Suspected tetanus in an unvaccinated pediatric patient.

Tetanus is a vaccine-preventable neuromuscular disease with a high mortality rate. The incidence of tetanus in developed countries has significantly declined due to preventive vaccination measures, but the potential for long-term complications and mortality from this disease remains high in the unvaccinated population. There are only a few individual case reports of tetanus in the pediatric population in the United States. We present a case of suspected tetanus in a 10-year-old unvaccinated child in Central Texas who sustained multiple cardiovascular and pulmonary complications during a 1-month hospitalization course. This case highlights the importance of pediatric immunization for prevention of this potentially fatal disease process and its long-term complications. Physicians should maintain a high clinical suspicion for tetanus infection in unvaccinated children to prevent delay in necessary treatment.

Response effort and resurgence.

This study provides an initial translational examination of response effort and resurgence. Eleven typically developing adults and five adolescents with autism served as participants across two experiments. Participants received points for touching moving stimuli on a computer screen. The resurgence evaluation consisted of three phases: establishment wherein R1 was reinforced, elimination wherein R1 was placed on extinction while R2 was reinforced, and extinction wherein R1 and R2 no longer resulted in reinforcement. Rate of R1 during extinction was compared across three conditions: intermediate, easy, and difficult. Disparity in effort was created by manipulations of the size and speed of objects that moved about on a computer screen. In Experiment 2, control stimuli were added to the experimental arrangement. Across the two experiments, the magnitude of resurgence was greater when R1 was easy. In Experiment 2, both R1 and control responding were greater in the extinction phase than in the elimination phase in all conditions with all participants. The present study supports the hypothesis that response effort affects resurgence and that less effortful responses are likely to recur with greater magnitude under conditions that produce resurgence than are their more effortful counterparts.

Retropharyngeal abscess in the setting of multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a potentially severe inflammatory syndrome following recent infection with SARS-CoV-2 (COVID-19). In this report, we describe a 13-year-old boy with a retropharyngeal abscess unresponsive to initial antibiotic therapy who was found to have findings consistent with MIS-C, which included elevated interleukin-6, ferritin, and troponin levels. The patient had COVID-19 infection due to the Omicron variant.

The effects of a workplace intervention on employees' cortisol awakening response.

Work-related stressors are known to adversely affect employees' stress physiology, including the cortisol awakening response (CAR) - or the spike in cortisol levels shortly after people wake up that aids in mobilizing energy. A flat or blunted CAR has been linked to chronic stress and burnout. This daily diary study tested the effects of a workplace intervention on employed parents' CAR. Specifically, we tested whether the effects of the intervention on CAR were moderated by the type of days (workday versus non-work day). Data came from 94 employed parents from an information technology firm who participated in the baseline and 12-month diurnal cortisol components of the Work, Family, and Health Study, a group-randomized field experiment. The workplace intervention was designed to reduce work-family conflict (WFC) and implemented after the baseline data collection. Diurnal salivary cortisol was collected on 4 days at both baseline and 12 months. Multilevel modeling revealed that the intervention significantly increased employees' CAR at 12 months on non-workdays, but this was not evident on workdays or for employees in the usual practice condition. The results provide evidence that the intervention was effective in enhancing employees' biological stress physiology particularly during opportunities for recovery that are more likely to occur on non-work days.

Substance Use Disorders among Patients with Type 2 Diabetes: a Dangerous but Understudied Combination.

PURPOSE OF REVIEW: This paper reviews research on substance use and disorders (SUDs) among adults with diabetes. It describes epidemiological data on SUDs in persons with type 2 diabetes, overviews effects of substance use on diabetes outcomes, and discusses treatments for SUDs in patients with diabetes. RECENT FINDINGS: Rates of current smoking range from 10 to 26% and alcohol use disorders are 0-5%. Rates of illicit SUDs are 3-4%, but there are no population-based studies using nationally representative samples. Smoking increases the risk for long-term diabetes complications and premature death. Alcohol and illicit drug use can also impact long-term diabetes complications by impairing glucose homeostasis and adversely influencing self-management behaviors. There is mixed evidence about psychosocial smoking cessation interventions in adults with diabetes and little on alcohol and illicit SUD interventions. Limited data exist on pharmacotherapies for SUDs in this population, but a recent study suggests that varenicline is safe and effective for treating smoking in patients with diabetes. Substance use is an understudied problem in type 2 diabetes, and addressing substance use holds potential for improving outcomes. Additional large population-based epidemiological studies in those with type 2 diabetes are needed, particularly for alcohol and illicit SUDs. Longitudinal studies should be conducted to better understand the time course of diabetes onset and outcomes in relation to SUDs. Randomized controlled trials are needed to assess safety and efficacy of promising psychosocial and pharmacological interventions.

StressHacker: Towards Practical Stress Monitoring in the Wild with Smartwatches.

In modern life, the nonstop and pervasive stress tends to keep us on long-lasting high alert, which over time, could lead to a broad range of health problems from depression, metabolic disorders to heart diseases. However, there is a stunning lack of practical tools for effective stress management that can help people navigate through their daily stress. This paper presents the feasibility evaluation of StressHacker, a smartwatch-based system designed to continuously and passively monitor one's stress level using bio-signals obtained from the on-board sensors. With the proliferation of smartwatches, StressHacker is highly accessible and suited for daily use. Our preliminary evaluation is based on 300 hours of data collected in a real-life setting (12 subjects, 29 days). The result suggests that StressHacker is capable of reliably capturing daily stress dynamics (precision = 86.1%, recall = 91.2%), thus with great potential to enable seamless and personalized stress management.

The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.

ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.

Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant.

Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study.

Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110ß.

Activation of the PI3K pathway occurs commonly in a wide variety of cancers. Experience with other successful targeted agents suggests that clinical resistance is likely to arise and may reduce the durability of clinical benefit. Here, we sought to understand mechanisms underlying resistance to PI3K inhibition in PTEN-deficient cancers. We generated cell lines resistant to the pan-PI3K inhibitor GDC-0941 from parental PTEN-null breast cancer cell lines and identified a novel PIK3CB D1067Y mutation in both cell lines that was recurrent in cancer patients. Stable expression of mutant PIK3CB variants conferred resistance to PI3K inhibition that could be overcome by downstream AKT or mTORC1/2 inhibitors. Furthermore, we show that the p110ß D1067Y mutant was highly activated and induced PIP3 levels at the cell membrane, subsequently promoting the localization and activation of AKT and PDK1 at the membrane and driving PI3K signaling to a level that could withstand treatment with proximal inhibitors. Finally, we demonstrate that the PIK3CB D1067Y mutant behaved as an oncogene and transformed normal cells, an activity that was enhanced by PTEN depletion. Collectively, these novel preclinical and clinical findings implicate the acquisition of activating PIK3CB D1067 mutations as an important event underlying the resistance of cancer cells to selective PI3K inhibitors.

Motivation and Contingency Management Treatments for Substance Use Disorders.

Contingency management (CM) is a highly efficacious psychosocial treatment for substance use disorders based on the principles of behavioral analysis. CM involves delivering a tangible positive reinforcer following objective evidence of submission of a drug-negative urine sample. Although CM interventions primarily involve applying extrinsic rewards, a patient's intrinsic motivation to change substance use behavior may also be impacted by CM. This chapter provides an introduction to CM interventions for substance use disorders and examines the impact of CM on intrinsic motivation . It also addresses applications of this intervention to other conditions and patient populations.

Lifetime suicide attempt history, quality of life, and objective functioning among HIV/AIDS patients with alcohol and illicit substance use disorders.

This cross-sectional study evaluated lifetime prevalence of suicide attempts in 170 HIV/AIDS patients with substance use disorders and the impact of suicide attempt history on subjective indices of quality of life and objective indices of cognitive and physical functioning. All patients met the diagnostic criteria for past-year cocaine or opioid use disorders and 27% of patients also had co-occurring alcohol use disorders. Compared to their counterparts without a history of a suicide attempt, patients with a history of a suicide attempt (n = 60, 35.3%) had significantly poorer emotional and cognitive quality of life scores (ps < .05), but not physical, social, or functional/global quality-of-life scores. Lifetime suicide attempt status was unrelated to objective indices of cognitive functioning, but there was a non-significant trend (p = .07) toward lower viral loads in those with a lifetime suicide attempt relative to those without. The findings indicate that suicide attempt histories are prevalent among HIV/AIDS patients with substance use disorders and relate to poorer perceived emotional and cognitive quality of life, but not objective functioning. HIV/AIDS patients with substance use disorders should be screened for lifetime histories of suicide attempts and offered assistance to improve perceived emotional and cognitive functioning.

Patients with diabetes respond well to contingency management treatment targeting alcohol and substance use.

Alcohol and drug use contribute to the pathogenesis of diabetes and are associated with adverse health outcomes, but little research exists on treatments for substance use disorders (SUDs) in patients with diabetes. The aim of this study was to evaluate contingency management (CM) treatments targeting substance use in patients with diabetes. A secondary analysis evaluated the main and interactive effects of diabetes status and treatment condition on outcomes of 681 substance abusers. All participants were enrolled in randomized clinical trials comparing CM to standard care (SC). Overall, CM treatment improved outcomes. There was also a significant treatment condition X diabetes status interaction effect in terms of duration of abstinence achieved and proportion of negative samples submitted; patients with diabetes responded even more favorably than their counterparts without diabetes when receiving CM. Analyses of post-treatment effects revealed that patients with diabetes, regardless of the type of SUD treatment to which they were earlier assigned, were more likely than those without diabetes to be abstinent at the nine-month follow-up. The findings suggest CM may be an effective treatment for this vulnerable subgroup of substance-abusing patients.

Discovery and development of DNA methylation-based biomarkers for lung cancer.

Lung cancer remains the primary cause of cancer-related deaths worldwide. Improved tools for early detection and therapeutic stratification would be expected to increase the survival rate for this disease. Alterations in the molecular pathways that drive lung cancer, which include epigenetic modifications, may provide biomarkers to help address this major unmet clinical need. Epigenetic changes, which are defined as heritable changes in gene expression that do not alter the primary DNA sequence, are one of the hallmarks of cancer, and prevalent in all types of cancer. These modifications represent a rich source of biomarkers that have the potential to be implemented in clinical practice. This perspective describes recent advances in the discovery of epigenetic biomarkers in lung cancer, specifically those that result in the methylation of DNA at CpG sites. We discuss one approach for methylation-based biomarker assay development that describes the discovery at a genome-scale level, which addresses some of the practical considerations for design of assays that can be implemented in the clinic. We emphasize that an integrated technological approach will enable the development of clinically useful DNA methylation-based biomarker assays. While this article focuses on current literature and primary research findings in lung cancer, the principles we describe here apply to the discovery and development of epigenetic biomarkers for other types of cancer.

Integrative analysis of two cell lines derived from a non-small-lung cancer patient--a panomics approach.

Cancer cells derived from different stages of tumor progression may exhibit distinct biological properties, as exemplified by the paired lung cancer cell lines H1993 and H2073. While H1993 was derived from chemo-naive metastasized tumor, H2073 originated from the chemo-resistant primary tumor from the same patient and exhibits strikingly different drug response profile. To understand the underlying genetic and epigenetic bases for their biological properties, we investigated these cells using a wide range of large-scale methods including whole genome sequencing, RNA sequencing, SNP array, DNA methylation array, and de novo genome assembly. We conducted an integrative analysis of both cell lines to distinguish between potential driver and passenger alterations. Although many genes are mutated in these cell lines, the combination of DNA- and RNA-based variant information strongly implicates a small number of genes including TP53 and STK11 as likely drivers. Likewise, we found a diverse set of genes differentially expressed between these cell lines, but only a fraction can be attributed to changes in DNA copy number or methylation. This set included the ABC transporter ABCC4, implicated in drug resistance, and the metastasis associated MET oncogene. While the rich data content allowed us to reduce the space of hypotheses that could explain most of the observed biological properties, we also caution there is a lack of statistical power and inherent limitations in such single patient case studies.

Loss of NAPRT1 expression by tumor-specific promoter methylation provides a novel predictive biomarker for NAMPT inhibitors.

PURPOSE: We sought to identify predictive biomarkers for a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor. EXPERIMENTAL DESIGN: We use a NAMPT inhibitor, GNE-617, to evaluate nicotinic acid rescue status in a panel of more than 400 cancer cell lines. Using correlative analysis and RNA interference (RNAi), we identify a specific biomarker for nicotinic acid rescue status. We next determine the mechanism of regulation of expression of the biomarker. Finally, we develop immunohistochemical (IHC) and DNA methylation assays and evaluate cancer tissue for prevalence of the biomarker across indications. RESULTS: Nicotinate phosphoribosyltransferase (NAPRT1) is necessary for nicotinic acid rescue and its expression is the major determinant of rescue status. We demonstrate that NAPRT1 promoter methylation accounts for NAPRT1 deficiency in cancer cells, and NAPRT1 methylation is predictive of rescue status in cancer cell lines. Bisulfite next-generation sequencing mapping of the NAPRT1 promoter identified tumor-specific sites of NAPRT1 DNA methylation and enabled the development of a quantitative methylation-specific PCR (QMSP) assay suitable for use on archival formalin-fixed paraffin-embedded tumor tissue. CONCLUSIONS: Tumor-specific promoter hypermethylation of NAPRT1 inactivates one of two NAD salvage pathways, resulting in synthetic lethality with the coadministration of a NAMPT inhibitor. NAPRT1 expression is lost due to promoter hypermethylation in most cancer types evaluated at frequencies ranging from 5% to 65%. NAPRT1-specific immunohistochemical or DNA methylation assays can be used on archival formalin paraffin-embedded cancer tissue to identify patients likely to benefit from coadministration of a Nampt inhibitor and nicotinic acid.

The role of daily activities in youths' stress physiology.

PURPOSE: This study examined links between diurnal patterns of the stress hormone cortisol and time spent by adolescents in nine common daily activities. METHODS: During eight consecutive nightly telephone interviews, 28 youths (n = 12 girls), 10-18 years of age, reported their daily activities. On 4 days, four saliva samples were also collected and assayed for cortisol. Multilevel models assessed within- and between-person associations between time in each activity and cortisol area under the curve (AUC), cortisol awakening response (CAR), morning peak (30 minutes after wake up), and daily decline (morning peak to bedtime). RESULTS: Links with AUC were found for most activities; significant associations with cortisol rhythms suggested that most effects were due to anticipation of the day's activities. Specifically, on days when youths spent more time than usual on video games and television, they had lower AUCs, with lower morning peaks. Youths who spent more time reading (within-person) and in computer-related activities (between-person) had higher AUCs, with stronger CARs (within-person). Youths who slept more had lower AUCs, with lower morning peaks on both the between- and within-person levels. Amounts of time spent in clubs, and for older adolescents in sports, were also linked to lower AUCs. Finally, youths who spent more time in school/schoolwork had lower average AUCs, but on days when youths spent more time than usual in school, they had higher AUCs, stronger CARs, and steeper daily declines. CONCLUSION: Beyond their known implications for psychological adjustment, youths' everyday activities are linked to stress physiology.

Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and women.

BACKGROUND: Recent attention has been given to subclinical hypothyroidism, defined as an elevation of TSH (4.5-10 uIU/L) with T4 and T3 levels still within the normal range. Controversy exists about the proper lower limit of TSH that defines patients in the subclinical hypothyroidism range and about if/when subclinical hypothyroidism should be treated. Additional data are needed to examine the relationship between markers of thyroid function in the subclinical hypothyroidism range, biomarkers of health and ultimately health outcomes. OBJECTIVE: We aimed to assess the relationship between serum TSH levels in the 0.5-10 uIU/L range and serum cortisol in a cohort of healthy young men and women without clinical evidence of hypothyroidism. Based on data in frank hypothyroidism, we hypothesized that serum TSH levels would be positively correlated with serum cortisol levels, suggesting derangement of the cortisol axis even in subclinical hypothyroidism. METHODS: We conducted a cross sectional study in 54 healthy, young (mean 20.98 +/- 0.37 yrs) men (19) and women (35). Lab sessions took place at 1300 hrs where blood was drawn via indwelling catheter for later assessment of basal serum TSH, free T3, free T4, and cortisol levels. RESULTS: All but 1 participant had free T3 levels within the normal reference intervals; free T4 levels for all participants were within the normal reference intervals. Linear regression modeling revealed that TSH levels in the 0.5-10 uIU/L were significantly and positively correlated with cortisol levels. This positive TSH-cortisol relationship was maintained below the accepted 4.5 uIU/L subclinical hypothyroid cutoff. Separate regression analyses conducted by systematically dropping the TSH cutoff by 0.50 uIU/L revealed that the TSH-cortisol relationship was maintained for TSH levels (uIU/L) ≤4.0, ≤3.5, ≤3.0, and ≤2.5 but not ≤2.0. Linear regression modeling did not reveal a relationship between free T3 or free T4 levels and cortisol levels. CONCLUSIONS: Results suggest a positive relationship between TSH and cortisol in apparently healthy young individuals. In as much as this relationship may herald a pathologic disorder, these preliminary results suggest that TSH levels > 2.0 uIU/L may be abnormal. Future research should address this hypothesis further, for instance through an intervention study.

Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events.

Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole-genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and three lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit distinguishable patterns of mutations. A number of epigenetic regulators, including KDM6A, ASH1L, SMARCA4, and ATAD2, are frequently altered by mutations or copy number changes. A systematic survey of splice-site mutations identified 106 splice site mutations associated with cancer specific aberrant splicing, including mutations in several known cancer-related genes. RAC1b, an isoform of the RAC1 GTPase that includes one additional exon, was found to be preferentially up-regulated in lung cancer. We further show that its expression is significantly associated with sensitivity to a MAP2K (MEK) inhibitor PD-0325901. Taken together, these data present a comprehensive genomic landscape of a large number of lung cancer samples and further demonstrate that cancer-specific alternative splicing is a widespread phenomenon that has potential utility as therapeutic biomarkers. The detailed characterizations of the lung cancer cell lines also provide genomic context to the vast amount of experimental data gathered for these lines over the decades, and represent highly valuable resources for cancer biology.