2 Minute Medicine Rewind December 19, 2022

Association of Direct-Acting Antiviral Therapy With Liver and Nonliver Complications and Long-term Mortality in Patients with Chronic Hepatitis C

1. In this retrospective cohort study, adult patients with hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents had significantly lower mortality and a 27% lower risk of developing hepatocellular carcinoma (HCC) than patients with untreated HCV infection.

2. Patients who received DAA treatment for HCV had a lower risk of developing diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD) than patients with untreated HCV.

Evidence Rating Level: 2 (Good)

Untreated chronic hepatitis C (CHC) commonly progresses to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). In addition to these hepatic complications, CHC may cause extrahepatic manifestations that increase morbidity and mortality. Previous research surrounding interferon-based treatment has revealed that it reduces overall mortality, liver-related complications, and non-liver-related complications. However, interferon-based treatment lacks efficacy and is poorly tolerated, especially in older adults. In recent times, there have been major improvements in hepatitis C virus (HCV) therapies, specifically direct-acting antiviral (DAA) agents. A short course of all-oral DAA treatment can achieve virologic cure in almost all treated patients, but the effects of DAAs on other non-liver comorbidities have not yet been studied. This was a large retrospective cohort study of adults with HCV infection, drawing data from a large deidentified administrative health claims database. Included were patients with HCV infection from January 2010 to March 2021, and baseline characteristics were collected prior to the diagnosis of HCV infection. The primary endpoints were the incidence of liver-related outcomes and mortality, while the secondary endpoints included the incidence of non-liver outcomes. 245,596 patients with HCV infection met the inclusion criteria and were included in the analysis. 40654 (16.6%) patients had received at least 1 prescription for DAA medication, and 204942 (83.4%) had not. With respect to baseline characteristics, DAA-patients were more likely than untreated patients to be male (P<.001) and to have compensated cirrhosis (P<.001) or diabetes (P<.001). Regarding the primary endpoints, the mortality rate per 1000 person-years was twice as high in untreated patients compared with DAA-treated patients (64.7 vs 36.5, P<.001). Furthermore, DAA treatment was associated with a 27% lower risk of developing HCC (adjusted HRs [aHRs], 0.73; 95% CI, 0.68-0.77; P<.001) and a 64% reduction in the risk of developing liver decompensation (aHR, 0.36; 95% CI, 0.35-0.38; P<.001). In addition, DAA treatment was associated with a lower risk of developing diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD). Overall, this large retrospective cohort study found that patients with DAA-treated HCV had significantly lower mortality and incidence of liver and non-liver complications that patients with untreated HCV. A major limitation of this study is the inclusion of patients only covered with private insurance, which may not be generalizable to the overall population. This study adds to the growing body of evidence support DAA use for treatment of Hepatitis C.

Effectiveness of Fecal Microbiota Transplantation for Weight Loss in Patients With Obesity Undergoing Bariatric Surgery

1. In this randomized controlled trial, from baseline to 4 months following fecal microbiota transplant (FMT) or placebo in obese adult patients, there was no statistically significant reduction in weight compared to baseline or between the two groups.

2. Following bariatric surgery, there was a significant reduction in weight in both patients who received FMT and who received placebo. There were no between-group differences with respect to weight reduction.

Evidence Rating Level: 1 (Excellent)

Obesity is a growing global health concern, associated with multiple comorbidities, a decreased quality of life (QoL), and increased mortality. With respect to treatment options, surgery remains the most effective strategy to treat severe obesity; bariatric surgery has been found to reduce mortality and improve quality of life (QoL). In recent times, intestinal microbiota has aroused interest as a potential target for the treatment of obesity; previous research has shown improvements in insulin sensitivity, abdominal adiposity, and lipid metabolism following a fecal microbiota transplant (FMT). In particular, patients with severe obesity have been found to harbour intestinal microbiota with decreased bacterial diversity and microbial gene richness when compared to healthy controls. This randomized controlled trial studied the effect of FMT on the outcomes of bariatric surgery. 41 adult patients with obesity were recruited from hospitals in Finland from January 2018 to March 2021 and randomized in a 1:1 ratio to receive FMT from a healthy lean donor or autologous placebo by gastroscopy. The primary outcomes were reduction in body weight (change in BMI compared with baseline), percentage of total weight loss (TWL), and percentage of excess BMI loss (EBMIL). With respect to baseline characteristics, the FMT group had a significantly higher QoL than the placebo group (P=.02). From the baseline to the end of follow up, there was a 10.4 reduction in mean BMI in the FMT group (95% CI, 9.2 to 12.5; P<.0001), and a 10.15 reduction in the placebo group (95% CI, 7.8-12.5; P<.001). However, the percentage of total weight loss from baseline to the 2- and 4-month time points was not significant in either study group, but the percentage of TWL from baseline to the 6-month time point was significant in both groups: 4.8% (95% CI, 7.0% to 2.7%; P<.001) in the FMT group and 4.6% (95% CI, 7.6% to 1.5%; P=.006) in the placebo group. However, there was no difference observed between the groups at any time point. Regarding secondary outcomes, the participants’ mean fat percentage did not significantly decrease from baseline to 4 months, but significantly decreased from baseline to the end of the follow-up at 12 months after surgery. However, there were no significant differences observed between the groups. In addition, regarding blood biochemistry and quality of life, there were again no differences between the FMT and placebo groups. Overall, following FMT or placebo administration, there were no significant changes in body weight until bariatric surgery, after which there were no significant differences between the two groups. A major limitation of this study is the small sample size, which increases the risk of type II error. Further studies with larger sample sizes and longer follow up would be essential to better understand the effects of FMT.

Association of shift work with incident dementia: a community-based cohort study

1. In this retrospective cohort study, shift workers, defined as working outside of the normal hours of 9 am to 5 pm, were found to have a significantly higher incidence of development of dementia than non-shift workers.

2. Among shift workers, there were no differences in the incidence of dementia development between night shift workers and non-night shift workers.

Evidence Rating Level: 2 (Good)

Dementia is a progressive cognitive disorder that significantly interferes with independent daily activities, typically with a neurodegenerative or cerebrovascular etiology. Dementia is a widespread disorder, with an estimated prevalence of 113 million people worldwide by 2050. Unfortunately, trials that have aimed to treat dementia have been largely ineffective; and without therapeutic agents, understanding of the risk factors that contribute to the development of dementia and prevention is instrumental. In previous research, various genetic and environmental risk factors have been found to be associated with dementia. In today’s society, shift work, where an individual’s working hours are outside the normal working day, is becoming increasingly common. Shift work has been found to be associated with an increased incidence of other diseases and comorbidities, and this retrospective cohort study aimed to study the association between shift work and dementia. Data were extracted from a UK database with over 500,000 community-dwelling participants aged 37-73 when they were recruited between 2006 and 2010. Participants were categorized as non-shift workers or shift workers, depending if their schedule fell outside of 9 am to 5 pm, and shift workers were further stratified into night shift workers or shift but non-night shift workers. The primary outcome studied was all-caused dementia. 170,722 eligible participants were identified; 17,450 (16.1%) reported shift work status and 143,272 (83.9%) were not shift workers. There were 716 cases of dementia during a median follow-up period of 12.4 years; 134 (18.7%) in shift workers and 582 (81.3%) in non-shift workers. Shift workers had a higher incidence of all-cause dementia than non-shift workers (unadjusted-HR, 1.21; 95% CI, 1.00 to 1.46, P=.04), and this statistical significance persisted after multivariable adjustment (adjusted-HR, 1.30; 95% CI, 1.08 to 1.58; P=0.006). Among shift workers, there was no significant association with night shift work and development of dementia after multivariable adjustment (P=.83). In addition, the impact of shift work on the incidence of dementia did not differ among participants who were more genetically predisposed to develop dementia. Overall, this large retrospective cohort study showed that shift workers had an increased risk of all-cause dementia when compared to non-shift workers. This study was limited by a biased sample, as those volunteering for the health database may generally be in better health. In addition, dementia may have been misdiagnosed or underdiagnosed, as the study relied on electronic health records to identify dementia. Given the increasing prevalence of dementia, this study is an excellent step toward understanding risk factors, and further health policy developments will be needed to identify strategies to effectively mitigate these factors.

Neutrophil CD64 index for diagnosis of infectious disease in the pediatric ICU: a single-center prospective study

1. In this prospective observational study, infected pediatric intensive care unit (ICU) patients had a significantly higher neutrophil CD 64 (nCD64), C-reactive protein (CRP), and procalcitonin (PCT) than patients without an infection.

2. The nCD64 index was found to have a greater diagnostic value than both CRP and PCT in this study, and the median nCD64 index was found to have a sensitivity of 68.8% and specificity of 90.7% for the presence of infection.

Evidence Rating Level: 2 (Good)

Sepsis is a major cause of death in pediatrics, and while blood cultures are a gold standard to determine bloodstream infection etiology, results may take 2 to 3 days or more, and there are multiple confounding factors including contamination, previous antibiotic use, and sampling time. Thus, blood cultures for detection of pathogens have limited clinical utility. To differentiate between systemic inflammatory response syndrome (SIRS) and an infection as soon as possible, current biomarkers including procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (IL-6) may be used. However, these biomarkers may also be increased in patients with non-infectious inflammatory responses and conditions. Neutrophil CD64 (nCD64) is a high affinity receptor mainly expressed on the plasma membranes of antigen-presenting cells, and expression of CD64 is increased significantly after activation by pro-inflammatory markers. It is thought that nCD64 may be a sensitive biomarker to distinguish between patients with and without infection. This prospective observational study aimed to evaluate the use of nCD64 index for identification of children in the pediatric ICU (PICU) with and without infection. 201 children were included in the study, admitted in a 3 month study period from April to June 2021. Patients with an infection were classified as having pneumonia, skin and soft-tissue infection, bloodstream infection, digestive stream infection, or central nervous infection. nCD64 was collected from these patients and analyzed with flow cytometry. 201 pediatric patients were included in the study, with 93 (46.3%) children found to have an infection and 108 (53.7%) children that were classified as not infected. With respect to baseline characteristics, the median age was 49 months old, the median length of hospital stay was 15 days, and the median length of PICU stay was 2 days. The infected group was younger, had longer hospital and ICU stays, and were more likely to receive ventilator therapy than the non-infected group (P<.05). Regarding the biomarkers, compared to the noninfected group, the infected group had a significantly greater median nCD64 index (0.18 vs. 0.09, P<.001), median CRP level (5 vs. 0.5 mg/L, P<.001), and median PCT level (0.19 vs. 0.08 ng/mL, P<.001). The median nCD64 index was found to have a sensitivity of 68.8% and specificity of 90.7%, having a greater diagnostic value than both CRP and PCT. In addition, nCD64 was found to be slightly more sensitive and specific than CRP for the identification of infection in postoperative pediatric fevers. Overall, the findings from this study suggest that the nCD64 index was an effective biomarker for infections and had a better diagnostic performance than PCT and CRP for the diagnosis of infection at PICU admission. A major limitation of this study is the small sample size and nature of the study – further high-quality studies would be essential to better understand nCD64 index as a potential infective biomarker. Further research with a larger sample size would be useful to use nCD64 as a potential biomarker to differentiate between viral and bacterial infections, especially given the prevalence of serious viral infections in the pediatric population.

Variations in the use of cemented implants for hip fracture repair in Nova Scotia, Canada

1. In this retrospective observational study, there were significant between-hospital and within-hospital variations of cemented implant use in Nova Scotia in patients who suffered a femoral neck fracture and who underwent hip arthroplasty.

Evidence Rating Level: 2 (Good)

Femoral neck fractures are a high priority area for policymakers in Canada due to high prevalence and high mortality rates. Arthroplasty is a common method of treatment, but there is a lack of consensus for the use of cemented versus uncemented implants. A large body of evidence indicates better outcomes with the use of cement, yet there still exist wide variations in the use of cement. Previous studies have concluded that surgical cultures have developed within each culture, explaining the differences in rates. However, this conclusion assumes that there is homogeneity within countries in cement use. This retrospective study aims to measure the variation in the use of cemented implants for the treatment of fractures across Nova Scotia hospitals. Included in this study were patients who underwent primary arthroplasty for femoral neck fracture in Nova Scotia between 2010 and 2020. Rates of cemented implants were computed for each surgeon in each of the five study hospitals. Three measures of variation were calculated for each facility; the extremal quotient (EQ) is the ratio of the highest to the lowest rate. The population-weighted coefficient of variation (WCV) is the standard deviation divided by the mean, and the systematic component of variation (SCV) nets out the random component, meaning the SCV isolates within-surgeon variation. In total, 3787 hip arthroplasties were included in the study, with 2219 (58.6%) having a cemented implant. There was a wide range of cemented implants at the five hospitals included, from 36.6% to 71.1%. At one of the hospitals, surgeons were more than twice as likely to use cement when compared to surgeons at the hospital with the lowest rate of cemented implants. Over time, the rates of cemented implant use increased overall, from 45.7% in 2010/2011 to 70.2% in 2019/2020. With respect to variation, hospital 4 had the largest EQ, where the surgeon with the highest rate of cementing ((98.1%) was 30 times that of the surgeon with the lowest rate (3.2%). The smallest EQ was observed in hospital 5, which was 3.4. Using the SCV, four hospitals were categorized as having “very high” in-between surgeon variation. Overall, the findings from this study suggest that there is a significant between-hospital and between-surgeon variation in cemented implant use. A major limitation of this study is the population, as it is limited to surgeons in Nova Scotia. In addition, unfortunately, age and training were not available for analysis in this study due to confidentiality. This study is an important step for understanding that the division extends down to individual surgeons, rather than being a result of an entire country’s surgical culture. This knowledge, as well as further research to understand the reasoning behind choosing cemented versus uncemented implants, will allow policymakers to effectively encourage the use of cemented implants in the future.

Image: PD

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