Adverse Events Reported by Patients With Cancer After Administration of a 2-Dose mRNA COVID-19 Vaccine.

BACKGROUND: Most safety and efficacy trials of the SARS-CoV-2 vaccines excluded patients with cancer, yet these patients are more likely than healthy individuals to contract SARS-CoV-2 and more likely to become seriously ill after infection. Our objective was to record short-term adverse reactions to the COVID-19 vaccine in patients with cancer, to compare the magnitude and duration of these reactions with those of patients without cancer, and to determine whether adverse reactions are related to active cancer therapy. PATIENTS AND METHODS: A prospective, single-institution observational study was performed at an NCI-designated Comprehensive Cancer Center. All study participants received 2 doses of the Pfizer BNT162b2 vaccine separated by approximately 3 weeks. A report of adverse reactions to dose 1 of the vaccine was completed upon return to the clinic for dose 2. Participants completed an identical survey either online or by telephone 2 weeks after the second vaccine dose. RESULTS: The cohort of 1,753 patients included 67.5% who had a history of cancer and 12.0% who were receiving active cancer treatment. Local pain at the injection site was the most frequently reported symptom for all respondents and did not distinguish patients with cancer from those without cancer after either dose 1 (39.3% vs 43.9%; P=.07) or dose 2 (42.5% vs 40.3%; P=.45). Among patients with cancer, those receiving active treatment were less likely to report pain at the injection site after dose 1 compared with those not receiving active treatment (30.0% vs 41.4%; P=.002). The onset and duration of adverse events was otherwise unrelated to active cancer treatment. CONCLUSIONS: When patients with cancer were compared with those without cancer, few differences in reported adverse events were noted. Active cancer treatment had little impact on adverse event profiles.

Crossed Connections From Insular Cortex to the Contralateral Thalamus.

Sensory information in all modalities, except olfaction, is processed at the level of the thalamus before subsequent transmission to the cerebral cortex. This incoming sensory stream is refined and modulated in the thalamus by numerous descending corticothalamic projections originating in layer 6 that ultimately alter the sensitivity and selectivity for sensory features. In general, these sensory thalamo-cortico-thalamic loops are considered strictly unilateral, i.e., no contralateral crosstalk between cortex and thalamus. However, in contrast to this canonical view, we characterize here a prominent contralateral corticothalamic projection originating in the insular cortex, utilizing both retrograde tracing and cre-lox mediated viral anterograde tracing strategies with the Ntsr1-Cre transgenic mouse line. From our studies, we find that the insular contralateral corticothalamic projection originates from a separate population of layer 6 neurons than the ipsilateral corticothalamic projection. Furthermore, the contralateral projection targets a topographically distinct subregion of the thalamus than the ipsilateral projection. These findings suggest a unique bilateral mechanism for the top-down refinement of ascending sensory information.

Yak-Kong Soybean (Glycine max) Fermented by a Novel Pediococcus pentosaceus Inhibits the Oxidative Stress-Induced Monocyte-Endothelial Cell Adhesion.

Yak-Kong (YK), a small black soybean (Glycine max) in Korea, contained higher concentrations of antioxidants than ordinary black soybean or yellow soybean in our previous study. We prepared the fermented YK extract by using a novel lactic acid bacterium, Pediococcus pentosaceus AOA2017 (AOA2017) isolated from Eleusine coracana, and found that the antioxidant ability was enhanced after fermentation. In order to investigate the cause of the enhanced antioxidant ability in the fermented YK extract, we conducted a phenolic composition analysis. The results show that proanthocyanidin decreased and phenolic acids increased with a statistical significance after fermentation. Among the phenolic acids, p-coumaric acid was newly produced at about 11.7 mg/100 g, which did not exist before the fermentation. Further, the fermented YK extract with increased p-coumaric acid significantly inhibited the lipopolysaccharide-induced THP-1 monocyte-endothelial cell adhesion compared to the unfermented YK extract. The fermented YK extract also suppressed the protein expression levels of vascular cell adhesion molecule (VCAM)-1 in human umbilical vein endothelial cells (HUVECs). Together with the previous studies, our results suggest that the extract of YK fermented by AOA2017 has potential to be a new functional food material with its enhanced bioactive compounds which may help to prevent atherosclerosis caused by oxidative stress.

Effects of physician's specialty on regular chronic kidney disease care in predialysis: A population-based cross-sectional study.

Late referral in chronic kidney disease (CKD) is associated with irregular care and poor prognosis. How the specialty of healthcare provider affect late referral and irregular CKD care remain unclear.We conducted a population-based cross-sectional study to include incident dialysis patients from 2002 to 2007 in Taiwan and observed for 1, 2, and 3 years before dialysis. The medical visits-related information was evaluated every 3 months, retrospectively. Irregular follow-up was defined as missing a follow-up during more than one interval every year.A total of 46,626 patients were included. At 1, 2, and 3 years prior to maintenance dialysis, 87%, 66%, and 50% of patients had regular medical visits; however, only 49%, 23%, and 12% had estimated glomerular filtration rate (eGFR) regularly monitored, respectively. Independent factors of less regular eGFR follow-up included age (adjusted odds ratio (OR) 0.995, 95% confidence interval 0.993-0.998), cardiac disorder (0.90, 0.82-0.99), and stroke (0.76, 0.69-0.84), as well as regular visits at some other specialties (adjusted OR range: from 0.77 to 0.88); whereas, independent factors of less regular visits at nephrology included diabetes mellitus (0.48, 0.46-0.51), cardiac disorder (0.61, 0.56-0.66), stroke (0.53, 0.48-0.58), and regular visits at any other specialty (adjusted OR range: from 0.22 to 0.78).Regular medical visits were quite common in late CKD patients, but they received regular eGFR measurement and visit at nephrology much less frequently. Physicians play a major role in the late referrals in CKD and its irregular care.

PKCι is a target of 7,8,4'-trihydroxyisoflavone for the suppression of UVB-induced MMP-1 expression.

The soy isoflavone daidzein is bioconverted to 7,8,4'-trihydroxyisoflavone (7,8,4'-THIF) by microorganisms. Here, we investigated the matrix metalloproteinase (MMP)-1 inhibitory properties of 7,8,4'-THIF that arise through the suppression of UVB-induced MMP-1 expression. 7,8,4'-THIF reduced UVB-induced MMP-1 expression at the transcriptional level in primary human dermal fibroblasts and inhibited UVB-induced transcriptional activity of AP-1, a major activator of MMP-1 expression. Additionally, it was observed that the mitogen-activated protein kinase (MAPK) pathway, a crucial signalling cascade for MMP-1 expression, was suppressed by 7,8,4'-THIF. Protein kinase C iota (PKCι) was suspected to be a direct target of 7,8,4'-THIF. The direct interaction between 7,8,4'-THIF and PKCι was confirmed using pull-down assays and immobilized metal ion affinity-based fluorescence polarization assays. Finally, we observed that 7,8,4'-THIF inhibited UVB-induced MMP-1 expression in a human skin equivalent model. Taken together, these results suggest that 7,8,4'-THIF, a bioconversion product of daidzein, suppresses UVB-induced MMP-1 expression.

Influence of seafood and vitamin supplementation on maternal and umbilical cord blood mercury concentration.

BACKGROUND: The purpose of this study was to examine the influence of maternal seafood consumption and vitamin supplementation during pregnancy on maternal and umbilical cord blood mercury (Hg) concentration. METHODS: In this study of 145 healthy pregnant women (mean age 28.1±5.2 years), we administered questionnaires, collected paired maternal/umbilical cord blood samples, and measured the anthropometrics of newborns. Blood Hg concentration was assayed by inductively coupled plasma-mass spectrometry. RESULTS: Sixty-one of these women (42.1%) used vitamins >3 times/wk prenatally. Seventy-eight of our study participants (61.9%) reported eating higher amounts of seafood during pregnancy. We found a strong correlation (r=0.76, p<0.001) between Hg levels in the paired maternal/umbilical cord blood samples. Mothers with high seafood consumption had a 2.91-fold greater risk (adjusted odds ratio 2.91, 95% confidence interval: 1.04-8.15, p=0.042) of high Hg levels (>5.8 µg/L). However, mothers whose prenatal vitamin intake was >3 times/wk were found to have low Hg levels (≤5.8 µg/L) (adjusted odds ratio 0.06, 95% confidence interval: 0.01-049, p=0.008). CONCLUSION: High seafood consumption was an independent risk factor for high maternal Hg level, while vitamin supplementation was a protective factor. Further study is needed to investigate the specific effect of vitamins on Hg level.

Asthma, corticosteroid use and schizophrenia: A nationwide population-based study in Taiwan.

OBJECTIVE: Asthma and corticosteroid use have been implicated as possible risk factors for schizophrenia. The retrospective cohort study herein aimed to investigate the association between asthma, corticosteroid use, and schizophrenia. METHOD: Longitudinal data (2000 to 2007) from adults with asthma (n = 50,046) and without asthma (n = 50,046) were compared on measures of schizophrenia incidence using Taiwan's National Health Insurance Research Database (NHIRD). Incidence of schizophrenia diagnosis (ICD-9 codes 295.XX) between 2000 and 2007 were compared between groups. Competing risk-adjusted Cox regression analyses were conducted, adjusting for sex, age, residence, socioeconomic status, corticosteroid use, outpatient and emergency room visit frequency, Charlson comorbidity index, and total length of hospital stays days for any disorder. RESULTS: Of the 75,069 subjects, 238 received a diagnosis of schizophrenia. The mean (SD) follow-up interval for all subjects was 5.8 (2.3) years. After adjusting for potential confounding factors, asthma was associated with significantly greater hazard ratio for incident schizophrenia 1.40 (95% CI = 1.05, 1.87). Additional factors associated with greater incidence of schizophrenia were rural residence, lower economic status, and poor general health. Older age (i.e. ≥65 years) was negatively associated with schizophrenia incidence. Corticosteroid use was not associated with increased risk for schizophrenia. CONCLUSIONS: Asthma was associated with increased risk for schizophrenia. The results herein suggest that a convergent disturbance in the immune-inflammatory system may contribute to the pathoetiology of asthma and schizophrenia.

Thalamic dopaminergic neurons projects to the paraventricular nucleus-rostral ventrolateral medulla/C1 neural circuit.

Paraventricular nuclei (PVN) projections to the rostral ventrolateral medulla (RVLM)/C1 catecholaminergic neuron group constitute the pre-autonomic sympathetic center involved in the neural control of systemic cardiovascular function. However, the role of extra-hypothalamic and thalamic dopaminergic (DA) inputs in this circuit remains underexplored. Using retrograde neuroanatomical tracing and high contrast confocal imaging methods, we investigated the projections and morphology of the discrete thalamic DA neuron groups in the dorsal hypothalamic area and their contribution to the PVN-RVLM neural circuit. We found that DA neuron subgroups in the Zona Incerta (Zi; 60%) and Reuniens thalamic nuclei (Re; 40%) were labeled comparably to the PVN (85%) after a retrograde tracer was injected into the RVLM/C1 (P < 0.01 mean ± SEM). The Re/Zi DA neuron subgroups were characterized by angulated cell bodies, superiomedial and inferiomedial projections reaching the contralateral Re/Zi and ipsilateral PVN DA neurons respectively. Ultimately, we deduced that the DA projections of the Re/Zi to the PVN contribute to the PVN-RVLM/C1 neural circuit. As a result of these connections, the Re/Zi DA neuron groups may regulate preautonomic sympathetic events associated with the PVN-RVLM pathway. Anat Rec, 300:1307-1314, 2017. © 2016 Wiley Periodicals, Inc.

Maternal and umbilical cord blood levels of mercury, manganese, iron, and copper in southern Taiwan: A cross-sectional study.

BACKGROUND: The effect of maternal exposure to essential minerals and heavy metals on fetus is an important issue, which affects women around the world. Few data are available on the concentration of both essential minerals and heavy metals in maternal/fetal medicine. The aims of this study were to (1) assess the correlation of mercury (Hg), manganese (Mn), iron (Fe), and copper (Cu) in paired maternal/fetal blood samples, and (2) study potential confounding factors during pregnancy. METHODS: Our study recruited 145 healthy pregnant women with a mean age of 28.06 years, gathering information by collecting interviewer-administered questionnaires. Paired maternal/fetal blood samples were collected by delivery. RESULTS: There was a positive correlation of Hg (r = 0.78, p<0.001), Mn (r = 0.31, p<0.001), Fe (r = 0.17, p = 0.038), and Cu (r = 0.21, p = 0.010) in paired maternal/fetal samples. Prenatal vitamin use (>3 times/wk) was significantly associated with lower maternal Hg (adjusted odds ratio 0.272, p = 0.005) and lower maternal Cu (adjusted odds ratio 0.267, p = 0.004) levels. Median fetal Hg, Mn, and Fe levels were higher than corresponding maternal levels, while median fetal Cu level was lower than maternal Cu level. CONCLUSION: There was a positive correlation of Hg, Fe, Cu, and Mn in paired maternal/fetal samples in this series. Our findings have raised the possibility of reducing maternal Hg and Cu by way of prenatal vitamin supplementation.

Risk of bipolar disorder in patients with COPD: a population-based cohort study.

BAKCGROUND: Few studies have investigated the relationship between chronic obstructive pulmonary disease (COPD) and bipolar outcomes in the world. We sought to investigate the association between COPD and risk of bipolar disorder in a large national sample. METHODS: The insured aged 15 years or more with a new primary diagnosis of COPD (ICD-9: 491, 492, 494 and 496) between 2000 and 2007 were identified from Taiwan's National Health Insurance Research Database. We included individuals with an inpatient diagnosis of COPD and/or at least 1 year of two diagnoses of COPD in outpatient services. These 35,558 cases were compared to 35,558 sex-, age-, residence- and insurance premium-matched controls. We followed both groups until the end of 2008 for incidence of bipolar disorder, defined as ICD-9 codes 296.0-296.16, 296.4-296.81 and 296.89. Competing risk-adjusted Cox regression analyses were applied with adjusting for sex, age, residence, insurance premium, prednisone use, Charlson comorbidity index, diabetes, hypertension, hyperlipidemia, cardiovascular diseases, hospital admission days, outpatients' visits and mortality. RESULTS: Of the total 71,116 subjects, 202 were newly diagnosed with bipolar disorder during the study period. The mean follow-up time was 6.0 (SD=2.2) years. COPD, younger age, lower economic status, lower dose of prednisone use, higher hospital admission days and higher outpatient visits were independent predictors of bipolar disorder. CONCLUSIONS: COPD was associated with increased risk of bipolar disorder independent of a number of potential confounding factors in this study.

An Integrative Approach to Precision Cancer Medicine Using Patient-Derived Xenografts.

Cancer is a heterogeneous disease caused by diverse genomic alterations in oncogenes and tumor suppressor genes. Despite recent advances in high-throughput sequencing technologies and development of targeted therapies, novel cancer drug development is limited due to the high attrition rate from clinical studies. Patient-derived xenografts (PDX), which are established by the transfer of patient tumors into immunodeficient mice, serve as a platform for co-clinical trials by enabling the integration of clinical data, genomic profiles, and drug responsiveness data to determine precisely targeted therapies. PDX models retain many of the key characteristics of patients' tumors including histology, genomic signature, cellular heterogeneity, and drug responsiveness. These models can also be applied to the development of biomarkers for drug responsiveness and personalized drug selection. This review summarizes our current knowledge of this field, including methodologic aspects, applications in drug development, challenges and limitations, and utilization for precision cancer medicine.

Association of asthma and anxiety: A nationwide population-based study in Taiwan.

BACKGROUND: Few studies have investigated the bidirectional relationship between asthma and anxiety; we sought to investigate asthma and anxiety in a large national sample. METHODS: Cases were identified from Taiwan's National Health Insurance Research Database with a new primary diagnosis of asthma (ICD-9:493) aged more than 15 years between 2000 and 2007. Case status required the presence of any inpatient diagnosis of asthma and/or at least one year diagnosis of asthma in outpatient service. These 22,797 cases were compared to 22,797 sex-, age-, residence- and insurance premium-matched controls and both groups were followed until the end of 2008 for instances of anxiety, defined as ICD-9 codes 300.0, 300.01, 300.02, 300.2, 300.21, 300.23, 300.3. Competing risk adjusted Cox regression analyses were applied, adjusting for sex, age, residence, insurance premium, prednisone use, Charlson comorbidity index, cardiovascular disease, diabetes, depression disorder, and hospital admission days for any disorder. The effect of asthma on the risk of panic disorder and the effect of anxiety disorder on the risk of later asthma were also examined as competing risk adjusted Cox regression analyses RESULTS: Of the 45,594 subjects, 2792 were ascertained as having anxiety during a mean (SD) follow-up period of 5.3 (2.5) years. Asthma, females, older age, rural residence, depression disorder, and prednisone use were independent risks on anxiety in the fully adjusted model. Anxiety, older age, rural residence, and prednisone use were independent risks on asthma in the fully adjusted model. LIMITATIONS: The severity of asthma and anxiety disorder, the duration of prednisone treatment and adherence, stressful life events, smoking, family history and relationship were not evaluated. CONCLUSIONS: Bidirectional relationship between asthma and anxiety disorder was confirmed in this population, in dependent of a number of potential confounding factors.

Exploring functions for the non-lemniscal auditory thalamus.

The functions of the medial geniculate body (MGB) in normal hearing still remain somewhat enigmatic, in part due to the relatively unexplored properties of the non-lemniscal MGB nuclei. Indeed, the canonical view of the thalamus as a simple relay for transmitting ascending information to the cortex belies a role in higher-order forebrain processes. However, recent anatomical and physiological findings now suggest important information and affective processing roles for the non-primary auditory thalamic nuclei. The non-lemniscal nuclei send and receive feedforward and feedback projections among a wide constellation of midbrain, cortical, and limbic-related sites, which support potential conduits for auditory information flow to higher auditory cortical areas, mediators for transitioning among arousal states, and synchronizers of activity across expansive cortical territories. Considered here is a perspective on the putative and unresolved functional roles of the non-lemniscal nuclei of the MGB.

Association of prescribed Chinese herbal medicine use with risk of end-stage renal disease in patients with chronic kidney disease.

The evidence on whether Chinese herbal medicines affect outcome in patients with chronic kidney disease (CKD) is limited. Here we retrospectively explored the association of prescribed Chinese herbal medicine use and the risk of end-stage renal disease (ESRD) in patients with CKD. Patients with newly diagnosed CKD in the Taiwan National Health Insurance Research Database from 2000 to 2005 were categorized into new use or nonuse of prescribed Chinese herbal medicine groups. These patients were followed until death, dialysis initiation, or till the end of 2008. Among the 24,971 study patients, 11,351 were new users of prescribed Chinese herbal medicine after CKD diagnosis. Overall, after adjustment for confounding variables, the use group exhibited a significant 60% reduced ESRD risk (cause-specific hazard ratio 0.41, 95% confidence interval 0.37-0.46) compared with the nonuse group. The change was significantly large among patients using wind dampness-dispelling formulas (0.63, 0.51-0.77) or harmonizing formulas (0.59, 0.46-0.74), suggesting an independent association between specific Chinese herbal medicines and reduced ESRD risk. The findings were confirmed using propensity score matching, stratified analyses, and three weighting methods. However, dampness-dispelling and purgative formulas were associated with increased ESRD risk. Thus, specific Chinese herbal medicines are associated with reduced or enhanced ESRD risk in patients with CKD.

Nicotinic alteration of functional thalamocortical topography.

The thalamocortical pathways form highly topographic connections from the primary sensory thalamic nuclei to the primary cortical areas. The synaptic properties of these thalamocortical connections are modifiable by activation from various neuromodulators, such as acetylcholine. Cholinergic activation can alter functional properties in both the developing and the mature nervous system. Moreover, environmental factors, such as nicotine, can activate these receptors, although the circuit-level alterations resulting from such nicotinic activation of sensory neural circuits remain largely unexplored. Therefore, we examined alterations to the functional topography of thalamocortical circuits in the developing sensory pathways of the mouse. Photostimulation by uncaging of glutamate was used to map these functional thalamocortical alterations in response to nicotinic receptor activation. As a result, we found that activation of forebrain nicotinic acetylcholine receptors results in an expansion and enhancement of functional thalamocortical topographies as assessed in brain slice preparations using laser-scanning photostimulation by uncaging of glutamate. These physiological changes were correlated with the neuroanatomical expression of nicotinic acetylcholine receptor subtypes (α7 and ß2). These circuit-level alterations may provide a neural substrate underlying the plastic development and reshaping of thalamocortical circuitry in response to nicotinic receptor activation.

Incidence, prevalence, and medical expenditures of classical amyotrophic lateral sclerosis in Taiwan, 1999-2008.

BACKGROUND/PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rare disease, which makes the estimation of incidence and prevalence difficult in Taiwan. This study was conducted to investigate the incidence, prevalence, and medical expenditure of ALS in Taiwan. METHODS: Patients who had at least one service claim either as an outpatient or inpatient between the years 2004 and 2007 and were over 15 years of age with a primary diagnosis of ALS were identified from the National Health Insurance Research Database. Additionally, ALS patients with serious disability database certificates over 15 years of age were included for the calculation of incidence and prevalence between the years 1999 and 2008. Lastly, the total medical expenditure, including ventilator use and riluzole, were reported. RESULTS: In 2006 and 2008, the average annual incidence and prevalence of ALS was 0.51 and 1.97 (per 10(5)), respectively, in Taiwan. The male-to-female ratio of incidence for ALS was 1.67. The average medical expenditure for ALS patients stayed steady at 16-fold greater than the general population of Taiwan in 2008. The percentage of ventilator and riluzole expenditure as a proportion of total medical expense decreased from 55% in 2000 to 33% in 2008. CONCLUSION: The incidence and average medical expenditure of ALS patients remained stable over the years in Taiwan, however, as a proportion of total medical expenses, expenditure on ventilator and riluzole decreased over the study period.

Brown Pine Leaf Extract and Its Active Component Trans-Communic Acid Inhibit UVB-Induced MMP-1 Expression by Targeting PI3K.

Japanese red pine (Pinus densiflora) is widely present in China, Japan, and Korea. Its green pine leaves have traditionally been used as a food as well as a coloring agent. After being shed, pine leaves change their color from green to brown within two years, and although the brown pine leaves are abundantly available, their value has not been closely assessed. In this study, we investigated the potential anti-photoaging properties of brown pine leaves for skin. Brown pine leaf extract (BPLE) inhibited UVB-induced matrix metalloproteinase-1 (MMP-1) expression to a greater extent than pine leaf extract (PLE) in human keratinocytes and a human skin equivalent model. HPLC analysis revealed that the quantity of trans-communic acid (TCA) and dehydroabietic acid (DAA) significantly increases when the pine leaf color changes from green to brown. BPLE and TCA elicited reductions in UVB-induced MMP-1 mRNA expression and activator protein-1 (AP-1) transactivation by reducing DNA binding activity of phospho-c-Jun, c-fos and Fra-1. BPLE and TCA also inhibited UVB-induced Akt phosphorylation, but not mitogen activated protein kinase (MAPK), known regulators of AP-1 transactivation. We additionally found that BPLE and TCA inhibited phosphoinositide 3-kinase (PI3K), the upstream kinase of Akt, in vitro. In summary, both BPLE and its active component TCA exhibit protective effects against UVB-induced skin aging. Taken together, these findings underline the potential for BPLE and TCA to be utilized as anti-wrinkling agents and cosmetic ingredients, as they suppress UVB-induced MMP-1 expression.

Ginsenosides and their metabolites: a review of their pharmacological activities in the skin.

Ginsenosides are representative pharmaceutical compounds found in various forms in Panax ginseng, a traditional medicinal plant. They are converted to their metabolites Rg2, Rg3, compound K, and others by human intestinal microflora following ingestion. Numerous studies have demonstrated beneficial effects of ginsenosides against aberrant molecular processes responsible for cancer, metabolic diseases and neurodegenerative diseases. Recently, antiaging effects of ginsenosides in human skin have been reported from clinical trial and in vitro model data. Ginsenosides have hence been proposed as promising natural cosmeceutical agents. In this review, we will critically review the known biological effects of several ginsenosides (Rb1, Rg3, Rd and compound K), such as anti-inflammatory and anticancer activities, which arise from the modulation of diverse molecular pathways. The application potential of ginsenosides as cosmeceutical ingredients will also be reviewed.

Angiotensin-converting enzyme inhibitors and amyotrophic lateral sclerosis risk: a total population-based case-control study.

IMPORTANCE: Although several studies have shown that use of angiotensin-converting enzyme inhibitors (ACEIs) potentially decreased amyotrophic lateral sclerosis (ALS) risk in animal models, to our knowledge, there has been no human study in the literature discussing this issue. OBJECTIVE: To investigate the association between the use of ACEIs and the risk for developing ALS. DESIGN, SETTING, AND PARTICIPANTS: This case-control study was conducted using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The case group comprised 729 patients with newly diagnosed ALS and a severely disabling disease certificate between January 1, 2002, and December 31, 2008. These cases were compared with 14,580 sex-, age-, residence-, and insurance premium-matched control individuals. EXPOSURES: Use of ACEIs was analyzed using a conditional logistic regression model that controlled for other antihypertensives, aspirin, steroids, nonsteroidal anti-inflammatory drugs, Charlson Comorbidity Index score, length of hospital stay, and number of outpatient visits. The cumulative defined daily dose (cDDD), which indicates the exposed duration of drug use, was estimated as the sum of dispensed DDD of drug and compared with the risk for ALS. MAIN OUTCOMES AND MEASURES: All patients with ALS fulfilled El Escorial criteria in this study. Medical claim data past 1 to 5 years of ALS first diagnosis date for patients and claim data from their matched control individuals were included in the analysis. RESULTS: There was a dose-dependent inverse association between ACEI use and the risk for developing ALS. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 (95% CI, 0.65-1.07; P = .15) for the group prescribed ACEIs lower than 449.5 of the cDDD and 0.43 cDDD (95% CI, 0.26-0.72; P = .001) for the group with a cumulative ACEI use of greater than 449.5 cDDD. The association was most predominant in men older than 55 years. CONCLUSIONS AND RELEVANCE: Use of ACEIs exhibited a dose-dependent inverse association with ALS. This study demonstrated a 57% risk reduction in the chance for developing ALS in people who used ACEIs greater than 449.5 cDDD in 4 years.

Frequency transformation in the auditory lemniscal thalamocortical system.

The auditory lemniscal thalamocortical (TC) pathway conveys information from the ventral division of the medial geniculate body to the primary auditory cortex (A1). Although their general topographic organization has been well characterized, functional transformations at the lemniscal TC synapse still remain incompletely codified, largely due to the need for integration of functional anatomical results with the variability observed with various animal models and experimental techniques. In this review, we discuss these issues with classical approaches, such as in vivo extracellular recordings and tracer injections to physiologically identified areas in A1, and then compare these studies with modern approaches, such as in vivo two-photon calcium imaging, in vivo whole-cell recordings, optogenetic methods, and in vitro methods using slice preparations. A surprising finding from a comparison of classical and modern approaches is the similar degree of convergence from thalamic neurons to single A1 neurons and clusters of A1 neurons, although, thalamic convergence to single A1 neurons is more restricted from areas within putative thalamic frequency lamina. These comparisons suggest that frequency convergence from thalamic input to A1 is functionally limited. Finally, we consider synaptic organization of TC projections and future directions for research.