2 Minute Medicine Rewind September 16, 2024

Sleep patterns, physical activity, genetic susceptibility, and incident rheumatoid arthritis: a prospective cohort study 

1. In this prospective cohort study, a healthy sleep pattern and moderate levels of physical activity (PA) were significantly associated with a decreased risk of developing rheumatoid arthritis (RA) counteracting unfavourable genetics.   

2. Healthy sleep patterns and risk of RA had a dose-response relationship whereas physical activity and RA risk had a non-linear relationship.  

Evidence Rating Level: 1 (Excellent) 

Rheumatoid arthritis (RA) is an inflammatory condition affecting joints and limiting mobility. RA has been on the rise globally partially due to the aging population and increasing obesity rates. Identifying modifiable risk factors such as sleep disturbances and lack of physical activity (PA), both associated with inflammation, could help reduce the RA global burden but little research has been done on their interactions. Due to the gap in knowledge, this prospective cohort study evaluated the association between sleep patterns, physical activity, and genetic risk of RA independently and combined interactions.  Using participants from the UK Biobank cohort study, 363,211 participants were enrolled after excluding for RA diagnosis or missing values for sleep, PA, and genetic risk score (GRS). Sleep disturbances included sleep duration, chronotype, insomnia, snoring, and daytime sleepiness, which were assessed using a questionnaire. Data for PA was also collected from a questionnaire and included the frequency and duration of walking, moderate-intensity, and vigorous activity. To determine the associated effects of PA, sleep, and genetics on RA, a multivariate-adjusted Cox proportional hazard model was used. Amongst the participants, 4262 RA cases were documented during the median follow-up time of 12.5 years (interquartile range [IQR]: 11.7-13.2 years; 4,367,592 total person years). Healthy sleep was associated in a dose-response manner with a decreased risk of developing RA (HR, 0.72 [95% CI = 0.68-0.76]). Participants with a moderate PA level was associated with a decreased risk of RA in individuals with poor and intermediate sleep patterns. The group with an intermediate sleep pattern with low or high PA had a relative excess risk due to interaction (RERI) of 0.45 (95% CI=0.02-0.87). The standardized risk reduction was the greatest among the high GRS group (10.58 [95% CI = 4.05-16.69] per 1000 person-years) suggesting they had the most to gain from adopting a healthy sleep pattern and moderate levels of PA. This prospective cohort study shows that a decreased RA risk was associated with healthy sleep patterns and a medium level of PA. 

Iloprost and organ dysfunction in adults with septic shock and endotheliopathy

1. In a randomized clinical trial of adults with septic shock and endotheliopathy in the intensive care unit (ICU), administering iloprost did not reduce the mean daily Sequential Organ Failure Assessment (SOFA) score compared to administering placebo. 

Evidence Rating Level: 1 (Excellent) 

Septic shock leads to high rates of organ failure and death and requires emergent intervention. Endotheliopathy, dysfunction of the endothelium may play a role in the development of septic shock. This study was conducted to understand the effects of intravenous iloprost infusion on organ dysfunction in adults undergoing septic shock in the intensive care unit (ICU). Eligible participants were 18 years of age or older, admitted to the ICU, and had septic shock and severe endotheliopathy. These individuals were randomized in a 1:1 ratio to receive either intravenous Iloprost or placebo (sodium chloride) in equal volumes. The sequential organ failure assessment (SOFA) score was used as the primary outcome since it assessed respiration, coagulation, assessing liver, cardiovascular, and kidney functions. Several items were used as secondary measures including 28- and 90-day mortality, and number of days alive without mechanical ventilation in the ICU at 90 days. Of the 760 patients screened, 278 were included and randomized (median [IQR] age, 69 [58-77] years; 107 [38%] female and 171 [62%] male). The Iloprost group had 142 participants while the placebo group had 136. At the interim analysis, futility had been met so the trial was stopped. The outcome of interest, the mean (IQR) SOFA score, was 10.6 (6.4-14.8) in the Iloprost group and 10.5 (5.9-15.5) in the placebo group (adjusted mean difference, 0.2 [95% CI, -0.8 to 1.2]; P=.70). at 28 days 70 patients (49%) in the iloprost group and 60 patients (44%) in the placebo group had died (adjusted relative risk, 1.13 [95% CI, 0.88-1.46]; P=.34). While at 90 days, 81 patients (57%) in the Iloprost group and 70 patients (51%) in the placebo group had died (adjusted relative risk, 1.12 [95% CI, 0.91-1.40]; P=.33). Adverse events occurred in 18% (26) of the iloprost group and 15% (20 patients) in the placebo group within the first week (adjusted relative risk, 1.25 [95% CI, 0.73-2.17]; P=.52). Overall, administering iloprost compared to placebo did not reduce the mean daily SOFA score in adults undergoing septic shock in the ICU. Generalizability of the results was difficult since only Denmark ICUs were involved. 

Homelessness and risk of end-stage kidney disease and death in veterans with chronic kidney disease 

1. In a cohort of veterans with incident chronic kidney disease (CKD), homelessness was significantly associated with increased risk of end-stage kidney disease (ESKD) and death after adjusting for incident, age, sex, race, and ethnicity. 

Evidence Rating Level: 2 (Good) 

Over 600,000 people were experiencing homelessness on any given day in the United States during 2023. People experiencing homelessness can develop a multitude of health issues ranging from increased risk of infection to death. One health issue that may be developed, chronic kidney disease (CKD) requires intensive management and would likely have worse consequences in people experiencing homelessness. Previous research focusing on end-stage kidney disease (ESKD) in veterans experiencing homelessness is lacking. To address this research gap, this retrospective cohort study evaluated if there was an association between risk of ESKD and death and experiencing homelessness in a populations of veterans with CKD. Participants included veterans in the Veterans Health Administration, with incident CKD between stages 3 to 5 at baseline. The primary outcomes were new cases of ESKD, which was defined as the initiation of kidney replacement therapy, and death, including all deaths whether caused by ESKD or not, evaluated separately.  The participants included 836,361 veterans with incident CKD, of which 46,561 (5.6%) had experienced homelessness, 26,037 (3.1%) developed ESKD, and 359,991 (43.0%) had died. After adjusting for year of incident, age, sex, race, and ethnicity, there was a significant association between experiencing homelessness and an increase in ESKD risk (HR, 1.15; 95% CI, 1.10-1.20). After adjusting for age, homelessness was also associated with death (HR, 1.48; 95% CI, 1.46-1.50). In further secondary analysis, adjusting for possible confounders such as body mass index (BMI), or smoking status, there was no significant association between homelessness status and ESKD risk (HR, 1.09; 95% CI, 1.07-1.11). In this cohort study of veterans with incident CKD, there was a significant association between experiencing homelessness and an increased risk of ESKD and death.  

Replacement of sedentary behavior with various physical activities and the risk of all-cause and cause-specific mortality

1. In two cohorts from the UK Biobank and the National Health and Nutrition Examination Survey (NHANES), there was an increased risk of death from respiratory disease, cardiovascular disease, cancer, and an increased risk for all-cause mortality associated with sedentary behaviour (SB).  

2. Substituting SB with physical activity was associated with a decreased risk of mortality. 

Evidence Rating Level: 1 (Excellent) 

In modern society, people exhibit more sedentary behaviour (SB), which has profound impacts on people’s health. Previous meta-analyses have shown increased SB increasing all around mortality, while increasing physical activity (PA) levels was seen with a corresponding decrease. This study, using data from UK Biobank and the US based National Health and Nutrition Examination Survey (NHANES) examined the connection between SB and cause-specific and all-cause mortality, while also using the isotemporal model (ISM) to discover which types of PA were best suited to replace SB. A total of 490,659 individuals were included for the Biobank cohort while 33,534 individuals were included for the NHANES cohort. SB was defined as time on a computer, driving, or watching TV and grouped into < 5 hours a day, 5-8 hours a day and > 8 hours a day. PA was self-defined, categorized by sports, exercise, light/heavy DIY and walking, while for NHANES it was recreational/work activities, further divided into moderate/vigorous, and walking/cycling for transportation. The Biobank and NHANES data pool saw 36,109 and 3057 deaths recorded respectively. A substantial increase for all-cause mortality was seen in individuals with SB > 8 hours a day (HR 1.412, 95% CI 1.100–1.186 for the UK Biobank; HR 1.695, 95% CI 1.525–1.883 for the NHANES) compared to those with < 5. The greatest 3 specific causes of mortality risk seen were respiratory disease (HR 1.347, 95% CI 1.149–1.579 for the UK Biobank; HR 2.355, 95% CI 1.517–3.468 for the NHANES), cardiovascular disease (CVD) (HR 1.347, 95% CI 1.149–1.579 for the UK Biobank; HR 2.355, 95% CI 1.517–3.468 for the NHANES), and cancer (HR 1.106, 95% CI 1.047–1.167 for the UK Biobank). With regards to ISM, a replacement of 30 minutes of SB with PA saw a decrease of mortality of 5.1% in Biobank (HR 0.949, 95% CI 0.943–0.955) and 5.5% in NHANES (HR 0.945, 95% CI 0.933–0.957). Increasing PA intensity saw even greater reductions in all-cause and specific mortalities. Overall, SB was associated with increased risk of all-cause mortality and mortality due to respiratory disease, CVD, and cancer. 

Naldemedine for opioid-induced constipation in patients with cancer: a multicenter, double-blind, randomized, placebo-controlled trial

1. In a randomized double-blind placebo-controlled study, naldemedine use was associated with constipation prevention and a significant improvement of constipation-related quality of life (QOL) in cancer patients initiating opioid pain therapy.  

Evidence Rating Level: 1 (Excellent) 

Along with cancer treatment comes pain which has often been treated with opioids. However, these opioids have some adverse effects such as constipation which can diminish one’s quality of life (QOL). The most commonly seen adverse effect is opioid induced constipation (OIC), sometimes so bad it may limit adherence. Due to this lack of prior research, this study employed a double-blind randomized controlled trial to determine the effects of preventative naldemedine versus placebo for OIC in cancer patients. The main research outcome was the amount of patients with a Bowel Function Index (BFI) of less than 28.8 on day 14 of the trial. Other outcomes of interest included frequency of opioid-induced nausea and vomiting (OINV), the number of patients who had three or more spontaneous bowel moments (SBM) per week and complete SBM (CSBM) per week. To be included in the trial, patients had to be 20 years or older with cancer beginning opioid therapy. The patients that met the criteria were randomly assigned to either receive naldemedine (Symproic 0.2 mg) or placebo in a 1:1 basis. They received their first dose of either placebo or naldemedine at the same time as their first dose of opioids. A total of 99 patients were enrolled, with 49 receiving naldemedine and 50 receiving placebo. On day 14 of the trial, 31 patients (64.6%; 95% CI, 51.1 to 78.1) in the naldemedine group and 8 patients (17.0%; 95% CI, 6.3 to 27.8) in the placebo group had a BFI of <28.8. Thus, the difference seen between the groups was 47.6% (95% CI, 30.3 to 64.8; P<.0001). On day 7, halfway through the trial, there were more patients in the naldemedine group compared to the placebo group that had a BFI of <28.8, had three or more SBM per week and CSBM per day. There was less use of antiemetic drugs in the naldemedine group compared to the placebo group. The patients in the naldemedine reported higher overall QOL at day 7 and 14 compared to patients in the placebo group. The results of this study show that prophylactic naldemedine was an effective way to prevent constipation and improve QOL in cancer patients receiving opioid for pain management.

Image: PD

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