Management and referral patterns for new-onset chronic cough in primary care patients.

Background: The diagnosis and management of chronic cough in primary care is challenging despite it being one of the most common chronic conditions. Objective: Clinical characterization of patients with new-onset chronic cough in the primary care setting. Methods: This was a retrospective study of adult patients (ages ≥ 18 years) with at least three visits with primary care providers (PCP) for new-onset cough, with at least 8 weeks between the first and third visits, within a tertiary-care center and affiliated clinics between January 1, 2010, and January 1, 2019 (N = 174). We calculated the frequency of primary care visits, diagnostic testing, specialist referrals, and prescribed medications up to 18 months after the third visit with a PCP for cough. Results: Of 174 patients who met the criteria of new-onset chronic cough, >50% had four or more primary care visits related to cough. Despite that, 91 (52.3%) did not receive a referral to a specialist, and 41 (23.5%) did not receive an order for a chest radiograph during the evaluation of the chronic cough. Antibiotics and systemic corticosteroids were prescribed to 106 (61%) and 63 (36%) of the patients, respectively, and 20% were prescribed opiates. No patients were prescribed central-neuromodulating agents, and angiotensin-converting enzyme inhibitors were discontinued in 48% of the patients who were taking them (12/25). Conclusion: We found considerable heterogeneity and discrepancies with clinical guideline recommendations in patients who presented with new chronic cough. There is a substantial unmet need to study chronic cough in the primary care setting to inform important stakeholders.

microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance.

A disequilibrium between immunosuppressive Tregs and inflammatory IL-17-producing Th17 cells is a hallmark of autoimmune diseases, including multiple sclerosis (MS). However, the molecular mechanisms underlying the Treg and Th17 imbalance in CNS autoimmunity remain largely unclear. Identifying the factors that drive this imbalance is of high clinical interest. Here, we report a major disease-promoting role for microRNA-92a (miR-92a) in CNS autoimmunity. miR-92a was elevated in experimental autoimmune encephalomyelitis (EAE), and its loss attenuated EAE. Mechanistically, miR-92a mediated EAE susceptibility in a T cell-intrinsic manner by restricting Treg induction and suppressive capacity, while supporting Th17 responses, by directly repressing the transcription factor Foxo1. Although miR-92a did not directly alter Th1 differentiation, it appeared to indirectly promote Th1 cells by inhibiting Treg responses. Correspondingly, miR-92a inhibitor therapy ameliorated EAE by concomitantly boosting Treg responses and dampening inflammatory T cell responses. Analogous to our findings in mice, miR-92a was elevated in CD4+ T cells from patients with MS, and miR-92a silencing in patients' T cells promoted Treg development but limited Th17 differentiation. Together, our results demonstrate that miR-92a drives CNS autoimmunity by sustaining the Treg/Th17 imbalance and implicate miR-92a as a potential therapeutic target for MS.

Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells.

Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-ß on their surface and LAPHi MCs that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-ß inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.

Myeloablative Versus Reduced Intensity Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplant for Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Retrospective Analysis.

The conditioning regimens used for the allo-HSCT include either myeloablative conditioning (MAC) or reduced intensity conditioning (RIC) regimens based on the age, performance status and co-morbidities. Studies comparing the survival outcomes of RIC and MAC allo-HSCT in AML and MDS patients have reported contradictory results. We therefore retrospectively analyzed our data of AML and MDS patients who received MAC and RIC allo-HSCT at our center and compared the long term outcome of the two conditioning regimens. One hundred twenty six consecutive patients were evaluated, 32 (25.4%) underwent MAC allo-HSCT and 94 (74.6%) underwent RIC allo-HSCT. The most common MAC regimen used was busulfan plus cyclophosphamide and the most common RIC regimen used was fludarabine plus melphalan. The median age was higher in RIC group (44 years, range 4-75 years) compared to MAC group (31 yrs, range 6-51 yrs, p = 0.001). There was no significant difference in terms of overall survival (p = 0.498), relapse-free survival (p = 0.791) and non-relapse mortality (p = 0.366) between the two groups. In multivariate analysis, only chronic graft-versus-host disease resulted in decreased risk of relapse and improved overall survival irrespective of the conditioning regimens used.

Polysomnography in children with obstructive sleep apnoea and neurocognitive disorders.

OBJECTIVE: The neurocognitive associations in paediatric obstructive sleep apnoea (OSA) are well known; however, whether polysomnographic features can predict these associations is unknown. Therefore, the primary objective of this study was to compare common polysomnographic parameters in children with OSA in the presence and absence of neurocognitive dysfunction. METHODS: Polysomnography data for children ages 3-6 years with mild-moderate OSA who as defined by AHI between 5 and 10 were analysed from a single sleep centre at a tertiary paediatric hospital from January 2016 to December 2018. The following parameters were identified: arousals per hour, percentage of time asleep, apnoea-hypopnoea index (AHI), oxygen desaturation nadir during sleeps, baseline oxygen saturation during sleep, time spent with SpO2 less than 90%, maximum transcutaneous CO2, per cent of the total sleep time spent with TcCO2 greater than 50 mmHg, age, body mass index (BMI), gender and type of disability in the neurocognitive dysfunction group. Neurocognitive diagnoses were recorded. Those with syndromic comorbidities were excluded. The study cohort was then compared to a cohort of 200 subjects with OSA and no neurocognitive disorders matched for age, gender and BMI. A paired column analysis by chi-squared analysis was then undertaken between the two groups. RESULTS: A total of 200 children were identified (126 males and 74 females) in the neurocognitive dysfunction group (OSA with neurocognitive dysfunction) and compared with 200 children in the control group (OSA without neurocognitive dysfunction) (113 males and 87 females). There were no statistical differences between groups. CONCLUSION: Commonly used polysomnographic indices are not predictive of neurocognitive dysfunction in paediatric OSA.

Faecal microbiota transplantation: looking beyond clostridium difficile infection at inflammatory bowel disease.

Gastrointestinal (GI) microbiota are known to play paramount role in inflammatory bowel disease (IBD). Innovative sequencing methods have radically expanded our ability to analyze the intestinal microbiome. However, alterations of the GI microbiome in IBD have not yet been fully evaluated. Irregular colonization of the gut has been implicated in chronic intestinal inflammation. Faecal microbiota transplantation (FMT) is a procedure which aims to restore microbial disturbances to the individual's gut microbiome. The success of FMT in Clostridium difficile infection (CDI) has inspired studies to explore transplantation in other conditions such as IBD. Ulcerative colitis (UC) and Crohn's disease (CD), the two principal manifestations of IBD, are emerging as a worldwide epidemic and are multifactorial in aetiology. There have been various case series in the past looking at the use of FMT in IBD, with a large number of them focusing on UC; however, two new randomized controlled trials shed up-to-date light on the complex interactions between the GI microbiome and patients. Regardless of these new studies, much more remains unknown about the efficacy and safety profile of FMT in IBD, ultimately casting a shadow over its use as a therapeutic intervention in conditions other than CDI. Further researches are necessary to fully evaluate the role of FMT as a management option in IBD. In this review, we discuss and summarize the functions of FMT in IBD, and the relationship between IBD and the GI microbial variations present.

Measuring Adherence to Hepatitis C Direct-Acting Antiviral Medications: Using the VAS in an HCV Treatment Clinic.

OBJECTIVES: To implement the widespread treatment of hepatitis C virus (HCV), validated self-report measures to assess medication adherence are needed for monitoring patients who are prescribed HCV direct-acting antivirals (DAAs). The Visual Analog Scale (VAS) is an efficient and well-validated tool for measuring adherence to antiretrovirals in human immunodeficiency virus populations. This study compared VAS scores with pill counts and serum levels of HCV RNA in a sample of HCV-infected veterans prescribed DAAs. METHODS: Veterans initiating HCV DAAs were offered enrollment in our study. HCV treatment was prescribed in accordance with the standard of care. Follow-up study visits were scheduled every 28 days for a total of 12 weeks. Adherence to DAAs was assessed at weeks 4, 8, and 12 using pill counts and the VAS score. Serum levels of HCV RNA were measured at baseline, week 4 of DAA therapy, and week 12 (Ampliprep/Taqman, lower limit of quantification 43 IU/mL). RESULTS: Between May 2013 and December 2014, 30 veterans were enrolled. Mean adherence via pill count at weeks 4, 8, and 12 (96.2%, 95.2%, and 98.2%, respectively) was nearly identical to the mean VAS scores (96.2%, 96.0%, and 98.2%, respectively). Wilcoxon signed rank tests demonstrated no differences between each VAS and pill count pair. The VAS score inversely correlated with HCV viral load 4 weeks after DAA initiation (r -0.98) and at 12 weeks of treatment (r -0.97). CONCLUSIONS: The VAS score compared favorably with objective measures of adherence. If future studies confirm our results, then the VAS will provide a simple and reliable method of assessing adherence to HCV DAAs in real-world treatment clinics.

Imaging Features of Spindle Cell Breast Lesions.

OBJECTIVE: The purpose of our study is to review the clinical presentation, multimodality appearance, and management of the most common benign and malignant spindle cell lesions of the breast. CONCLUSION: Spindle cell lesions of the breast exhibit characteristic features at mammography, ultrasound, and MRI. Although a definitive diagnosis of these lesions cannot be made with diagnostic imaging alone, knowledge of their characteristic imaging features can assist in refining the differential diagnosis and guiding appropriate management.

Prevalence and risk factors of nonalcoholic fatty liver disease in HIV-monoinfection.

OBJECTIVE: To identify the prevalence and risk factors of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and fibrosis in HIV-monoinfected patients. DESIGN: Systematic review and meta-analysis. METHODS: We searched Medline and Embase and included studies that enrolled HIV-monoinfected patients with NAFLD defined by imaging and/or liver histology. Data on prevalence and risk factors for NAFLD, NASH and fibrosis were collected for meta-analysis using random effects models. RESULTS: Ten studies were included from the United States of America (n = 4), Canada (n = 1), France (n = 2), Italy (n = 1), Japan (n = 1) and China (n = 1). The prevalence of NAFLD (Imaging studies), NASH and fibrosis (biopsied populations) were 35% [95% confidence interval (CI) 29-42], 42% (95% CI 22-64) and 22% (95% CI 13-34), respectively. Meta-analysis of risk factors showed that high BMI, waist circumference, type 2 diabetes, hypertension, triglycerides and high CD4 cell count were associated with NAFLD, whereas HIV viral load, duration of HIV infection, duration of antiretroviral therapy and CD4 cell count nadir were not. Patients with high BMI [mean difference (MD) 1.38, 95% CI 0.04-2.71 P = 0.04], fasting glucose (MD 0.80, 95% CI 0.47-1.13 P < 0.00001) and AST level (MD 13.00, 95% CI 4.34-21.65 P = 0.003) were at increased risk of significant liver fibrosis. CONCLUSION: NAFLD is frequently observed in HIV-monoinfected patients, and NASH is a common cause of unexplained abnormal liver function in patients selected for liver biopsy. Metabolic disorders are key risk factors independently of HIV parameters. Future trials on pharmacological interventions in NASH with fibrosis should include patients with HIV.

The impact of intolerance of emotional distress and uncertainty on veterans with co-occurring PTSD and substance use disorders.

The risk of developing a substance use disorder (SUD) is significantly higher among veterans with posttraumatic stress disorder (PTSD). Veterans with this co-occurrence have poorer outcomes than singly diagnosed veterans, which may be related to two risk factors: intolerance uncertainty (IU) and low tolerance of emotional distress (TED). We hypothesized low TED and high IU would independently and interactively relate to heightened PTSD symptomatology and trauma-cue elicited SUD cravings. A sample of 70 veterans (M age=50; 95% men; 65% Black) with co-occurring PTSD-SUD was recruited. The Posttraumatic Stress Disorder Checklist (PCL), Craving Questionnaire, Distress Tolerance Scale, and Intolerance of Uncertainty Scale were administered. In general, low TED and high IU were significantly correlated with the PCL total and subscale scores. When examined within regression models, low TED was associated with elevated PCL scores and trauma-cue elicited SUD cravings; IU was not. However, there was a significant interaction between IU and TED; veterans with elevated IU and low TED had higher PCL Total, Hyperarousal, and Intrusions scores. This highlights the importance of assessing TED and IU among veterans with co-occurring PTSD-SUD, as these risk factors may not only be prognostic indicators of outcomes, but also treatment targets.

A Pilot Study of the Pediatric Oral Medications Screener (POMS).

OBJECTIVE: Oral medications are commonly used to treat acute and chronic conditions, but formal evaluation of a child's pill-swallowing ability rarely occurs. In this pilot study, the Pediatric Oral Medication Screener (POMS) was used to physically assess a child's pill swallowing ability and identify children who would benefit from a targeted intervention. METHODS: We identified children 3 to 17 years old admitted to a general pediatric service over a 3-month period in 2014. Patients were asked to swallow several different-sized placebo formulations. If subjects did not meet age-based goals, they were referred for pill swallowing interventions (POMS+). Follow-up parental surveys were performed for patients completing the intervention. RESULTS: The prospective pilot study recruited 34 patients. Twenty-eight patients (82%) passed the screening, and a majority of this group started or continued taking pill medications. Six did not pass the screen. Three of the 6 completed the intervention, improved their pill swallowing ability, and were taking oral pill medications at discharge. Parent prediction of pill swallowing was accurate only 56% of the time. Follow-up survey of the 3 families who completed POMS+ reported satisfaction with the program, and 2 of the patients had continued success with swallowing pills 5 months later. CONCLUSIONS: The POMS was effective at identifying children who could benefit from an intervention to improve pill-swallowing ability. Our analysis demonstrated that POMS has the potential to improve patient satisfaction and discharge planning.

Effectiveness of pediatric pill swallowing interventions: a systematic review.

BACKGROUND AND OBJECTIVE: Pediatric patients commonly have difficulty swallowing pills. Targeted interventions have shown to improve medication administration and treatment compliance. The objective was to evaluate studies performed on pill swallowing interventions in the pediatric population since 1987. METHODS: We performed a comprehensive PubMed search and a bibliography review to identify articles for our review. We selected articles published in English between December 1986 and December 2013 that included >10 participants aged 0 to 21 years with pill swallowing difficulties without a comorbid condition affecting their swallowing. Reviewers extracted the relevant information and rated the quality of each study as "poor," "fair," or "good" based on the sample size and study design. RESULTS: We identified 4 cohort studies and 1 case series that met our criteria. All 5 studies found their intervention to be successful in teaching children how to swallow pills. Interventions included behavioral therapies, flavored throat spray, verbal instructions, specialized pill cup, and head posture training. Quality ratings differed between the articles, with 3 articles rated as "fair," 1 article as "good," and 1 article as "poor." CONCLUSIONS: Pill swallowing difficulties are a barrier that can be overcome with a variety of successful interventions. Addressing this problem and researching more effective ways of implementing these interventions can help improve medication administration and compliance in the pediatric population.

Future disposition and suicidal ideation: mediation by depressive symptom clusters.

BACKGROUND: In line with hopelessness theory, both increased negative expectancies and reduced positive expectancies for the future have been associated with suicidal ideation. This study evaluated two depression symptom clusters as mediators of the relationship between future disposition and suicide: subjective feelings of depression and self-blame. METHODS: Data from 140 undergraduate students with moderate to severe depression symptoms are presented who completed the Beck Scale for Suicidal Ideation, Beck Depression Inventory, and the Future Disposition Inventory. RESULTS: On mediation analysis, subjective depression mediated the relationship between positive disposition and suicidal ideation. In contrast, the relationship between negative disposition and suicidal ideation was mediated by self-blame. The reverse of these relationships was not significant. LIMITATIONS: This is a cross-sectional study of an undergraduate sample and results warrant replication in clinical samples with clinician-administered assessments. CONCLUSIONS: Findings suggest two potential pathways to suicidal thoughts with implications for assessment and treatment. Depressed individuals with few positive expectations of the future may benefit from interventions focusing on subjective depression symptoms, such as sadness or anhedonia. For depressed individuals with negative expectations for the future, a clinical focus on negative attributions or self-blame may be warranted.

The critical warzone experiences (CWE) scale: initial psychometric properties and association with PTSD, anxiety, and depression.

The objective of the present research was to develop and evaluate a critical warzone experiences (CWE) scale for use with Iraq/Afghanistan veterans. The psychometric properties of the CWE were evaluated across three independent samples of Iraq/Afghanistan veterans. Despite its brevity (7 items), the CWE exhibited good internal consistency (average α =0.83), good temporal stability (1-year test-retest reliability=0.73), good concurrent validity with lengthier measures of warzone experiences (average r=0.74), and a clear unidimensional factor structure (average factor loading=0.69). Study 2 confirmed the CWE׳s factor structure through confirmatory factor analysis, and structural equation modeling demonstrated a strong association between CWE and post-deployment mental health, ß =0.49, p<0.001. Study 3 provided further support for the predictive validity of the CWE by demonstrating that it was associated with PTSD diagnosis, clinician-rated PTSD symptom severity, and global functional impairment in an independent sample of Iraq/Afghanistan veterans (average r=0.59). While replication of these findings in more diverse samples is needed, the preliminary evidence from these studies indicates that the CWE is a brief, reliable, and valid measure of critical warzone experiences among Iraq/Afghanistan war veterans.

Association between right ventricular dysfunction and restrictive lung disease in childhood cancer survivors as measured by quantitative echocardiography.

BACKGROUND: Restrictive lung disease is a complication in childhood cancer survivors who received lung-toxic chemotherapy and/or thoracic radiation. Left ventricular dysfunction is documented in these survivors, but less is known about right ventricular (RV) function. Quantitative echocardiography may help detect subclinical RV dysfunction. The aim of this study was to assess RV function quantitatively in childhood cancer survivors after lung-toxic therapy. PROCEDURES: We identified records of 33 childhood cancer survivors who (1) were treated with lung-toxic therapy and/or radiation, (2) were cancer-free for ≥ one year after therapy, and (3) had pulmonary function tests and echocardiograms from their most recent follow-up visit. RESULTS: Participants' mean age was 11.6 ± 4.5 years at cancer diagnosis and 23 ± 8.6 years at evaluation. The most common diagnosis was lymphoma/leukemia (n = 27). Twenty-nine subjects had anthracycline exposure. Eleven of the 33 subjects demonstrated restrictive pulmonary impairment (total lung capacity 3.69 ± 1.5 L [69.3 ± 22.4% predicted]). Among quantitative measures of RV function, isovolumetric acceleration (IVA), a measure of contractility, was significantly lower in the group with restrictive lung disease (2.42 ± 0.56 vs. 1.83 ± 0.78 m/sec(2); P < 0.05). There was a trend towards lower tissue Doppler derived S' and tricuspid annular plane systolic excursion in the group with restrictive lung disease. Subjects with restrictive lung disease were found to have ≥ 2 abnormal parameters (P < 0.01). CONCLUSION: IVA may detect early RV dysfunction in childhood cancer survivors with restrictive lung disease. Our findings require confirmation in a larger study population and validation by cardiac MRI.

Loneliness and suicidal ideation in drug-using college students.

The college years are marked by social changes and behavioral experimentation which may increase risk of suicidal ideation. We propose a novel pathway for the development of suicidal thoughts between two established suicide risk factors, loneliness and drug use, which have not been examined in a nonclinical sample. Data were collected from 207 undergraduate drug-using students at a large southeastern university. As hypothesized, suicidal ideation was positively correlated with both loneliness (r = .40) and drug use (r = .29). After controlling for several demographic variables, social desirability, and anxiety sensitivity, drug use was tested as a potential mediator in the loneliness-suicidal ideation link using a single-mediator model. Results indicated a significant indirect (mediated) effect of loneliness on suicidal ideation via drug use (ab = 0.09, 95% CI: 0.02-0.18), suggesting that loneliness may contribute to suicidal ideation through increased drug use among college students. Identification of and intervention with students reporting loneliness and drug use may be a promising suicide prevention strategy on college campuses.

PAK1 mediates resistance to PI3K inhibition in lymphomas.

PURPOSE: The phosphoinositide 3-kinase (PI3K) pathway is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B-cell lymphomas. EXPERIMENTAL DESIGN: We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs. RESULTS: We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference-mediated knockdown of the PAK1 gene, we showed a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small-molecule inhibitor of PAK1 and found significant synergy between PI3K and PAK1 inhibition. CONCLUSION: Thus, we show that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.

Factor structure and convergent validity of the inventory of interpersonal problems in an inpatient setting.

The Inventory of Interpersonal Problems (IIP32) is a self-report measure designed to be used in clinical settings to assess interpersonal difficulties. However, it has been exclusively used in either outpatient or non-clinical settings, and psychometric data concerning its use in inpatients are limited. The current study examined the factor structure and construct validity of the IIP-32, and ways to optimally use this measure with inpatients at a private hospital providing intensive treatment. The original eight-factor structure was a poor fit to the data, whereas a five-factor structure provided a somewhat better fit. Although the five factors (Nonassertive, Detached, Intrusive, Self-Sacrificing, and Socially Inhibited) demonstrated adequate internal consistency, reliability, and limited convergent validity, the IIP is ultimately useful insofar as it engages patients in collaborative self-awareness during intensive psychotherapeutically oriented treatment.