Changes in disability before and after myocardial infarction in older adults

BACKGROUND: Disability in older adults is thought to occur primarily as a consequence of clinical disease episodes. However, the temporal relationship between clinical disease and disability has received little systematic attention. METHODS: Data from a prospective population-based study of 2812 older adults were analyzed to examine changes in disability before and after acute myocardial infarction. Disability outcomes included up to 9 yearly assessments of disability in activities in daily living, disability in basic physical functions, and disability in tasks requiring basic mobility and strength. RESULTS: A total of 279 myocardial infarctions occurred during 9 years of follow-up. After adjustment for age and sex, the average yearly increase in disability in activities of daily living and basic physical functions was not significantly greater in the 1-year period after myocardial infarction than in the 3-year period before myocardial infarction (P values >.20). Disability in basic mobility and strength showed a significantly greater increase in the year after myocardial infarction (P = .02). The results did not change after adjustment for comorbidity and chest pain or when restricted to incident cases of myocardial infarction or survivors. An additional exploratory analysis suggested that the rate of increase in some forms of disability may start to accelerate at about 1 year before the event, rather than after the event. CONCLUSIONS: The increase in disability after myocardial infarction may form a continuation of increases that occur before the event and challenge commonly held notions about the temporal relationship between clinical disease and disability. Changes in disability before acute disease episodes may be related to subclinical disease.     

Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis

BACKGROUND: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to 1 or more antituberculosis drugs is an increasingly common clinical problem, although the impact on outcome is uncertain. METHODS: We performed a prospective study of 180 Vietnamese adults admitted consecutively for TBM. M. tuberculosis was cultured from the cerebrospinal fluid (CSF) of all patients and was tested for susceptibility to first-line antituberculosis drugs. Presenting clinical features, time to CSF bacterial clearance, clinical response to treatment, and 9-month morbidity and mortality were compared between adults infected with susceptible and those infected with drug-resistant organisms. RESULTS: Of 180 isolates, 72 (40.0%) were resistant to at least 1 antituberculosis drug, and 10 (5.6%) were resistant to at least isoniazid and rifampicin. Isoniazid and/or streptomycin resistance was associated with slower CSF bacterial clearance but not with any differences in clinical response or outcome. Combined isoniazid and rifampicin resistance was strongly predictive of death (relative risk of death, 11.63 [95% confidence interval, 5.21-26.32]) and was independently associated with human immunodeficiency virus infection. CONCLUSIONS: Isoniazid and/or streptomycin resistance probably has no detrimental effect on the outcome of TBM when patients are treated with first-line antituberculosis drugs, but combined isoniazid and rifampicin resistance is strongly predictive of death.     

Impact of hypothyroidism on the development of non-alcoholic fatty liver disease: A 4-year retrospective cohort study

Background/Aims

Hypothyroidism is reported to contribute to the development of nonalcoholic fatty liver disease (NAFLD). We compared the risk of the development of NAFLD among three groups with different thyroid hormonal statuses (control, subclinical hypothyroidism, and overt hypothyroidism) in a 4-year retrospective cohort of Korean subjects.

Methods

Apparently healthy Korean subjects without NAFLD and aged 20-65 years were recruited (n=18,544) at health checkups performed in 2008. Annual health checkups were applied to the cohort for 4 consecutive years until December 2012. Based on their initial serum-free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels, they were classified into control, subclinical hypothyroidism (TSH >4.2 mIU/L, normal fT4), and overt hypothyroidism (TSH >4.2 mIU/L, fT4 <0.97 ng/dL) groups. NAFLD was diagnosed on the basis of ultrasonography findings.

Results

NAFLD developed in 2,348 of the 18,544 subjects, representing an overall incidence of 12.7%: 12.8%, 11.0%, 12.7% in the control, subclinical hypothyroidism, and overt hypothyroidism groups, respectively. The incidence of NAFLD did not differ significantly with the baseline thyroid hormonal status, even after multivariate adjustment (subclinical hypothyroidism group: hazard ratio [HR]=0.965, 95% confidence interval [CI]=0.814-1.143, P=0.67; overt hypothyroidism group: HR=1.255, 95% CI=0.830-1.899, P=0.28).

Conclusions

Our results suggest that the subclinical and overt types of hypothyroidism are not related to an increased incidence of NAFLD.     

Ten Changes Psychotherapists Typically Make as They Mature Into the Role of Supervisor

Stage models have largely informed scholarship on supervisor developmental processes. We argue that understanding this development as occurring along dimensions is more useful for both supervision practitioners and educators as well as for those engaged in research on supervisor development. Building on the work of Heid ( 1997 ) and working with a panel of 7 supervision experts, we identify 10 themes and validate their salience to supervisor development using a sample of 22 clinical supervisors. We describe and elaborate on each theme, and then present and discuss a case vignette that illustrates many of the supervisor developmental themes.     

Prevalence and Risk Factors for Iron Deficiency Anemia in the Korean Population: Results of the Fifth Korea National Health and Nutrition Examination Survey

This study assessed the prevalence of, and risk factors for, iron deficiency (ID) and iron deficiency anemia (IDA) among participants of the fifth Korean Health and Nutrition Examination Survey, 2010. Of 8,958 participants, 6,758 individuals ≥10 yr had sufficient data for the analysis of anemia and iron status. ID was defined as a transferrin saturation <10% or serum ferritin <15 µg/L. The prevalence of ID and IDA was 2.0% (95% confidence interval [CI], 1.3%-2.6%) and 0.7% (95% CI, 0.3%-1.0%), respectively, in males, and 22.4% (95% CI, 20.7%-24.2%) and 8.0% (95% CI, 6.8%-9.2%), respectively, in females. In reproductive age females, the prevalence of ID and IDA was 31.4% (95% CI, 28.9%-33.8%) and 11.5% (95% CI, 9.6%-13.4%), respectively. Compared to the prevalence of IDA in adult males 18-49 yr, the relative risks of IDA in adults ≥65 yr, lactating females, premenopausal females, and pregnant females were 8.1, 35.7, 42.8, and 95.5, respectively. Low income, underweight, iron- or vitamin C-poor diets were also associated with IDA. For populations with defined risk factors in terms of age, gender, physiological state and socioeconomic and nutritional status, national health policy to reduce IDA is needed.

Graphical Abstract

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Clinical outcomes of spontaneous bacterial peritonitis due to extended-spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumoniae: a retrospective cohort study

Purpose

The aim of this study was to (1) evaluate the clinical outcomes of spontaneous bacterial peritonitis (SBP) due to extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli or Klebsiella pneumoniae (EK) and (2) investigate the relationship between the adequacy of initial antibiotic treatments and patient outcomes.

Methods

We conducted a retrospective cohort study of cirrhotic patients with SBP caused by EK. We evaluated the 30-day mortality rate and used Cox proportional hazard models to identify risk factors for mortality.

Results

Between January 2006 and December 2012, a total of 231 episodes of SBP due to EK were recorded. Among them, 52 were caused by ESBL-producing EK (ESBL-EK). The 30-day mortality rate was significantly higher in patients with SBP due to ESBL-EK than in those with non-ESBL-producing EK (non-ESBL-EK) (34.6 vs. 18.4 %, respectively; p = 0.013). Multivariate analysis revealed that ESBL production [adjusted HR (aHR) 1.82, 95 % confidence interval (CI) 1.00–3.31], nosocomial infection (aHR 2.24, 95 % CI 1.26–3.95), septic shock (aHR 4.84, 95 % CI 2.70–8.65), higher Child-Pugh score (aHR 1.57, 95 % CI 1.28–1.92), and higher Charlson comorbidity index (aHR 1.37, 95 % CI 1.15–1.64) were independent risk factors for 30-day mortality in the total cohort. When we analyzed patients with SBP due to ESBL-EK separately, septic shock (aHR 3.64, 95 % CI 1.40–9.77), accompanying bacteremia (aHR 3.71, 95 % CI 1.37–10.08), and hepatocellular carcinoma (aHR 3.21, 95 % CI 1.20–8.56) were independent risk factors.

Conclusions

Both 7- and 30-day mortalities for SBP due to ESBL-EK were significantly higher than for SBP due to non-ESBL-EK. Initial antibiotic choice was not associated with poor clinical outcomes in patients with SBP due to ESBL-EK.     

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFR-dependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival.The term “oncogene addiction” has been used to describe the phenomenon whereby tumor cells exhibit singular reliance on an oncogene or oncogenic pathway for their survival, despite the accumulation of multiple genetic lesions (1). In non-small cell lung cancer (NSCLC), this principle is perhaps best exemplified with the finding that epidermal growth factor receptor (EGFR) mutations predict response to EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, and thus represent a dependency in the subset of tumors harboring these alterations (2–6). However, though EGFR-mutant NSCLCs typically respond dramatically to EGFR TKIs, clinical responses are not universal, even within this genetically defined cohort, with the rate of objective response estimated to be ∼71% (5, 6). Furthermore, the overwhelming majority of patients who initially respond to EGFR inhibitors ultimately develop resistance to therapy (7). A deeper understanding of the genetic underpinnings of EGFR addiction, and how EGFR-mutant cells can overcome reliance on EGFR, may improve clinical outcomes.Here, we have applied an unbiased screening approach to identify genetic modifiers of EGFR dependence in NSCLC. Mounting evidence supports the existence of several genetic modifiers of EGFR dependence in EGFR-mutant NSCLC, which can reduce the degree to which these tumors rely on EGFR and thereby contribute to EGFR TKI resistance (8). Examples include amplification of the MET receptor tyrosine kinase (RTK) (9), activation of the NF-κB pathway (8), amplification of the HER2 (ERBB2) RTK (10), amplification of the CRKL gene (11), and activation of the AXL kinase (12). Notably, MET bypass can be reciprocally achieved via EGFR activation in MET-dependent cells (13), and analogous examples of reciprocal kinase switching have been reported in other kinase-driven cancer models (14, 15). These and other findings suggest that compensatory kinase switching may be a more general way in which oncogene-dependent cancers overcome reliance on their primary driver kinase (14, 16), but the full-range of kinases capable of mediating EGFR bypass has not been systematically studied.Recent advances in large-scale functional genetic libraries have made it possible to query a wide range of genetic perturbations for their ability to modulate specific cellular phenotypes in mammalian systems (17, 18). Using the model of EGFR-mutant, erlotinib-sensitive NSCLC cells, we have performed a systematic ORF-based screen to identify kinase and kinase-related genes whose overexpression can complement loss of EGFR activity in an EGFR-dependent context. Our findings indicate broad potential for EGFR substitution in the setting of EGFR dependence, with compensatory mechanisms commonly conferring EGFR-independent activation of the PI3K-AKT and MEK-ERK signaling pathways. Importantly, this approach has recovered known mechanisms of erlotinib resistance as well as identified novel mediators of EGFR bypass in EGFR-mutant NSCLC. These data support the idea that the EGFR-dependent state can be redundantly driven by diverse genetic inputs that commonly converge on shared downstream signaling nodes.     

Prognostic factors for outcomes of allogeneic stem cell transplantation in chronic phase chronic myeloid leukemia in the era of tyrosine kinase inhibitors

The aim of this study was to estimate the prognostic factors for the outcomes of chronic myeloid leukemia (CML) patients receiving allogeneic stem cell transplantation (SCT) in chronic phase (CP) in the era of tyrosine kinase inhibitors (TKIs). Ninety-seven patients who underwent allogeneic SCT in CP were analyzed. Forty-seven were TKI-naïve at the time of transplant, and 50 received TKI(s) treatment before transplantation. After a median follow-up of 115.8 months, the 4-year overall survival and event-free survival were 80.4 and 58.8%, respectively. Multivariate analysis showed that there were no differences in survival outcomes based on prior TKI therapy. Older age was a prognostic factor for higher treatment-related mortality (TRM), and the type of graft source and younger age were associated with relapse, but prior TKI therapy and disease status at the time of transplant were not associated with either TRM or relapse. Additionally, a major molecular response at 1 month and an MR^4.5 at 3 months were important predictors of favorable long-term outcomes. This study demonstrates the prognostic factors for the outcomes of allogeneic SCT in CP CML and shows that survival outcomes were not affected by the administration of long-term multi-TKI treatment prior to transplantation.