Three-question set from Michigan Neuropathy Screening Instrument adds independent prognostic information on cardiovascular outcomes: analysis of ALTITUDE trial

Aims/hypothesis

The self-administered Michigan Neuropathy Screening Instrument (MNSI) is used to diagnose diabetic peripheral neuropathy. We examined whether the MNSI might also provide information on risk of death and cardiovascular outcomes.

Methods

In this post hoc analysis of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, we divided 8463 participants with type 2 diabetes and chronic kidney disease (CKD) and/or cardiovascular disease (CVD) into independent training (n = 3252) and validation (n = 5211) sets. In the training set, we identified specific questions that were independently associated with a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction/stroke, heart failure hospitalisation). We then evaluated the performance of these questions in the validation set.

Results

In the training set, three questions (‘Are your legs numb?’, ‘Have you ever had an open sore on your foot?’ and ‘Do your legs hurt when you walk?’) were significantly associated with the cardiovascular composite outcome. In the validation set, after multivariable adjustment for key covariates, one or more positive responses (n = 3079, 59.1%) was associated with a higher risk of the cardiovascular composite outcome (HR 1.54 [95% CI 1.28, 1.85], p < 0.001), heart failure hospitalisation (HR 1.74 [95% CI 1.29, 2.35], p < 0.001), myocardial infarction (HR 1.81 [95% CI 1.23, 2.69], p = 0.003), stroke (HR 1.75 [95% CI 1.20, 2.56], p = 0.003) and three-point major adverse cardiovascular events (MACE) (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) (HR 1.49 [95% CI 1.20, 1.85], p < 0.001) relative to no positive responses to all questions. Associations were stronger if participants answered positively to all three questions (n = 552, 11%). The addition of the total number of affirmative responses to existing models significantly improved Harrell’s C statistic for the cardiovascular composite outcome (0.70 vs 0.71, p = 0.010), continuous net reclassification improvement (+22% [+10%, +31%], p = 0.027) and integrated discrimination improvement (+0.9% [+0.4%, +2.1%], p = 0.007).

Conclusions/interpretation

We identified three questions from the MNSI that provide additional prognostic information for individuals with type 2 diabetes and CKD and/or CVD. If externally validated, these questions may be integrated into the clinical history to augment prediction of CV events in high-risk individuals with type 2 diabetes.

     

Role of tissue harmonic imaging in focal hepatic lesions: comparison with conventional sonography

Background: The purpose of the present study was to compare iissue harmonic imaging (THI) and conventional sonography in focal hepatic lesions. Methods: Fifty patients with focal hepatic lesions were enrolled for study. Conventional grayscale and THI was performed in all the patients and two sets of images of the lesions were recorded (one each for THI and conventional) and assessed for fluid–solid differentiation, detail and overall image quality. These images were compared with conventional sonographic images and graded better, same or worse as per the case. Lesions were confirmed by fine‐needle aspiration cytology (FNAC)/surgery/other modalities such as computed tomography (CT) or magnetic resonance imaging (MRI). Results: Out of 50 patients with focal hepatic lesions, 21 patients had metastatic lesions (two single; 19 multiple) five patients had hepatocellular carcinoma (HCC), five patients had hydatid cysts, nine had simple hepatic cyst whereas five patients had liver abscess, three had focal fatty infiltration; and lymphoma and hemangioma were seen in one patient each. The first observer ranked THI better than standard sonography in 40 patients (80%) for fluid–solid differentiation, in 38 (76%) for detail and in 39 (78%) for overall image quality. The second observer ranked THI better than standard sonography in 39 patients (78%) for fluid–solid differentiation, in 40 (80%) for detail and in 42 (84%) for overall image quality. Tissue harmonic imaging provided additional information in eight patients (16%) and resulted in treatment alteration in three patients (6%). Conclusion: Tissue harmonic imaging was significantly better than conventional sonography for fluid–solid differentiation, detail and total image quality in focal hepatic lesions, especially in obese patients and patients with poor acoustic window.     

Impact of Race and Socioeconomic Status on Outcomes in Patients Hospitalized with COVID-19

BackgroundThe impact of race and socioeconomic status on clinical outcomes has not been quantified in patients hospitalized with coronavirus disease 2019 (COVID-19).ObjectiveTo evaluate the association between patient sociodemographics and neighborhood disadvantage with frequencies of death, invasive mechanical ventilation (IMV), and intensive care unit (ICU) admission in patients hospitalized with COVID-19.DesignRetrospective cohort study.SettingFour hospitals in an integrated health system serving southeast Michigan.ParticipantsAdult patients admitted to the hospital with a COVID-19 diagnosis confirmed by polymerase chain reaction.Main MeasuresPatient sociodemographics, comorbidities, and clinical outcomes were collected. Neighborhood socioeconomic variables were obtained at the census tract level from the 2018 American Community Survey. Relationships between neighborhood median income and clinical outcomes were evaluated using multivariate logistic regression models, controlling for patient age, sex, race, Charlson Comorbidity Index, obesity, smoking status, and living environment.Key ResultsBlack patients lived in significantly poorer neighborhoods than White patients (median income: $34,758 (24,531–56,095) vs. $63,317 (49,850–85,776), p < 0.001) and were more likely to have Medicaid insurance (19.4% vs. 11.2%, p < 0.001). Patients from neighborhoods with lower median income were significantly more likely to require IMV (lowest quartile: 25.4%, highest quartile: 16.0%, p < 0.001) and ICU admission (35.2%, 19.9%, p < 0.001). After adjusting for age, sex, race, and comorbidities, higher neighborhood income ($10,000 increase) remained a significant negative predictor for IMV (OR: 0.95 (95% CI 0.91, 0.99), p = 0.02) and ICU admission (OR: 0.92 (95% CI 0.89, 0.96), p < 0.001).ConclusionsNeighborhood disadvantage, which is closely associated with race, is a predictor of poor clinical outcomes in COVID-19. Measures of neighborhood disadvantage should be used to inform policies that aim to reduce COVID-19 disparities in the Black community.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-020-06527-1.KEY WORDS: COVID-19, disparities, disadvantage, socioeconomic status, race     

Diethyldithiocarbamate Methyl Ester Sulfoxide, an Inhibitor of Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase and Putative Metabolite of Disulfiram

S-methyl N,N -diethylthiolcarbamate sulfoxide (DETC-MeSO) is a potent inhibitor of rat liver mitochondrial low K _m aldehyde dehydrogenase (ALDH₂) both in vivo and in vitro, and has been proposed to be the metabolite responsible for ALDH₂ inhibition by disulfiram. Diethyldithiocarbamate methyl ester (DDTC-Me), a key intermediate in the metabolism of disulfiram, has been shown to be bioactivated by microsomal monooxygenases to diethyldithiocarbamate methyl ester sulfoxide (DDTC-Me sulfoxide). Studies were conducted to determine if DDTC-Me sulfoxide was also an active metabolite of disulfiram and inhibitor of ALDH₂. DDTC-Me sulfoxide inhibited ALDH₂ in vitro with an IC₅₀ of 10 μm, and in vivo with an ID₅₀ of 31 mg/kg (170 μmol/kg). Maximal ALDH₂ inhibition in vivo was observed 8 hr after the administration of 45.2 mg/kg DDTC-Me sulfoxide, with ALDH₂ activity returning to control levels after 48 hr. Although DDTC-Me sulfoxide inhibited ALDH₂ in vivo, DDTC-Me sulfoxide was not detected in plasma from rats treated with either disulfiram (75 mg/kg), DDTC-Me (122.25 mg/kg), or DDTC-Me sulfoxide (45.2 mg/kg). However, DDTC-Me and S -methyl N,N -diethylthiolcarbamate (DETC-Me) were detected in plasma from rats treated with DDTC-Me sulfoxide. In rats treated with DDTC-Me sulfoxide and challenged with ethanol, a small increase of ∼9 μm in blood acetaldehyde and an inconsistent drop in blood pressure was observed. In conclusion, DDTC-Me sulfoxide inhibited ALDH₂ in vitro and in vivo, was less potent than DETC- MeSO, and was not detected after disulfiram administration.     

Patient‐level Factors and the Quality of Care Delivered in Pediatric Emergency Departments

Objective

Quality of care delivered to adult patients in the emergency department (ED) is often associated with demographic and clinical factors such as a patient's race/ethnicity and insurance status. We sought to determine whether the quality of care delivered to children in the ED was associated with a variety of patient‐level factors.

Methods

This was a retrospective, observational cohort study. Pediatric patients (<18 years) who received care between January 2011 and December 2011 at one of 12 EDs participating in the Pediatric Emergency Care Applied Research Network (PECARN) were included. We analyzed demographic factors (including age, sex, and payment source) and clinical factors (including triage, chief complaint, and severity of illness). We measured quality of care using a previously validated implicit review instrument using chart review with a summary score that ranged from 5 to 35. We examined associations between demographic and clinical factors and quality of care using a hierarchical multivariable linear regression model with hospital site as a random effect.

Results

In the multivariable model, among the 620 ED encounters reviewed, we did not find any association between patient age, sex, race/ethnicity, and payment source and the quality of care delivered. However, we did find that some chief complaint categories were significantly associated with lower than average quality of care, including fever (–0.65 points in quality, 95% confidence interval [CI] = –1.24 to –0.06) and upper respiratory symptoms (–0.68 points in quality, 95% CI = –1.30 to –0.07).

Conclusion

We found that quality of ED care delivered to children among a cohort of 12 EDs participating in the PECARN was high and did not differ by patient age, sex, race/ethnicity, and payment source, but did vary by the presenting chief complaint.

     

A Comparison of Liver Disease Mortality With HIV and Overdose Mortality Among Georgia Prisoners and Releasees: A 2-Decade Cohort Study of Prisoners Incarcerated in 1991

Objectives. We investigated whether eventual causes of death among a cohort of inmates imprisoned in the southeastern United States differed from those in previous prisoner studies.Methods. We matched 23 510 prisoners in Georgia, a state with historically low levels of heroin consumption but moderate amounts of injection drug use, who were incarcerated on June 30, 1991, to death registries through 2010. Main exposure was 4-year time intervals over 2 decades of observation; main outcome was mortality from liver disease, HIV, and overdose.Results. Although the HIV-related mortality rate exceeded that from liver-related conditions before 2003, liver disease subsequently surpassed HIV as a cause of death. Among 3863 deaths, 22 (0.6%) occurred within 2 weeks after release from prison. Of these, only 2 were caused by accidental poisoning (likely drug overdose). Cardiovascular disease and cancer were the most frequent causes of death in this aging cohort.Conclusions. Our study design deemphasized immediate deaths but highlighted long-term sequelae of exposure to viral hepatitis and alcohol. Treating hepatitis C and implementing interventions to manage alcohol use disorders may improve survival among prisoners in the Southeast.Drug use, incarceration, and mortality are intertwined: the use of illicit drugs can result in both incarceration and premature death. A 2010 international meta-analysis of prisoners'' survival after their release into the community emphasized mortality from overdose in the 2 weeks following discharge, possibly attributable to loss of opiate tolerance after forced sobriety in prison,1 but a more recent publication illustrates how this pattern may vary among subpopulations.2Long-term consequences of injection drug use include hepatitis C and HIV infection. In the United States, sexual exposure is the most common mode of HIV transmission, but the hepatitis C epidemic is mainly driven by the injection of drugs, even if the drug use is not sustained.3 HIV prevalence is 3 times as common among prisoners as among the general population,4 but hepatitis C prevalence is 13 times as high.5,6 Sequelae that could lead to death from hepatitis C typically occur 2 to 4 decades after injection drug use was initiated. Little is known about the long-term survival of inmates, particularly in the southeastern United States, where historical and recent patterns of drug use may differ from those in other regions.In contrast with other studies that have examined cohorts of released inmates, we sought to assess long-term prisoner survival by retrospectively following a cohort composed of a cross section of all imprisoned persons in the state of Georgia on a single day in 1991. In a previous study, we did not observe significantly higher mortality among members of this cohort immediately after release from prison than in the subsequent postrelease period.7 Multiple sources suggest that heroin use is less common in Georgia than in other states. Between 2002 and 2012, consistently fewer than 6.5% of men jailed in Atlanta, the capital of and largest city in Georgia, had evidence of heroin in their urine samples.8,9 The prevalence of opiate use in Atlanta was among the lowest for any city studied in the past decade by the Office of the National Drug Control Policy.8–10 In particular, heroin use was lower than in Washington State, site of a previous study of former inmate mortality.11 According to the Treatment Episode Data Set–Admissions for 1992 to 2010 from the Substance Abuse and Mental Health Services Administration, heroin addiction accounted for only 1.6% of admissions for drug rehabilitation in Georgia, but 9.7% in Washington State and 14.2% nationally.12In assessment of risk for hepatitis C, needle use—whether for heroin, cocaine, or another drug—is more important than what is injected. Needle use in Georgia is not uncommon. According to population-wide National Survey on Drug Use and Health data for 2002 to 2009, 1.1% of Georgians have ever used a needle to inject drugs, including cocaine—a moderate rate compared with the frequency in Washington State, where lifetime prevalence is 2.7%, and nationally, where prevalence is 1.6%.13 State-level data on needle use prior to 2002 are not publically available from the Substance Abuse and Mental Health Services Administration.The prevalence of hepatitis C in the Georgia general population is moderately high, especially in Atlanta. At Grady Memorial Hospital, the safety net charity hospital for Atlanta, the prevalence of hepatitis C among ambulatory primary care patients is 7%. A liver clinic established at this hospital saw 807 unique patients in its first 5 years of existence and was still receiving 60 new patient referrals each month through 2010.14 Three quarters of the patients were African American, and most patients were born between 1945 and 1965; 64% were former drug users, and only 4% were currently using.14 High prevalence of hepatitis C in this baby boomer birth cohort probably reflects time-limited parenteral drug use decades ago, perhaps as early as the Vietnam war era.15 Despite relatively low levels of heroin use in the state, we hypothesized that the prevalence of hepatitis C would be high among inmates in the Georgia prison system who were born between 1945 and 1965.We sought to describe the leading causes of death over 2 decades in a large cohort of all Georgians who were in state prisons on June 30, 1991, and to evaluate whether the immediate mortality following prison discharge was low, because Georgia is a state with low heroin use. In light of the moderate background rates of injection drug use in Georgia, we hypothesized that mortality from liver-related causes would rise over time as the cohort aged. Our first aim was to rank the causes of death and categorize which deaths occurred in prison, immediately after release, and subsequently. Second, we compared deaths from liver disease to those from HIV in 4-year intervals between 1991 and 2010.