Extent and causes of unused medications among patients in rural Ethiopia: a prospective multicenter cohort study.

BACKGROUND: Medication waste poses health, economic, and environmental challenges. However, the extent among patients living in rural areas is underexplored. This study assessed the proportion of prescribed medications remaining unused by patients living in rural areas of Ethiopia, and identify the causes thereof and disposal practices. METHODS: A prospective multicenter cohort study was conducted in 5 rural health centers in Ethiopia. Patients (≥ 18 years), who received a prescription for acute or chronic medication for pick up from the outpatient pharmacy were included. After 3 months, participants received a house visit by a health employee during which a questionnaire was verbally administered to assess the quantity of unused medication, reason thereof, and disposal practices used. Data were analyzed using descriptive statistics and multivariate logistic regression to identify factors associated with presence of unused medications. RESULTS: In total, 178 patients participated. Up to 136 out of 601 (22.6%) dispensed medications ended up unused, mainly antibiotics and analgesics, with an average economic value of $0.37. Of 178 patients, 72 (40.4%) ended up with unused medication, and 15 (8.4%) did not use 80% or more of the prescribed quantity. Early discontinuation of therapy was the main reason (61.8%) for patients' ending with unused medication. Patients reported to primarily dispose of unused medication either through the toilet (43.6%), household garbage (22.7%), burning (13.6%), or returning it to the pharmacy (2.7%). Medications dispensed to be administered with two or more-unit doses at a time were more likely to remain unused (adjusted OR 1.6 [1.0-3.4]) compared to medications dispensed to be administered one-unit dose. CONCLUSION: A substantial amount of prescribed medications remains unused by patients in rural areas, frequently not properly disposed. Interventions are needed to ensure medications are not wasted and reduce the unwanted consequences.

A model of dysregulated crosstalk between dendritic, natural killer, and regulatory T cells in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterized by infiltration of the airways and lung parenchyma by inflammatory cells. Lung pathology results from the cumulative effect of complex and aberrant interactions between multiple cell types. However, three cell types, natural killer cells (NK), dendritic cells (DCs), and regulatory T cells (Tregs), are understudied and underappreciated. We propose that their mutual interactions significantly contribute to the development of COPD. Here, we highlight recent advances in NK, DC, and Treg biology with relevance to COPD, discuss their pairwise bidirectional interactions, and identify knowledge gaps that must be bridged to develop novel therapies. Understanding their interactions will be crucial for therapeutic use of autologous Treg, an approach proving effective in other diseases with immune components.

Healthcare resource utilisation and economic burden attributable to back pain in primary care: A matched case-control study in the United Kingdom.

Objective: Incremental healthcare costs attributed to back pain, and characterisation by patient and clinical factors have rarely been documented. This study aimed to assess annual healthcare resource utilisation and costs associated with back pain in primary care. Methods: Using the IQVIA Medical Research Data (IMRD), patients with back pain were identified (study period: 01 January 2006 to 31 December 2015) using diagnostic records and analgesics prescriptions (n = 133,341), and propensity score matched 1:1 to patients without back pain. The annual incremental costs of back pain associated with consultations and prescriptions were estimated and extrapolated to a national level. Sensitivity analysis was conducted by restricting the study population to the most recent diagnosis of back pain. Variations in cost were assessed stratified by gender, age-groups, deprivation, and comorbidity categories. Results: The mean age was 57 years, and 62% were females in both the case and control groups. The total incremental healthcare costs associated with back pain was £32.5 million in 2015 (£35.9 million in 2020), with per-patient cost of £244 (£265 in 2020) per year. On a national level, this translated to an estimated £3.2 billion (£3.5 billion in 2020). Eighty percent of the costs were attributed to consultations; and female gender, older age, higher deprivation, and higher comorbidity were all associated with increased mean healthcare costs of patients with back pain. Conclusion: Our findings confirm the substantial healthcare costs attributed to back pain, even with primacy care costs only. The data also revealed significant cost variations across socio-demographic and clinical factors.

The cost of primary care consultations associated with long COVID in non-hospitalised adults: a retrospective cohort study using UK primary care data.

BACKGROUND: The economic impact of managing long COVID in primary care is unknown. We estimated the costs of primary care consultations associated with long COVID and explored the relationship between risk factors and costs. METHODS: Data were obtained on non-hospitalised adults from the Clinical Practice Research Datalink Aurum primary care database. We used propensity score matching with an incremental cost method to estimate additional primary care consultation costs associated with long COVID (12 weeks after COVID-19) at an individual and UK national level. We applied multivariable regression models to estimate the association between risk factors and consultations costs beyond 12 weeks from acute COVID-19. RESULTS: Based on an analysis of 472,173 patients with COVID-19 and 472,173 unexposed individuals, the annual incremental cost of primary care consultations associated with long COVID was £2.44 per patient and £23,382,452 at the national level. Among patients with COVID-19, a long COVID diagnosis and reporting of longer-term symptoms were associated with a 43% and 44% increase in primary care consultation costs respectively, compared to patients without long COVID symptoms. Older age, female sex, obesity, being from a white ethnic group, comorbidities and prior consultation frequency were all associated with increased primary care consultation costs. CONCLUSIONS: The costs of primary care consultations associated with long COVID in non-hospitalised adults are substantial. Costs are significantly higher among those diagnosed with long COVID, those with long COVID symptoms, older adults, females, and those with obesity and comorbidities.

Predictors of the likelihood that patients with rheumatoid arthritis will communicate information about rheumatoid arthritis risk to relatives: A quantitative assessment.

First-degree relatives (FDRs) of people with rheumatoid arthritis (RA) are increasingly recruited to prediction and prevention studies. Access to FDRs is usually via their proband with RA. Quantitative data on predictors of family risk communication are lacking. RA patients completed a questionnaire assessing likelihood of communicating RA risk information to their FDRs, demographic variables, disease impact, illness perceptions, autonomy preferences, interest in FDRs taking a predictive test for RA, dispositional openness, family functioning, and attitudes towards predictive testing. Ordinal regression examined associations between patients' characteristics and their median likelihood of communicating RA risk to FDRs. Questionnaires were completed by 482 patients. The majority (75.1%) were likely/extremely likely to communicate RA risk information to FDRs, especially their children. Decision-making preferences, interest in FDRs taking a predictive test, and beliefs that risk knowledge would increase people's empowerment over their health increased patients' odds of being likely to communicate RA risk information to FDRs. Beliefs that risk information would cause stress to their relatives decreased odds that patients would be likely to communicate RA risk. These findings will inform the development of resources to support family communication about RA risk.

A matched cohort study investigating premature, accentuated, and accelerated aging in people living with HIV.

INTRODUCTION: The impact of HIV infection on the aging process is disputed and largely unknown. We aimed to identify whether people living with HIV experience premature, accelerated, and/or accentuated aging by investigating the development of four age-related non-communicable diseases in people living with versus without HIV. METHODS: This population-based matched cohort study design used UK-based primary care electronic health records from the IQVIA Medical Research Database. Between January 2000 and January 2020, all people living with and without HIV aged ≥18 years were eligible. Outcomes included cardiovascular disease (CVD), hypertension, type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD), which were identified by Read codes. We used age at diagnosis to investigate premature aging and age at exit date to investigate accentuation and acceleration. For each outcome, people with and without HIV were excluded if they had the outcome of interest at baseline. Participants were matched based on propensity scores (1:1 ratio). Linear regression was used to report any difference in age at diagnosis between the two groups and to report the prevalence trends for age at exit date. RESULTS: In total, 8880 people living with HIV were matched with 8880 people without HIV and were found to have an earlier onset of CVD (54.5 vs. 56.8; p = 0.002). Similarly, people living with HIV had an earlier onset of hypertension (49.7 vs. 51.4; p = 0.002). No difference was found for T2DM or CKD (53.4 vs. 52.6; p = 0.368 and 57.6 vs. 58.1; p = 0.483, respectively). The burden of CKD increased over time, whereas no difference in the burden was found for the other conditions. CONCLUSION: The earlier development of CVD and hypertension in people living with HIV than in those without HIV indicates premature aging, whereas the increased burden of CKD indicates accelerated aging.

Early onset of immune-mediated diseases in minority ethnic groups in the UK.

BACKGROUND: The prevalence of some immune-mediated diseases (IMDs) shows distinct differences between populations of different ethnicities. The aim of this study was to determine if the age at diagnosis of common IMDs also differed between different ethnic groups in the UK, suggestive of distinct influences of ethnicity on disease pathogenesis. METHODS: This was a population-based retrospective primary care study. Linear regression provided unadjusted and adjusted estimates of age at diagnosis for common IMDs within the following ethnic groups: White, South Asian, African-Caribbean and Mixed-race/Other. Potential disease risk confounders in the association between ethnicity and diagnosis age including sex, smoking, body mass index and social deprivation (Townsend quintiles) were adjusted for. The analysis was replicated using data from UK Biobank (UKB). RESULTS: After adjusting for risk confounders, we observed that individuals from South Asian, African-Caribbean and Mixed-race/Other ethnicities were diagnosed with IMDs at a significantly younger age than their White counterparts for almost all IMDs. The difference in the diagnosis age (ranging from 2 to 30 years earlier) varied for each disease and by ethnicity. For example, rheumatoid arthritis was diagnosed at age 49, 48 and 47 years in individuals of African-Caribbean, South Asian and Mixed-race/Other ethnicities respectively, compared to 56 years in White ethnicities. The earlier diagnosis of most IMDs observed was validated in UKB although with a smaller effect size. CONCLUSION: Individuals from non-White ethnic groups in the UK had an earlier age at diagnosis for several IMDs than White adults.

Comorbidity phenotypes and risk of mortality in patients with osteoarthritis in the UK: a latent class analysis.

BACKGROUND: Osteoarthritis (OA) is a common chronic condition but its association with other chronic conditions and mortality is largely unknown. This study aimed to use latent class analysis (LCA) of 30 comorbidities in patients with OA and matched controls without OA to identify clusters of comorbidities and examine the associations between the clusters, opioid use, and mortality. METHODS: A matched cohort analysis of patients derived from the IQVIA Medical Research Data (IMRD-UK) database between 2000 and 2019. 418,329 patients with newly diagnosed OA were matched to 243,170 patients without OA to identify comorbidity phenotypes. Further analysis investigated the effect of opioid use on mortality in individuals with OA and their matched controls. RESULTS: The median (interquartile range (IQR)) number of comorbidities was 2 (1-4) and 1 (0-3) in the OA and control groups respectively. LCA identified six comorbidity phenotypes in individuals with and without OA. Clusters with a high prevalence of comorbidities were characterised by hypertension, circulatory, and metabolic diseases. We identified a comorbidity cluster with the aforementioned comorbidities plus a high prevalence of chronic kidney disease, which was associated with twice the hazard of mortality in hand OA with a hazard ratio (HR) (95% CI) of 2.53 (2.05-3.13) compared to the hazard observed in hip/knee OA subtype 1.33 (1.24-1.42). The impact of opioid use in the first 12 months on hazards of mortality was significantly greater for weak opioids and strong opioids across all groups HR (95% CI) ranging from 1.11 (1.07-11.6) to 1.80 (1.69-1.92)). There was however no evidence of association between NSAID use and altered risk of mortality. CONCLUSION: This study identified six comorbidity clusters in individuals with OA and matched controls within this cohort. Opioid use and comorbidity clusters were differentially associated with the risk of mortality. The analyses may help shape the development of future interventions or health services that take into account the impact of these comorbidity clusters.

Spinal anesthesia in infants undergoing urologic surgery duration greater than 60 minutes.

INTRODUCTION: Spinal anesthesia (SA) has been safely utilized in infants. There are limited data regarding the safety and efficacy of SA in pediatric urologic surgery lasting ≥60 min. We outlined the perioperative course for infants undergoing single-injection 0.5% plain bupivacaine SA-only for urologic procedures lasting ≥60 min. OBJECTIVE: To characterize the safety and efficacy of SA for urologic surgery in infants lasting ≥60 min. METHODS: We reviewed our prospectively maintained database of infants undergoing SA for urologic procedures lasting ≥60 min from May 2018 to March 2021. Patients received preoperative intranasal dexmedetomidine, some received intranasal fentanyl, and all patients received lidocaine cream applied preoperatively over the lumbar spine. Oral sucrose on a pacifier was provided as needed, and the patient's arms were swaddled for the procedure. Success was defined as no conversion to general anesthesia. Time points for start/end of spinal injection, procedure duration, wheels in/out of operating room (OR), and discharge were collected. RESULTS: Of 245 cases conducted with SA during the study period, 76 (31%) infants underwent surgery lasting ≥60 min. Of these, 73 (96%) were successfully completed with SA alone. In the 3 cases converted to general anesthesia, 2 (67%) required mask anesthesia after 96 and 169 min (for the last <10 min of surgery), and one was converted to intubation before start of surgery. Median patient age was 6 (IQR 5-7) months, and median procedure length was 95 (IQR 75-120) minutes. Following initial preoperative intranasal dexmedetomidine ± fentanyl, at least one additional dose of IV sedative was given in 27 (36%) cases at a median time of 90 (IQR 60-120) minutes into surgery. Following closure, patients exited the OR after a median 10 (IQR 8-12) minutes and subsequently discharged after spending a median of 73 (IQR 61-96) minutes in recovery. DISCUSSION: We describe pediatric urologic surgical cases lasting ≥60 min that employed single-injection intrathecal bupivacaine alone without adjunct intrathecal agents. In this report, SA was safely utilized in infants undergoing urologic procedures lasting at least 60 min, with about 40% of patients receiving additional IV dexmedetomidine and fentanyl. Non-medication measures (swaddling, oral sucrose) were important for maximizing patient comfort. Communication between surgeon and anesthesia as cases progress is key to maintaining adequate anesthesia. CONCLUSION: A single-injection bupivacaine-only spinal anesthesia approach for urologic surgery lasting over an hour and up to 3 h is safe and effective in infants. Selecting appropriate candidates for SA should be a joint decision between the surgeon and the anesthesiologist.

The association between inflammatory bowel disease and mental ill health: a retrospective cohort study using data from UK primary care.

BACKGROUND: Patients with active inflammatory bowel disease (IBD) and mental illnesses experience worse IBD outcomes. AIM: To describe the incidence of mental illnesses, including deliberate self-harm, in IBD patients. METHODS: A population-based retrospective cohort study using IQVIA medical research data of a primary care database covering the whole UK, between January 1995 and January 2021. IBD patients of all ages were matched 4:1 by demographics and primary care practice to unexposed controls. Following exclusion of patients with mental ill health at study entry, adjusted hazard ratios (HR) of developing depression, anxiety, deliberate self-harm, severe mental illness and insomnia were calculated using a Cox proportional hazards model. RESULTS: We included 48,799 incident IBD patients: 28,352 with ulcerative colitis and 20,447 with Crohn's disease. Incidence rate ratios of mental illness were higher in IBD patients than controls (all p < 0.001): deliberate self-harm 1.31 (95% CI 1.16-1.47), anxiety 1.17 (1.11-1.24), depression 1.36 (1.31-1.42) and insomnia 1.62 (1.54-1.69). Patients with Crohn's disease were more likely to develop deliberate self-harm HR 1.51 (95% CI 1.28-1.78), anxiety 1.38 (1.16-1.65), depression 1.36 (1.26-1.47) and insomnia 1.74 (1.62-1.86). Patients with IBD are at increased risk of deliberate self-harm (HR 1.20 [1.07-1.35]). The incidence rate ratios of mental illnesses were particularly high during the first year following IBD diagnosis: anxiety 1.28 (1.13-1.46), depression 1.62 (1.48-1.77) and insomnia 1.99 (1.78-2.21). CONCLUSION: Deliberate self-harm, depression, anxiety and insomnia were more frequent among patients with IBD. IBD is independently associated with an increased risk of deliberate self-harm.

Angiotensin-converting enzyme inhibitors and risk of age-related macular degeneration in individuals with hypertension.

AIMS: Several observational studies have examined the potential protective effect of angiotensin-converting enzyme inhibitor (ACE-I) use on the risk of age-related macular degeneration (AMD) and have reported contradictory results owing to confounding and time-related biases. We aimed to assess the risk of AMD in a base cohort of patients aged 40 years and above with hypertension among new users of ACE-I compared to an active comparator cohort of new users of calcium channel blockers (CCB) using data obtained from IQVIA Medical Research Data, a primary care database in the UK. METHODS: In this study, 53 832 and 43 106 new users of ACE-I and CCB were included between 1995 and 2019, respectively. In an on-treatment analysis, patients were followed up from the time of index drug initiation to the date of AMD diagnosis, loss to follow-up, discontinuation or switch to the comparator drug. A comprehensive range of covariates were used to estimate propensity scores to weight and match new users of ACE-I and CCB. Standardized mortality ratio weighted Cox proportional hazards model was used to estimate hazard ratios of developing AMD. RESULTS: During a median follow-up of 2 years (interquartile range 1-5 years), the incidence rate of AMD was 2.4 (95% confidence interval 2.2-2.6) and 2.2 (2.0-2.4) per 1000 person-years among the weighted new users of ACE-I and CCB, respectively. There was no association of ACE-I use on the risk of AMD compared to CCB use in either the propensity score weighted or matched, on-treatment analysis (adjusted hazard ratio: 1.07 [95% confidence interval 0.90-1.27] and 0.87 [0.71-1.07], respectively). CONCLUSION: We found no evidence that the use of ACE-I is associated with risk of AMD in patients with hypertension.

Therapies for Long COVID in non-hospitalised individuals: from symptoms, patient-reported outcomes and immunology to targeted therapies (The TLC Study).

INTRODUCTION: Individuals with COVID-19 frequently experience symptoms and impaired quality of life beyond 4-12 weeks, commonly referred to as Long COVID. Whether Long COVID is one or several distinct syndromes is unknown. Establishing the evidence base for appropriate therapies is needed. We aim to evaluate the symptom burden and underlying pathophysiology of Long COVID syndromes in non-hospitalised individuals and evaluate potential therapies. METHODS AND ANALYSIS: A cohort of 4000 non-hospitalised individuals with a past COVID-19 diagnosis and 1000 matched controls will be selected from anonymised primary care records from the Clinical Practice Research Datalink, and invited by their general practitioners to participate on a digital platform (Atom5). Individuals will report symptoms, quality of life, work capability and patient-reported outcome measures. Data will be collected monthly for 1 year.Statistical clustering methods will be used to identify distinct Long COVID-19 symptom clusters. Individuals from the four most prevalent clusters and two control groups will be invited to participate in the BioWear substudy which will further phenotype Long COVID symptom clusters by measurement of immunological parameters and actigraphy.We will review existing evidence on interventions for postviral syndromes and Long COVID to map and prioritise interventions for each newly characterised Long COVID syndrome. Recommendations will be made using the cumulative evidence in an expert consensus workshop. A virtual supportive intervention will be coproduced with patients and health service providers for future evaluation.Individuals with lived experience of Long COVID will be involved throughout this programme through a patient and public involvement group. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Solihull Research Ethics Committee, West Midlands (21/WM/0203). Research findings will be presented at international conferences, in peer-reviewed journals, to Long COVID patient support groups and to policymakers. TRIAL REGISTRATION NUMBER: 1567490.

Genetic diversity, population structure and relationship of Ethiopian barley (Hordeum vulgare L.) landraces as revealed by SSR markers.

Evaluation and characterization of genetic resources maintained at both in situ and ex situ GenBanks have important implications for future utilization in association mapping studies, genetic selection, breeding and conservation activities. The main objective of this study was to evaluate the genetic diversity, population structure and relationship of 384 Ethiopian barley genotypes collected from different barley growing regions of Ethiopia using 49 simple sequence repeat (SSR) markers. Analysis of these 49 SSR markers amplified a total of 478 alleles with an average of 9.755 alleles per locus were obtained of which 97.07% of the loci were observed to be polymorphic. Nei's genetic diversity index (h) was 0.654 and the Shannon diversity index (I) was 0.647, indicating that the genetic diversity in barley genotypes studied was moderately high. At the population level, mean per cent of polymorphic loci (PPL) showed 98.37%, h = 0.388 and I = 0.568. Highest level of genetic diversity was observed in the Arsi population (with PPL = 100%, h = 0.439, I = 0.624); the lowest value observed was in population from Jimma (with PPL = 75.51%, h = 0.291, I = 0.430). Analysis of molecular variance (AMOVA) result showed significant genetic differentiation within and between populations (P<0.001), with 84.21% and 15.79% of the variation occurring within and among populations, respectively. Further, genetic variation analysis showed a coefficient of gene differentiation of 0.053 and a gene flow value of 4.467 among populations. The 384 barley genotypes were divided into seven genetic clusters according to STRUCTURE, neighbour-joining tree and principal coordinate analysis, correlating significantly with geographic distribution. These results signified presence of significant variations within and among populations (P<0.001), with the highest of the variation occurring within populations. The results will also assist with the design of conservation strategies, such as genetic protection via both in situ and ex situ conservation.

Predictors of interest in predictive testing for rheumatoid arthritis among first degree relatives of rheumatoid arthritis patients.

OBJECTIVES: There is increasing interest in prediction and prevention of RA. It is important to understand the views of those at risk to inform the development of effective approaches. First-degree relatives (FDRs) of RA patients are at increased risk of RA. This study assessed predictors of their interest in predictive testing for RA. METHODS: Questionnaires were completed by RA patients (provided with their questionnaire by a healthcare professional) and their FDRs (provided with their questionnaire by their RA proband). FDR surveys assessed interest in taking a predictive test, demographic variables, perceived RA risk, attitudes about predictive testing, autonomy preferences, illness perceptions, avoidance coping and health anxiety. Patient surveys included demographic variables, disease impact, RA duration and treatment. Ordinal logistic regression examined the association between FDRs' characteristics and their interest in predictive testing. Generalized estimating equations assessed associations between patient characteristics and FDRs' interest in predictive testing. RESULTS: Three hundred and ninety-six FDRs responded. Paired data from the RA proband were available for 292. The proportion of FDRs interested in predictive testing was 91.3%. Information-seeking preferences, beliefs that predictive testing can increase empowerment over health and positive attitudes about risk knowledge were associated with increased interest. Beliefs that predictive testing could cause psychological harm predicted lower interest. Patient characteristics of the proband were not associated with FDRs' interest. CONCLUSIONS: FDRs' interest in predictive testing for RA was high, and factors associated with interest were identified. These findings will inform the development of predictive strategies and informational resources for those at risk.

Burden of chronic diseases associated with periodontal diseases: a retrospective cohort study using UK primary care data.

OBJECTIVES: To identify the association between periodontal diseases (gingivitis and periodontitis) and chronic diseases including cardiovascular disease, cardiometabolic disease, autoimmune disease and mental ill health. DESIGN: Retrospective cohort. SETTING: IQVIA Medical Research Data-UK between 1 January 1995 and 1 January 2019. PARTICIPANTS: 64 379 adult patients with a general practitioner recorded diagnosis of periodontal disease (exposed patients) were matched to 251 161 unexposed patients by age, sex, deprivation and registration date. MAIN OUTCOME MEASURES: Logistic regression models accounting for covariates of clinical importance were undertaken to estimate the adjusted OR (aOR) of having chronic diseases at baseline in the exposed compared with the unexposed group. Incidence rates for each outcome of interest were then provided followed by the calculation of adjusted HRs using cox regression modelling to describe the risk of outcome development in each group. RESULTS: The average age at cohort entry was 45 years and the median follow-up was 3.4 years. At study entry, the exposed cohort had an increased likelihood of having a diagnosis of cardiovascular disease (aOR 1.43; 95% CI 1.38 to 1.48), cardiometabolic disease (aOR 1.16; 95% CI 1.13 to 1.19), autoimmune disease (aOR 1.33; 95% CI 1.28 to 1.37) and mental ill health (aOR 1.79; 95% CI 1.75 to 1.83) compared with the unexposed group. During the follow-up of individuals without pre-existing outcomes of interest, the exposed group had an increased risk of developing cardiovascular disease (HR 1.18; 95% CI 1.13 to 1.23), cardiometabolic disease (HR 1.07; 95% CI 1.03 to 1.10), autoimmune disease (HR 1.33; 95% CI 1.26 to 1.40) and mental ill health (HR 1.37; 95% CI 1.33 to 1.42) compared with the unexposed group. CONCLUSIONS: In this cohort, periodontal diseases appeared to be associated with an increased risk of developing cardiovascular, cardiometabolic, autoimmune diseases and mental ill health. Periodontal diseases are very common; therefore, an increased risk of other chronic diseases represent a substantial public health burden.

Human lung cDC1 drive increased perforin-mediated NK cytotoxicity in chronic obstructive pulmonary disease.

In chronic obstructive pulmonary disease (COPD), lung natural killer cells (NKs) lyse autologous lung epithelial cells in vitro, but underlying mechanisms and their relationship to epithelial cell apoptosis in vivo are undefined. Although this cytolytic capacity of lung NKs depends on priming by dendritic cells (DCs), whether priming correlates with DC maturation or is limited to a specific DC subset is also unknown. We recruited ever-smokers (≥10 pack-years; n = 96) undergoing clinically indicated lung resections. We analyzed lung NKs for cytotoxic molecule transcripts and for cytotoxicity, which we correlated with in situ detection of activated Caspase-3/7+ airway epithelial cells. To investigate DC priming, we measured lung DC expression of CCR2, CCR7, and CX3CR1 and cocultured peripheral blood NKs with autologous lung DCs, either matured using lipopolysaccharide (LPS) (nonobstructed smokers) or separated into conventional dendritic cell type-1 (cDC1) versus cDC type-2 (cDC2) (COPD). Lung NKs in COPD expressed more perforin (P < 0.02) and granzyme B (P < 0.03) transcripts; inhibiting perforin blocked in vitro killing by lung NKs. Cytotoxicity in vitro correlated significantly (Sr = 0.68, P = 0.0043) with numbers of apoptotic epithelial cells per airway. In nonobstructed smokers, LPS-induced maturation enhanced DC-mediated priming of blood NKs, reflected by greater epithelial cell death. Although CCR7 expression was greater in COPD in both cDC1 (P < 0.03) and cDC2 (P = 0.009), only lung cDC1 primed NK killing. Thus, rather than being intrinsic to those with COPD, NK priming is a capacity of human lung DCs that is inducible by recognition of bacterial (and possibly other) danger signals and restricted to the cDC1 subset.

Outcomes of adult patients supported by extracorporeal membrane oxygenation (ECMO) following cardiopulmonary arrest. The Mayo Clinic experience.

INTRODUCTION: To describe our experience in use of extracorporeal life support (ECLS) as a rescue strategy in patients following cardiopulmonary resuscitation. METHODS: A retrospective analysis was performed for patients (n = 101) who received ECLS after cardiorespiratory arrest between May 2001 and December 2014. The primary outcome was survival to hospital discharge. RESULTS: In this cohort median (IQR) age was 56 (37-67) years, 53 (53%) were male, and 90 (89%) were Caucasian. Ventricular tachycardia or ventricular fibrillations were the initial cardiac rhythm in 49 (48.5%) and asystole/pulseless electrical activity in 37 (36.8%). Median (IQR) time to initiation of extracorporeal support from arrest time was 72 (43-170) min. The median (IQR) duration of support was 100 (47-157) hours. Renal failure (66%) and bleeding (66%) were the two most commonly observed complications during ECLS support. The survival to hospital discharge was seen in 47 (47%) patients, and good neurologic outcome (mRs 0-3) was seen in 29%. Acidosis, lactate and continuous renal replacement therapy were independent predictors of mortality. The median (IQR) intensive care unit stay was 14 (4-28) days and hospital stay was 17 (4-35) days. CONCLUSION: Our institutional experience with ECLS as a rescue measure following cardiac arrest is associated with improvement in mortality, and favorable neurologic status at hospital discharge.

Methodological considerations in the assessment of direct and indirect costs of back pain: A systematic scoping review.

BACKGROUND: Back pain is a common and costly health problem worldwide. There is yet a lack of consistent methodologies to estimate the economic burden of back pain to society. OBJECTIVE: To systematically evaluate the methodologies used in the published cost of illness (COI) literature for estimating the direct and indirect costs attributed to back pain, and to present a summary of the estimated cost burden. METHODS: Six electronic databases were searched to identify COI studies of back pain published in English up to February 2021. A total of 1,588 abstracts were screened, and 55 full-text studies were subsequently reviewed. After applying the inclusion criteria, 45 studies pertaining to the direct and indirect costs of back pain were analysed. RESULTS: The studies reported data on 15 industrialised countries. The national cost estimates of back pain in 2015 USD ranged from $259 million ($29.1 per capita) in Sweden to $71.6 billion ($868.4 per capita) in Germany. There was high heterogeneity among the studies in terms of the methodologies used for analysis and the resulting costs reported. Most of the studies assessed costs from a societal perspective (n = 29). The magnitude and accuracy of the reported costs were influenced by the case definition of back pain, the source of data used, the cost components included and the analysis method. Among the studies that provided both direct and indirect cost estimates (n = 15), indirect costs resulting from lost or reduced work productivity far outweighed the direct costs. CONCLUSION: Back pain imposes substantial economic burden on society. This review demonstrated that existing published COI studies of back pain used heterogeneous approaches reflecting a lack of consensus on methodology. A standardised methodological approach is required to increase credibility of the findings of COI studies and improve comparison of estimates across studies.