropriate, human-based tissue in vitro, therefore providing a route to a predictive in vitro model. However, OOC technologies are often created at the expense of throughput, industry-standard form factors, and compatibility with state-of-the-art data collection tools. Here we present an OOC platform with advanced culture capabilities supporting a variety of human tissue models including liver, vascular, gastrointestinal, and kidney. The platform has 96 devices per industry standard plate and compatibility with contemporary high-throughput data collection tools. Specifically, we demonstrate programmable flow control over two physiologically relevant flow regimes: perfusion flow that enhances hepatic tissue function and high-shear stress flow that aligns endothelial monolayers. In addition, we integrate electrical sensors, demonstrating quantification of barrier function of primary gut colon tissue in real-time. We utilize optical access to the tissues to directly quantify renal active transport and oxygen consumption via integrated oxygen sensors. Finally, we leverage the compatibility and throughput of the platform to screen all 96 devices using high content screening (HCS) and evaluate gene expression using RNA sequencing (RNA-seq). By combining these capabilities in one platform, physiologically-relevant tissues can be generated and measured, accelerating optimization of an in vitro model, and ultimately increasing predictive accuracy of in vitro drug screening.

Risk factors for the delayed diagnosis of extrapulmonary TB.

BACKGROUND: Extrapulmonary TB (EPTB) is more difficult to diagnose than pulmonary TB. The delayed management of EPTB can lead to complications and increase the socio-economic burden.METHODS: Patients newly diagnosed with EPTB were retrospectively enrolled from 11 general hospitals in South Korea from January 2017 to December 2018. The basic characteristics of patients were described. Univariable and multivariable analyses were performed between early and delayed diagnosis groups to identify risk factors for delayed diagnosis and treatment in EPTB.RESULTS: In total, 594 patients were enrolled. Lymph node TB (28.3%) was the predominant form, followed by abdominal (18.4%) and disseminated TB (14.5%). Concurrent lung involvement was 17.8%. The positivity of diagnostic tests showed no significant difference between the two groups. Acute clinical manifestations in disseminated, pericardial and meningeal TB, and immunosuppression were associated with early diagnosis. Delayed diagnosis was associated with outpatient clinic visits, delayed sample acquisition and diagnostic departments other than infection or pulmonology.CONCLUSION: The delay in diagnosis and treatment of EPTB was not related to differences in microbiological characteristics of Mycobacterium tuberculosis itself; rather, it was due to the indolent clinical manifestations that cause referral to non-TB-specialised departments in the outpatient clinic and delay the suspicion of TB and diagnostic testing.

Development of tetra-primer ARMS-PCR protocol to genotype the prolactin receptor SNP 39136666 and assessment of this SNP in Brazilian locally adapted cattle breeds / [Desenvolvimento de protocolo de tetra-primer ARMS- PCR para genotipagem do SNP 39136666 do receptor da prolactina e avaliação desse SNP em raças bovinas brasileiras localmente adaptadas]

As raças taurinas de origem ibérica Limonero e Carora (Bos primigenius taurus) possuem o fenótipo de pelo curto, liso e com baixa densidade folicular, o que confere a esses animais maior tolerância térmica e melhor produtividade em regiões quentes. Diferentes mutações associadas a esse fenótipo foram descritas no gene do receptor de prolactina PRLR, localizado no cromossomo bovino BTA20. Uma mutação recentemente encontrada é a substituição do nucleotídeo C por T, SNP 39136666 (p. R497*), no exon 11, que gera um códon de parada e, consequentemente, uma menor isoforma desse receptor. Neste trabalho, desenvolveu-se um protocolo rápido e de baixo custo para detecção desse SNP, utilizando-se a técnica de tetra-primer ARMS-PCR. Assim, foi possível detectar essa mutação nas raças brasileiras de origem ibérica localmente adaptadas: Caracu, Crioulo Lageano, Mocho Nacional e Pantaneiro. O alelo T foi mais frequente na raça Caracu (80%), enquanto o alelo C foi mais frequente na raça Crioulo Lageano (84%). Essa simples metodologia pode ser usada para genotipar esse SNP e ajudar na aplicação dessas informações moleculares em programas de melhoramento focados na tolerância térmica em bovinos taurinos e seus mestiços.(AU)

The value of interventional radiology in clinical trial teams: experience from the BATTLE lung cancer trials.

AIM: To report on the multidisciplinary approach, focusing specifically on the role of the interventional radiologist (IR), used to support the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) and BATTLE-2 trials. MATERIALS AND METHODS: Patients who underwent percutaneous image-guided biopsy for the BATTLE and BATTLE-2 trials were reviewed. A radiology-based, three-point, lesion-scoring system was developed and used by two IRs. Lesions were given a score of 3 (most likely to yield sufficient material for biomarker analysis) if they met the following criteria: size >2 cm, solid mass, demonstrated imaging evidence of viability, and were technically easy to sample. Lesions not meeting all four criteria were scored 2 with the missing criteria noted as negative factors. Lesions considered to have risks that outweighed potential benefits receive a score of 1 and were not biopsied. Univariate and multivariate analyses were performed to evaluate the score's ability to predict successful yield for biomarker adequacy. RESULTS: A total of 555 biopsies were performed. The overall yield for analysis of the required biomarkers was 86.1% (478/555), and 84% (268/319) and 88.9% (210/236) for BATTLE and BATTLE-2, respectively (p=0.09). Lesions receiving a score of 3 were adequate for biomarker analysis in 89% of cases. Lesions receiving a score of 2 with more than two negative factors were adequate for molecular analysis in 69.2% (IR1, p=0.03) and 74% (IR2, p=0.04) of cases. The two IRs scored 78.4% of the lesions the same indicating moderate agreement (kappa=0.55; 95% confidence interval [CI]: 0.48, 0.61). CONCLUSIONS: IRs add value to clinical trial teams by optimising lesions selected for biopsy and biomarker analysis.

Energy transfer from adipocytes to cancer cells in breast cancer.

Limitations of the current therapeutic approach have raised the need for a novel therapeutic agent in breast cancer. Recently, interest in drugs targeting the tumor microenvironment (TME) had drawn attention in the treatment of breast cancer. Furthermore, recent studies have suggested the role of adipocytes, which are part of the TME, in tumor initiation, growth, and metastasis. In this study, we investigated the metabolic interaction between adipocytes and breast cancer cells and its potential as a new therapeutic target in breast cancer. Breast cancer cell lines and human breast cancer tissue samples were evaluated. Compared to cancer cells cultured alone, or the control group, those co-cultured with adipocytes showed lipid transfer from adipocytes to cancer cells and it was different according to the molecular subtype of breast cancer. Breast cancer cells affected the lipolysis of adipocytes and adipocytes affected the ß-oxidation of breast cancer cells. The key molecule of the process was fatty acid binding protein 4 (FABP4), which is combined with free fatty acid (FFA) and supports its migration to cancer cells. When FABP4 was suppressed, lipid transfer between adipocytes and cancer cells, lipolysis of adipocytes, and ß-oxidation of breast cancer cells were reduced. Furthermore, the expression of lipid metabolism-related proteins and lipolysis-related proteins in breast cancer with adipose stroma showed significantly different expression according to the region of breast cancer tissue. Taken together, we demonstrated the metabolic interaction between adipocytes and breast cancer cells. Breast cancer cells increase the lipolysis in adipocytes and produce a fatty acid, and fatty acid enters into cancer cells. Also, adipocytes contribute to the survival and growth of cancer cells through increased mitochondrial ß-oxidation by using fatty acid from adipocytes. The key molecule of the process is FABP4 and when FABP4 is suppressed, the metabolic interaction is reduced, suggesting its role as a potential therapeutic target.

Current status of antimicrobial stewardship programmes in Korean hospitals: results of a 2018 nationwide survey.

BACKGROUND: Antimicrobial stewardship programmes (ASPs) are suggested as a vital strategy to address antimicrobial resistance. AIM: To examine the current status of ASPs in Korean hospitals, to identify problems and challenges for the implementation of proper ASPs, and to provide a reference for developing more effective ASP policies. METHODS: A questionnaire based on the 'Seven Core Elements of Hospital Antibiotic Stewardship Programs' from the US Centers for Disease Control and Prevention was developed, modified from the previous questionnaire on ASPs in Korea, 2015. ASP-participating physicians such as infectious disease specialists (IDSs), paediatric IDSs, and directors of infection control departments were targeted. Only one ASP-associated physician per hospital participated in the survey. FINDINGS: The survey response rate was 88.4% (84/95). The median number of medical personnel participating in ASPs was 3 (interquartile range (IQR): 1-5), most of whom were IDS (median: 2; IQR: 1-2). Only 6.0% (5/84) of hospitals had full-time workers for ASPs. Whereas restrictive measures for designated antimicrobials were widely implemented among Korean hospitals (88.1%, 74/84), the proportion of hospitals with interventions for inappropriate long-term antimicrobial use and a conversion strategy from parenteral to oral antimicrobial administration was only 9.5% (8/84) and 1.2% (1/84), respectively. Lack of time, personnel, and appropriate compensation was perceived as the major barrier to establishing an ASP in Korean hospitals. CONCLUSION: ASPs in Korean hospitals were primarily carried out by one or two IDSs, and programmes mostly comprised restrictive measures for designated antimicrobials. National-level support to implement appropriate ASPs in Korean hospitals is necessary.

Chlorhexidine sensitivity in staphylococci isolated from patients with central line-associated bloodstream infection.

Since 2011, 2% chlorhexidine in 70% isopropyl alcohol (2% chlorhexidine tincture) has been widely used in Korea. To investigate changes in chlorhexidine sensitivity of staphylococci causing central line-associated bloodstream infections, 264 blood culture isolates from adult patients treated in intensive care units of five university hospitals between 2008 and 2016 were analysed. We observed no significant changes in chlorhexidine minimum inhibitory and bactericidal concentrations, or in the prevalence of resistance-associated genes before and after introduction of 2% chlorhexidine tincture. Thus, there was no evidence of increased resistance to chlorhexidine in staphylococci causing central line-associated bloodstream infections.

Impact of antimicrobial treatment duration on outcome of Staphylococcus aureus bacteraemia: a cohort study.

OBJECTIVES: To assess the outcome of Staphylococcus aureus bacteraemia (SAB) according to factors associated with necessity for longer treatment in conjunction with the duration of treatment. METHODS: We prospectively collected the data of patients with SAB consecutively during 12 to 39 months from 11 hospitals. If multiple episodes of SAB occurred in one patient, only the first episode was enrolled. Factors associated with necessity for longer treatment were defined as follows: persistent bacteraemia, metastatic infection, prosthesis and endocarditis. If any of the factors were present, then the case was defined as longer antibiotic treatment warranted (LW) group; those without any factors were defined as shorter antibiotic treatment sufficient (SS) group. Poor outcome was defined as a composite of 90-day mortality or 30-day recurrence. Duration of antibiotic administration was classified as <14 or ≥14 days in the SS group and <28 or ≥28 days in the LW group. RESULTS: Among 2098 cases, the outcome was analysed in 1866 cases, of which 591 showed poor outcome. The SS group accounted for 964 cases and the LW group for 852. On multivariate analysis, age over 65 years, pneumonia, higher Sequential Organ Failure Assessment (SOFA) score and chronic liver diseases were risk factors for poor outcome. Administration of antibiotics less than the recommendation was associated with poor outcome, but this significance was observed only in the LW group (adjusted odds ratio = 1.68; 95% confidence interval, 1.00-2.83; p 0.05). CONCLUSIONS: Inappropriately short antibiotic treatment was associated with poor outcome in the LW group. Vigilant evaluation for risk factors to determine the duration of treatment may improve the outcome among patients with SAB.

Provisional standardization of hepcidin assays: creating a traceability chain with a primary reference material, candidate reference method and a commutable secondary reference material.

Background Hepcidin concentrations measured by various methods differ considerably, complicating interpretation. Here, a previously identified plasma-based candidate secondary reference material (csRM) was modified into a serum-based two-leveled sRM. We validated its functionality to increase the equivalence between methods for international standardization. Methods We applied technical procedures developed by the International Consortium for Harmonization of Clinical Laboratory Results. The sRM, consisting of lyophilized serum with cryolyoprotectant, appeared commutable among nine different measurement procedures using 16 native human serum samples in a first round robin (RR1). Harmonization potential of the sRM was simulated in RR1 and evaluated in practice in RR2 among 11 measurement procedures using three native human plasma samples. Comprehensive purity analysis of a candidate primary RM (cpRM) was performed by state of the art procedures. The sRM was value assigned with an isotope dilution mass spectrometry-based candidate reference method calibrated using the certified pRM. Results The inter-assay CV without harmonization was 42.1% and 52.8% in RR1 and RR2, respectively. In RR1, simulation of harmonization with sRM resulted in an inter-assay CV of 11.0%, whereas in RR2 calibration with the material resulted in an inter-assay CV of 19.1%. Both the sRM and pRM passed international homogeneity criteria and showed long-term stability. We assigned values to the low (0.95±0.11 nmol/L) and middle concentration (3.75±0.17 nmol/L) calibrators of the sRM. Conclusions Standardization of hepcidin is possible with our sRM, which value is assigned by a pRM. We propose the implementation of this material as an international calibrator for hepcidin.

Atypicalities of Gesture Form and Function in Autistic Adults.

While well-represented on clinical measures, co-speech gesture production has never been formally studied in autistic adults. Twenty-one verbally fluent autistic adults and 21 typically developing controls engaged in a controlled conversational task. Group differences were observed in both semantic/pragmatic and motoric features of spontaneously produced co-speech gestures. Autistic adults prioritized different functions of co-speech gesture. Specifically, they used gesture more than controls to facilitate conversational turn-taking, demonstrating a novel nonverbal strategy for regulating conversational dynamics. Autistic adults were more likely to gesture unilaterally than bilaterally, a motoric feature of gesture that was individually associated with autism symptoms. Co-speech gestures may provide a link between nonverbal communication symptoms and known differences in motor performance in autism.

Genome-wide scan reveals divergent selection among taurine and zebu cattle populations from different regions.

In this study, to identify genomic signatures of divergent selection, we genotyped 10 cattle breeds/populations (n = 275), representing eight Ethiopian cattle populations (n = 229) and two zebu populations (n = 46) adapted to tropical and sub-tropical environments, using the high-density single-nucleotide polymorphisms (SNPs) derived mainly from Bos indicus breeds, and using five reference taurine breeds (n = 212). Population genetic differentiation (FST ) values across sliding windows were estimated between zebu and reference combined taurine breeds. The most differentiated regions (FST  ≥ 0.53), representing the top 1% smoothed FST values, were considered to represent regions under diversifying selection. In total, 285 and 317 genes were identified in the comparisons of Ethiopian cattle with taurine and Asian zebu with taurine respectively. Some of these genes are involved in stress responses/thermo-tolerance and DNA damage repair (HSPA4, HSF1, CMPK1 and EIF2AK4), pigmentation (ERBB3 and MYO1A), reproduction/fertility (UBE2D3, ID3 and PSPC1), immune response (PIK3CD and AKIRIN2) and body stature and size (MBP2, LYN and NPM1). Additionally, the candidate genes were associated with functional terms (e.g. cellular response to stress, DNA repair, inflammatory response) important for physiological adaptation to environmental stresses. The results of our study may shed light on the influence of artificial and natural selection in shaping the genomic diversity of modern cattle breeds and also may serve as a basis for further genetic investigation of traits of tropical adaptation in cattle.

Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer.

Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.

IDH2-deficient mice develop spinal deformities with aging.

Spinal deformities such as scoliosis and kyphosis are incurable, and can lead to decreased physical function, pain, and reduced quality of life. Despite much effort, no clear therapies for the treatment of these conditions have been found. Therefore, the development of an animal model for spinal deformity would be extremely valuable to our understanding of vertebral diseases. In this study, we demonstrate that mice deficient in the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2) develop spinal deformities with aging. We use morphological analysis as well as radiographic and micro-CT imaging of IDH2-deficient mice to characterize these deformities. Histological analysis showed increased abnormalities in IDH2-deficient mice compared to wild type mice. Taken together, the results suggest that IDH2 plays a critical role in maintaining the spinal structure by affecting the homeostatic balance between osteoclasts and osteoblasts. This indicates that IDH2 might be a potent target for the development of therapies for spinal deformities. Our findings also provide a novel animal model for vertebral disease research.