A Controlled Trial of Inhaled Bronchodilators in Familial Dysautonomia

Background

Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible.

Methods

We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation. Albuterol, ipratropium bromide, and placebo were administered on 3 separate days via nebulizer in the seated position. Airway responsiveness was evaluated using spirometry and impulse oscillometry 30 min post dose. Cardiovascular effects were evaluated by continuous monitoring of blood pressure, RR intervals, cardiac output, and systemic vascular resistance.

Results

A total of 14 patients completed the trial. Neither active agent had significant detrimental effects on heart rate or rhythm or blood pressure. Albuterol and ipratropium were similar in their bronchodilator effectiveness causing significant improvement in forced expiratory volume in 1-s (FEV1, p?=?0.002 and p?=?0.030). Impulse oscillometry measures were consistent with a reduction in total airway resistance post nebulization (resistance at 5 Hz p?<?0.006).

Conclusion

Airway obstruction is pharmacologically reversible in a number of patients with FD. In the short term, both albuterol and ipratropium were well tolerated and not associated with major cardiovascular adverse events.

     

Type 1 diabetic patients with peripheral neuropathy have pan-enteric prolongation of gastrointestinal transit times and an altered caecal pH profile

Aims/hypothesis

We hypothesised that type 1 diabetic patients with established diabetic sensorimotor polyneuropathy (DSPN) would have segmental and/or pan-enteric dysmotility in comparison to healthy age-matched controls. We aimed to investigate the co-relationships between gastrointestinal function, degree of DSPN and clinical symptoms.

Methods

An observational comparison was made between 48 patients with DSPN (39 men, mean age 50 years, range 29–71 years), representing the baseline data of an ongoing clinical trial (representing a secondary analysis of baseline data collected from an ongoing double-blind randomised controlled trial investigating the neuroprotective effects of liraglutide) and 41 healthy participants (16 men, mean age 49 years, range 30–78) who underwent a standardised wireless motility capsule test to assess gastrointestinal transit. In patients, vibration thresholds, the Michigan Neuropathy Screening Instrument and Patient Assessment of Upper Gastrointestinal Symptom questionnaires were recorded.

Results

Compared with healthy controls, patients showed prolonged gastric emptying (299?±?289 vs 179?±?49 min; p?=?0.01), small bowel transit (289?±?107 vs 224?±?63 min; p?=?0.001), colonic transit (2140, interquartile range [IQR] 1149–2799 min vs 1087, IQR 882–1650 min; p?=?0.0001) and whole-gut transit time (2721, IQR 1196–3541 min vs 1475 (IQR 1278–2214) min; p?<?0.0001). Patients also showed an increased fall in pH across the ileocaecal junction (?1.8?±?0.4 vs ?1.3?±?0.4 pH; p?<?0.0001), which was associated with prolonged colonic transit (r?=?0.3, p?=?0.001). Multivariable regression, controlling for sex, disease duration and glycaemic control, demonstrated an association between whole-gut transit time and total GCSI (p?=?0.02).

Conclusions/interpretation

Pan-enteric prolongation of gastrointestinal transit times and a more acidic caecal pH, which may represent heightened caecal fermentation, are present in patients with type 1 diabetes. The potential implication of delayed gastrointestinal transit on the bioavailability of nutrition and on pharmacotherapeutic and glycaemic control warrants further investigation.

Trial registration

EUDRA CT: 2013-004375-12

     

Statin Use,Diabetes Incidence and Overall Mortality in Normoglycemic and Impaired Fasting Glucose Patients

BACKGROUND

The association between the use of statins and the risk of diabetes and increased mortality within the same population has been a source of controversy, and may underestimate the value of statins for patients at risk.

OBJECTIVE

We aimed to assess whether statin use increases the risk of developing diabetes or affects overall mortality among normoglycemic patients and patients with impaired fasting glucose (IFG).

DESIGN AND PARTICIPANTS

Observational cohort study of 13,508 normoglycemic patients (n?=?4460; 33 % taking statins) and 4563 IFG patients (n?=?1865; 41 % taking statin) among residents of Olmsted County, Minnesota, with clinical data in the Mayo Clinic electronic medical record and at least one outpatient fasting glucose test between 1999 and 2004. Demographics, vital signs, tobacco use, laboratory results, medications and comorbidities were obtained by electronic search for the period 1999–2004. Results were analyzed by Cox proportional hazards models, and the risk of incident diabetes and mortality were analyzed by survival curves using the Kaplan–Meier method.

MAIN MEASURES

The main endpoints were new clinical diagnosis of diabetes mellitus and total mortality.

KEY RESULTS

After a mean of 6 years of follow-up, statin use was found to be associated with an increased risk of incident diabetes in the normoglycemic (HR 1.19; 95 % CI, 1.05 to 1.35; p?=?0.007) and IFG groups (HR 1.24; 95%CI, 1.11 to 1.38; p?=?0.0001). At the same time, overall mortality decreased in both normoglycemic (HR 0.70; 95 % CI, 0.66 to 0.80; p?<?0.0001) and IFG patients (HR 0.77, 95 % CI, 0.64 to 0.91; p?=?0.0029) with statin use.

CONCLUSION

In general, recommendations for statin use should not be affected by concerns over an increased risk of developing diabetes, since the benefit of reduced mortality clearly outweighs this small (19–24 %) risk.

     

Symptom Domain Groups of the Patient-Reported Outcomes Measurement Information System Tools Independently Predict Hospitalizations and Re-hospitalizations in Cirrhosis

Background

Patient-Reported Outcomes Measurement Information System (PROMIS) tools can identify health-related quality of life (HRQOL) domains that could differentially affect disease progression. Cirrhotics are highly prone to hospitalizations and re-hospitalizations, but the current clinical prognostic models may be insufficient, and thus studying the contribution of individual HRQOL domains could improve prognostication.

Aim

Analyze the impact of individual HRQOL PROMIS domains in predicting time to all non-elective hospitalizations and re-hospitalizations in cirrhosis.

Methods

Outpatient cirrhotics were administered PROMIS computerized tools. The first non-elective hospitalization and subsequent re-hospitalizations after enrollment were recorded. Individual PROMIS domains significantly contributing toward these outcomes were generated using principal component analysis. Factor analysis revealed three major PROMIS domain groups: daily function (fatigue, physical function, social roles/activities and sleep issues), mood (anxiety, anger, and depression), and pain (pain behavior/impact) accounted for 77% of the variability. Cox proportional hazards regression modeling was used for these groups to evaluate time to first hospitalization and re-hospitalization.

Results

A total of 286 patients [57 years, MELD 13, 67% men, 40% hepatic encephalopathy (HE)] were enrolled. Patients were followed at 6-month (mth) intervals for a median of 38 mths (IQR 22–47), during which 31% were hospitalized [median IQR mths 12.5 (3–27)] and 12% were re-hospitalized [10.5 mths (3–28)]. Time to first hospitalization was predicted by HE, HR 1.5 (CI 1.01–2.5, p = 0.04) and daily function PROMIS group HR 1.4 (CI 1.1–1.8, p = 0.01), independently. In contrast, the pain PROMIS group were predictive of the time to re-hospitalization HR 1.6 (CI 1.1–2.3, p = 0.03) as was HE, HR 2.1 (CI 1.1–4.3, p = 0.03).

Conclusions

Daily function and pain HRQOL domain groups using PROMIS tools independently predict hospitalizations and re-hospitalizations in cirrhotic patients.

     

Diabetes was the only comorbid condition associated with mortality of invasive pneumococcal infection in ICU patients: a multicenter observational study from the Outcomerea research group

Purposes

Streptococcus pneumoniae is a leading pathogen of severe community, hospital or nursing facility infections. We sought to describe characteristics of invasive pneumococcal infection (IPI) and pneumonia (due to the high mortality of intensive care-associated pneumonia) and to report outcomes according to various types of comorbidity.

Methods

Multicenter observational cohort study on the prospective Outcomerea database, including adult patients, with a hospital stay?<?48 h before ICU admission and a documented IPI within the first 72 h of ICU admission. Comorbid conditions were defined according to the Knaus and Charlson classification.

Results

Of the 20,235 patients, 5310 (26.4%) had an invasive infection, including 560/5,310 (10.6%) who had an IPI. The ICU 28-day mortality was 109/560 (19.8%). Four factors were independently associated with mortality: SOFA day 1–2: [hazard ratio (HR) 1.21; 95% confidence interval (95% CI) 1.15–1.27, p?<?0.001]; maximum lactate level day 1–2: (HR 1.07, 95% CI 1.02–1.12, p?=?0.006); diabetes mellitus: (HR 1.91, 95% CI 1.23–3.03, p?=?0.006) and appropriate antibiotics (HR 0.28, 95% CI 0.15–0.50, p?<?0.001). Comparable results were obtained when other comorbid conditions were forced into the model. Diabetes impact was more pronounced in case of micro- or macro-angiopathy (HR 4.17, 95%CI 1.68–10.54, p?=?0.003), in patients?≥?65 years old (HR 2.59, 95% CI 1.56–4.28, <?0.001) and in those with body mass index (BMI)?<?25 kg/m² (HR 2.11, 95% CI 1.10–4.06, p?=?0.025).

Conclusions

Diabetes mellitus was the only comorbid condition which independently influenced mortality in patients with IPI. Its impact was more pronounced in patients with complications, aged?≥?65 years and with BMI?<?25 kg/m².

     

Insurance Coverage Predicts Mortality in Patients Transferred Between Hospitals: a Cross-Sectional Study

Background

Patients transferred between hospitals are at high risk of adverse events and mortality. The relationship between insurance status, transfer practices, and outcomes has not been definitively characterized.

Objective

To identify the association between insurance coverage and mortality of patients transferred between hospitals.

Design

We conducted a single-institution observational study, and validated results using a national administrative database of inter-hospital transfers.

Setting

Three ICUs at an academic tertiary care center validated by a nationally representative sample of inter-hospital transfers.

Patients

The single-institution analysis included 652 consecutive patients transferred from 57 hospitals between 2011 and 2012. The administrative database included 353,018 patients transferred between 437 hospitals.

Measurements

Adjusted inpatient mortality and 24-h mortality, stratified by insurance status.

Results

Of 652 consecutive transfers to three ICUs, we observed that uninsured patients had higher adjusted inpatient mortality (OR 2.67, p?=?0.021) when controlling for age, race, gender, Apache-II, and whether the patient was transferred from an ED. Uninsured were more likely to be transferred from ED (OR 2.3, p?=?0.026), and earlier in their hospital course (3.9 vs 2.0 days, p?=?0.002). Using an administrative dataset, we validated these observations, finding that the uninsured had higher adjusted inpatient mortality (OR 1.24, 95% CI 1.13–1.36, p?<?0.001) and higher mortality within 24 h (OR 1.33 95% CI 1.11–1.60, p?<?0.002). The increase in mortality was independent of patient demographics, referral patterns, or diagnoses.

Limitations

This is an observational study where transfer appropriateness cannot be directly assessed.

Conclusions

Uninsured patients are more likely to be transferred from an ED and have higher mortality. These data suggest factors that drive inter-hospital transfer of uninsured patients have the potential to exacerbate outcome disparities.

     

Prognostic Factors in Adult Patients with Non-Cystic Fibrosis Bronchiectasis

Background

Non-cystic fibrosis bronchiectasis (NCFB) is a heterogeneous disease. There are few studies about prognostic factors in these patients. Our study aims to assess mortality rates and related factors in a cohort of patients and test the ability of the BSI and FACED scores in predicting mortality in this cohort.

Methods

This was a prospective cohort analysis of 70 patients with NCFB recruited from May 2008 to August 2010. At baseline, patients underwent clinical evaluation, pulmonary function tests, 6-min walk test, and quality of life assessment. Outcomes were defined as favorable (survivors) and unfavorable (survivors who underwent lung transplantation and death from all causes). Baseline records provided data for determination of BSI and FACED.

Results

Twenty-seven patients (38.57%) died and 1 (1.43%) underwent lung transplantation. Mean time for occurrence of unfavorable outcomes was 74.67?±?4.00 months. Main cause of death was an acute infectious exacerbation of bronchiectasis (60.7). Cox regression identified age (p?=?0.035; HR 1.04; CI 1.01–1.08), FEV₁ % of predicted (p?=?0.045; HR 0.97; CI 0.93–0.99), and MEP (p?=?0.016; HR 0.96; CI 0.94–0.99) as independent predictors of unfavorable outcomes. FACED was better at predicting unfavorable outcomes in our cohort (log-rank test, FACED p?=?0.001 and BSI p?=?0.286). In ROC analysis, both scores were similar in predicting unfavorable outcomes (BSI 0.65; FACED 0.66).

Conclusions

Older age, lower FEV₁ % of predicted, and lower MEP were independently linked to unfavorable outcomes. FACED and BSI were not accurate in predicting mortality in our cohort.

     

Persistence of abnormalities in white matter in children with type 1 diabetes

Aims/hypothesis

Prior studies suggest white matter growth is reduced and white matter microstructure is altered in the brains of young children with type 1 diabetes when compared with brains of non-diabetic children, due in part to adverse effects of hyperglycaemia. This longitudinal observational study examines whether dysglycaemia alters the developmental trajectory of white matter microstructure over time in young children with type 1 diabetes.

Methods

One hundred and eighteen children, aged 4 to <10 years old with type 1 diabetes and 58 age-matched, non-diabetic children were studied at baseline and 18 months, at five Diabetes Research in Children Network clinical centres. We analysed longitudinal trajectories of white matter using diffusion tensor imaging. Continuous glucose monitoring profiles and HbA_1c levels were obtained every 3 months.

Results

Axial diffusivity was lower in children with diabetes at baseline (p?=?0.022) and at 18 months (p?=?0.015), indicating that differences in white matter microstructure persist over time in children with diabetes. Within the diabetes group, lower exposure to hyperglycaemia, averaged over the time since diagnosis, was associated with higher fractional anisotropy (p?=?0.037). Fractional anisotropy was positively correlated with performance (p?<?0.002) and full-scale IQ (p?<?0.02).

Conclusions/interpretation

These results suggest that hyperglycaemia is associated with altered white matter development, which may contribute to the mild cognitive deficits in this population.

     

The influence of gender on symptoms associated with obstructive sleep apnea

Background

It has been reported that the clinical expression of obstructive sleep apnea (OSA) may differ in women and men.

Objective

The objective of this study was to evaluate the influence of gender on reported OSA-related symptoms in a large clinical population of patients.

Methods

The database from the sleep laboratory of a tertiary care center was examined. Adult patients who had undergone a diagnostic polysomnography and completed the Berlin questionnaire, a sleep questionnaire, and the Epworth sleepiness scale were selected. Multiple logistic regression analysis was performed to assess the relationship between OSA-associated symptoms and different potential explanatory variables.

Results

The study sample included 1084 patients, median age was 53 years, 46.5% (504) were women, 72.7% (788) had OSA (apnea/hypopnea index ≥?5), and 31.2% were obese. After adjusting for age, body mass index, and apnea/hypopnea index, men were more likely to report snoring (OR 4.06, p?<?0.001), habitual or loud snoring (OR 2.34, p?<?0.001; 2.14, p?<?0.001, respectively) and apneas (OR 2.44, p?<?0.001), than women. After controlling for multiple variables, female gender was an independent predictive factor for reported tiredness (OR 0.57, p 0.001), sleep onset insomnia (OR 0.59, p 0.0035), and morning headaches (OR 0.32, p?<?0.001). Reports of excessive daytime sleepiness, nocturia, midnight insomnia, and subjective cognitive complaints were not significantly associated with gender.

Conclusion

Women with OSA were more likely to report tiredness, initial insomnia, and morning headaches, and less likely to complain of typical OSA symptoms (snoring, apneas) than men.

     

So Tired: Predictive Utility of Baseline Sleep Screening in a Longitudinal Observational Survey Cohort of First-Year Residents

Background

Sleep impairment is highly prevalent among resident physicians and is associated with both adverse patient outcomes and poor resident mental and physical health. Risk factors for sleep problems during residency are less clear, and no screening model exists to identify residents at risk for sleep impairment.

Objective

The objective of this study was to assess change in resident sleep during training and to evaluate utility of baseline sleep screening in predicting future sleep impairment.

Design

This is a prospective observational repeated-measures survey study.

Participants

The participants comprised PGY-1 residents across multiple specialties at Partners HealthCare hospitals.

Main Measures

Main measures used for this study were demographic queries and two validated scales: the Pittsburgh Sleep Quality Index (PSQI), measuring sleep quality, and the Epworth Sleepiness Scale (ESS), measuring excessive daytime sleepiness.

Key Results

Two hundred eighty-one PGY-1 residents completed surveys at residency orientation, and 153 (54%) completed matched surveys 9 months later. Mean nightly sleep time decreased from 7.6 to 6.5 hours (p?<?0.001). Mean PSQI score increased from 3.6 to 5.2 (p?<?0.001), and mean ESS score increased from 7.2 to 10.4 (p?<?0.001). The proportion of residents exceeding the scales’ clinical cutoffs increased over time from 15 to 40% on the PSQI (p?<?0.001) and from 26 to 59% on the ESS (p?<?0.001). Baseline normal sleep was not protective: 68% of residents with normal scores on both scales at baseline exceeded the clinical cutoff on at least one scale at follow-up. Greater age and fewer children increased follow-up PSQI score (p?<?0.001) but not ESS score.

Conclusions

During PGY-1 training, residents experience worsening sleep duration, quality of sleep, and daytime sleepiness. Residents with baseline impaired sleep tend to remain impaired. Moreover, many residents with baseline normal sleep experience sleep deterioration over time. Sleep screening at residency orientation may identify some, but not all, residents who will experience sleep impairment during training.

     

Alcohol-related acute-on-chronic liver failure—Comparison of various prognostic scores in predicting outcome

Background and Aims

Various prognostic scores are available for predicting outcome in acute-on-chronic liver failure (ACLF). We compared the available prognostic models as predictors of outcome in alcohol-related ACLF patients.

Methods

All consecutive patients with alcohol-related ACLF were included. At admission, prognostic indices-acute physiology and chronic health evaluation score (APACHE II), model for end-stage liver disease (MELD), MELD-Na, Maddrey’s discriminant function (DF), age-bilirubin-INR-creatinine (ABIC), and Chronic Liver Failure Consortium (CLIF-C) ACLF score (CLIF-C ACLF) score were calculated. Receiver operator characteristic (ROC) curves were plotted for all prognostic scores with in-hospital, 90-day, and 1-year mortality as outcome.

Results

Of the 171 patients, 170 were males, and grade 1 ACLF in 20 (11.7%), grade 2 in 52 (30.4%), and grade 3 in 99 (57.9%) patients. One hundred and nineteen (69.6%) died in-hospital. The median (IQR) Maddrey’s score, MELD, MELD-Na, ABIC, APACHE II, and CLIF-C ACLF were 87.8 (66.5–123.0), 33.1 (27.6–40.0), 34.4 (29.5–40.0), 8.5 (7.3–9.6), 15 (12–21), and 51.1 (44.1–56.4), respectively. On multivariate Cox regression analysis, independent predictors of in-hospital outcome were presence of hepatic encephalopathy (early HR, 2.078; 95%CI, 1.173–3.682, p?=?0.012 and advanced, HR, 2.330; 95% CI, 1.270–4.276, p?=?0.006), elevated serum creatinine (HR, 1.140; 95% CI, 1.023–1.270, p?=?0.018), and infection at admission (HR, 1.874; 95% CI, 1.160–23.029, p?=?0.010). On comparison of ROC curves, APACHE II and CLIF-C ACLF AUROC were significantly higher than MELD, MELD-Na, DF, and ABIC (p?<?0.05) for predicting in-hospital, 90-day, and 1-year mortality. The AUROC was highest for APACHE II followed by CLIF-C ACLF (Hanley and McNeil, p?=?0.660).

Conclusions

Alcohol-related ACLF has high in-hospital mortality. Among the available prognostic scores, CLIF-C ACLF and APACHE II perform best.

     

Macroscopic serosal invasion and small tumor size as independent prognostic factors in stage IIA colon cancer

Background

This study aimed to investigate the prognostic factors of patients with stage IIA (T3N0M0) colon cancer in terms of macroscopic serosal invasion and small tumor size.

Methods

We enrolled 375 stage IIA colon cancer patients who underwent curative resection between January 2004 and December 2011. Macroscopic serosal invasion was defined as tumor nodules or colloid changes protruding the surface of the serosa. The clinicopathologic characteristics were analyzed to identify independent prognostic factors.

Results

The median follow-up was 47 months (range, 1–90 months). On multivariate survival analysis, macroscopic serosal invasion (adjusted hazard ratio [HR]?=?4.750; p?=?0.013), tumor size <?5 cm (adjusted HR?=?3.112, p?=?0.009), perineural invasion (adjusted HR?=?3.528; p?=?0.002), <?12 retrieved lymph nodes (adjusted HR?=?4.257; p?=?0.002), and localized perforation (adjusted HR?=?7.666; p?=?0.008) were independent risk factors for recurrence.

Conclusion

We found novel prognostic factors of stage IIA colon cancer, including macroscopic serosal invasion and small tumor size (<?5 cm). Further studies are needed to evaluate the benefit of adjuvant chemotherapy in patients with these prognostic factors.

     

Communication Skills Training for Physicians Improves Patient Satisfaction

BACKGROUND

Skilled physician communication is a key component of patient experience. Large-scale studies of exposure to communication skills training and its impact on patient satisfaction have not been conducted.

OBJECTIVE

We aimed to examine the impact of experiential relationship-centered physician communication skills training on patient satisfaction and physician experience.

DESIGN

This was an observational study.

SETTING

The study was conducted at a large, multispecialty academic medical center.

PARTICIPANTS

Participants included 1537 attending physicians who participated in, and 1951 physicians who did not participate in, communication skills training between 1 August 2013 and 30 April 2014.

INTERVENTION

An 8-h block of interactive didactics, live or video skill demonstrations, and small group and large group skills practice sessions using a relationship-centered model.

MAIN MEASURES

Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS), Clinician and Group Consumer Assessment of Healthcare Providers and Systems (CGCAHPS), Jefferson Scale of Empathy (JSE), Maslach Burnout Inventory (MBI), self-efficacy, and post course satisfaction.

KEY RESULTS

Following the course, adjusted overall CGCAHPS scores for physician communication were higher for intervention physicians than for controls (92.09 vs. 91.09, p?<?0.03). No significant interactions were noted between physician specialty or baseline CGCAHPS and improvement following the course. Significant improvement in the post-course HCAHPS Respect domain adjusted mean was seen in intervention versus control groups (91.08 vs. 88.79, p?=?0.02) and smaller, non-statistically significant improvements were also seen for adjusted HCAHPS communication scores (83.95 vs. 82.73, p?=?0.22). Physicians reported high course satisfaction and showed significant improvement in empathy (116.4?±?12.7 vs. 124?±?11.9, p?<?0.001) and burnout, including all measures of emotional exhaustion, depersonalization, and personal accomplishment. Less depersonalization and greater personal accomplishment were sustained for at least 3 months.

CONCLUSIONS

System-wide relationship-centered communication skills training improved patient satisfaction scores, improved physician empathy, self-efficacy, and reduced physician burnout. Further research is necessary to examine longer-term sustainability of such interventions.

     

Serum metabolomic profile of incident diabetes

Aims/hypothesis

Metabolomic profiling offers the potential to reveal metabolic pathways relevant to the pathophysiology of diabetes and improve diabetes risk prediction.

Methods

We prospectively analysed known metabolites using an untargeted approach in serum specimens from baseline (1987–1989) and incident diabetes through to 31 December 2015 in a subset of 2939 Atherosclerosis Risk in Communities (ARIC) study participants with metabolomics data and without prevalent diabetes.

Results

Among the 245 named compounds identified, seven metabolites were significantly associated with incident diabetes after Bonferroni correction and covariate adjustment; these included a food additive (erythritol) and compounds involved in amino acid metabolism [isoleucine, leucine, valine, asparagine, 3-(4-hydoxyphenyl)lactate] and glucose metabolism (trehalose). Higher levels of metabolites were associated with increased risk of incident diabetes (HR per 1 SD increase in isoleucine 2.96, 95% CI 2.02, 4.35, p?=?3.18?×?10^?8; HR per 1 SD increase in trehalose 1.16, 95% CI 1.09, 1.25, p?=?1.87?×?10^?5), with the exception of asparagine, which was associated with a lower risk of diabetes (HR per 1 SD increase in asparagine 0.78, 95% CI 0.71, 0.85, p?=?4.19?×?10^?8). The seven metabolites modestly improved prediction of incident diabetes beyond fasting glucose and established risk factors (C statistics 0.744 vs 0.735, p?=?0.001 for the difference in C statistics).

Conclusions/interpretation

Branched chain amino acids may play a role in diabetes development. Our study is the first to report asparagine as a protective biomarker of diabetes risk. The serum metabolome reflects known and novel metabolic disturbances that improve prediction of diabetes.

     

Mast Cells and Serotonin Synthesis Modulate Chagas Disease in the Colon: Clinical and Experimental Evidence

Background

Trypanosoma cruzi (T. cruzi) infects millions of Latin Americans each year and can induce chagasic megacolon. Little is known about how serotonin (5-HT) modulates this condition. Aim We investigated whether 5-HT synthesis alters T. cruzi infection in the colon.

Materials and Methods

Forty-eight paraffin-embedded samples from normal colon and chagasic megacolon were histopathologically analyzed (173/2009). Tryptophan hydroxylase 1 (Tph1) knockout (KO) mice and c-Kit^W-sh mice underwent T. cruzi infection together with their wild-type counterparts. Also, mice underwent different drug treatments (16.1.1064.60.3).

Results

In both humans and experimental mouse models, the serotonergic system was activated by T. cruzi infection (p?<?0.05). While treating Tph1KO mice with 5-HT did not significantly increase parasitemia in the colon (p?>?0.05), rescuing its synthesis promoted trypanosomiasis (p?<?0.01). T. cruzi-related 5-HT release (p?<?0.05) seemed not only to increase inflammatory signaling, but also to enlarge the pericryptal macrophage and mast cell populations (p?<?0.01). Knocking out mast cells reduced trypanosomiasis (p?<?0.01), although it did not further alter the neuroendocrine cell number and Tph1 expression (p?>?0.05). Further experimentation revealed that pharmacologically inhibiting mast cell activity reduced colonic infection (p?<?0.01). A similar finding was achieved when 5-HT synthesis was blocked in c-Kit^W-sh mice (p?>?0.05). However, inhibiting mast cell activity in Tph1KO mice increased colonic trypanosomiasis (p?<?0.01).

Conclusion

We show that mast cells may modulate the T. cruzi-related increase of 5-HT synthesis in the intestinal colon.

     

Longitudinal Changes in Health-Related Quality of Life for Chronic Diseases: An Example in Hemophilia A

BACKGROUND

Patients with well-managed rare chronic diseases such as hemophilia maintain a stable health state and health-related quality of life (HrQoL) that may be affected by acute events. Longitudinal HrQoL assessments analyzed using multivariate multilevel (MVML) modelling can determine the impact of such events on individuals (within-person effect) and identify factors influencing within-population differences (between-person effect).

OBJECTIVES

To demonstrate the application of MVML modelling in a longitudinal study of HrQoL in hemophilia A.

METHODS/DESIGN/PARTICIPANTS

Using data on 136 adults and 125 children from a two-year observational cohort study of burden of illness in US hemophilia A patients, MVML modelling determined the effect of time-invariant (sociodemographic and clinical characteristics) and time-varying factors (bleeding frequency, emergency room visits, and missed work/school days) on within-person and between-person HrQoL changes. HrQoL was assessed using the SF-12 health survey (adults) and PedsQL inventory (children) at baseline, then every 6 months.

RESULTS

In children, within-person (p?<?0.0001) and between-person (p?<?0.0001) psychosocial functioning was reduced by each additional bleed and missed day (within-person: p?=?0.0089; between-person: p?=?0.0060). Within-person physical functioning was reduced by each additional bleed (p?<?0.0001), emergency room (ER) visit (p?=?0.0284), and missed day (p?=?0.0473). Between-persons, additional missed days (p?<?0.0001) significantly decreased physical functioning. In adults, each additional missed day reduced SF-12 Health Survey mental (p?=?0.0025) and physical (p?=?0.0093) component summary scores. Each additional bleed also decreased physical component summary (PCS) significantly (p?=?0.0093).

CONCLUSIONS

This study demonstrated the applicability of MVML modelling in identifying time-invariant and time-varying factors influencing HrQoL in a rare chronic disease population. Small but significant within-person and between-person changes in HrQoL with each additional acute event experienced were identified, which if frequent, could have a large cumulative impact. The results suggest that MVML modelling may be applied to future studies of longitudinal change in HrQoL in other rare chronic disease populations.

     

Medical Students’ Exposure to the Humanities Correlates with Positive Personal Qualities and Reduced Burnout: A Multi-Institutional U.S. Survey

Background

Literature, music, theater, and visual arts play an uncertain and limited role in medical education. One of the arguments often advanced in favor of teaching the humanities refers to their capacity to foster traits that not only improve practice, but might also reduce physician burnout—an increasing scourge in today’s medicine. Yet, research remains limited.

Objective

To test the hypothesis that medical students with higher exposure to the humanities would report higher levels of positive physician qualities (e.g., wisdom, empathy, self-efficacy, emotional appraisal, spatial skills), while reporting lower levels of negative qualities that are detrimental to physician well-being (e.g., intolerance of ambiguity, physical fatigue, emotional exhaustion, and cognitive weariness).

Design

An online survey.

Participants

All students enrolled at five U.S. medical schools during the 2014–2015 academic year were invited by email to take part in our online survey.

Main Measures

Students reported their exposure to the humanities (e.g., music, literature, theater, visual arts) and completed rating scales measuring selected personal qualities.

Key Results

In all, 739/3107 medical students completed the survey (23.8%). Regression analyses revealed that exposure to the humanities was significantly correlated with positive personal qualities, including empathy (p?<?0.001), tolerance for ambiguity (p?<?0.001), wisdom (p?<?0.001), emotional appraisal (p?=?0.01), self-efficacy (p?=?0.02), and spatial skills (p?=?0.02), while it was significantly and inversely correlated with some components of burnout (p?=?0.01). Thus, all hypotheses were statistically significant, with effect sizes ranging from 0.2 to 0.59.

Conclusions

This study confirms the association between exposure to the humanities and both a higher level of students’ positive qualities and a lower level of adverse traits. These findings may carry implications for medical school recruitment and curriculum design.“[Science and humanities are] twin berries on one stem, grievous damage has been done to both in regarding [them]... in any other light than complemental.” (William Osler, Br Med J. 1919;2:1–7).

     

Teaching Medical Students to Help Patients Quit Smoking: Outcomes of a 10-School Randomized Controlled Trial

Background

Early in medical education, physicians must develop competencies needed for tobacco dependence treatment.

Objective

To assess the effect of a multi-modal tobacco dependence treatment curriculum on medical students’ counseling skills.

Design

A group-randomized controlled trial (2010–2014) included ten U.S. medical schools that were randomized to receive either multi-modal tobacco treatment education (MME) or traditional tobacco treatment education (TE).

Setting/Participants

Students from the classes of 2012 and 2014 at ten medical schools participated. Students from the class of 2012 (N?=?1345) completed objective structured clinical examinations (OSCEs), and 50 % (N?=?660) were randomly selected for pre-intervention evaluation. A total of 72.9 % of eligible students (N?=?1096) from the class of 2014 completed an OSCE and 69.7 % (N?=?1047) completed pre and post surveys.

Interventions

The MME included a Web-based course, a role-play classroom demonstration, and a clerkship booster session. Clerkship preceptors in MME schools participated in an academic detailing module and were encouraged to be role models for third-year students.

Measurements

The primary outcome was student tobacco treatment skills using the 5As measured by an objective structured clinical examination (OSCE) scored on a 33-item behavior checklist. Secondary outcomes were student self-reported skills for performing 5As and pharmacotherapy counseling.

Results

Although the difference was not statistically significant, MME students completed more tobacco counseling behaviors on the OSCE checklist (mean 8.7 [SE 0.6] vs. mean?8.0 [SE 0.6], p?=?0.52) than TE students. Several of the individual Assist and Arrange items were significantly more likely to have been completed by MME students, including suggesting behavioral strategies (11.8 % vs. 4.5 %, p?<?0.001) and providing information regarding quitline (21.0 % vs. 3.8 %, p?<?0.001). MME students reported higher self-efficacy for Assist, Arrange, and Pharmacotherapy counseling items (ps?≤0.05).

Limitations

Inclusion of only ten schools limits generalizability.

Conclusions

Subsequent interventions should incorporate lessons learned from this first randomized controlled trial of a multi-modal longitudinal tobacco treatment curriculum in multiple U.S. medical schools.NIH Trial Registry Number: NCT01905618

     

Total laser cycles—a measure of transvenous lead extraction difficulty

Background

Several variables have been identified as predictors for difficult or complicated transvenous lead extraction (TLE), including age and number of implanted leads, as well as patient’s age; however, a standard measure of TLE difficulty has not been described.

Objective

Total laser cycles (TLCs) delivered during laser-assisted TLE is an objective variable that could reflect the difficulty of TLE. This study investigated whether TLC is correlated with known predictors of difficult TLE.

Methods

In a retrospective study of TLE procedures using the laser sheath, we analyzed TLC delivered and compared it to established predictors of procedural failure and complications.

Results

Of 166 patients undergoing TLE, the laser sheath (SLS II or Glidelight, Spectranetics Inc.,) was used as the primary extraction sheath in 130 patients, and 100 patients had complete TLC data available. The mean age of the oldest lead (AOL) was 7.1?±?3.2 years with a median of 6.91 (interquartile range [IQR] 0.48–16.69) years, and 1.6?±?0.7 leads (range, 1–4) were extracted per procedure. Two thirds of procedures involved ICD leads. Clinical success was 99%, with one patient (1%) experiencing a major complication. Median TLC delivered was 1165 (IQR, 567–2062; range, 49–9522). TLC was positively correlated with AOL (r =?0.227, p =?0.023), and the combined age of leads was extracted (r =?0.307, p =?0.002). TLC was also positively correlated with number of leads extracted per procedure (ρ?=?0.227, p =?0.024). There was a non-significant negative trend towards correlation between TLC and patient’s age (r =??0.112, p =?0.268).

Conclusion

TLC showed significant correlation with known predictors of difficulty during TLE using the laser sheath. TLC is an objective method to report the difficulty of TLE and could usefully be reported in future series of laser lead extractions.