Dear Editor,aO2/FiO2 and intracranial pressure in 10 patients during PP. Although PaO2/FiO2 improved, PP was discontinued due to a raised intracranial pressure (ICP) in 50% of patients. Additionally, they found that all patients with ICP > 17.5 mmHg and 28% of patients with ICP < 17.5 mmHg prior PP had intracranial hypertension  following PP. They concluded that monitoring of the brain compliance, ICP and the tolerance to venous return obstruction (Queckenstedt’s maneuver) could be useful before decision of PP.Recently, Bernon et al. evaluated in a retrospective study the safety and efficacy of prone position (PP) in patients treated for traumatic brain injury (TBI) and moderate-to-severe acute respiratory distress syndrome (ARDS) . They anSevere ARDS makes the ventilator management of patients with TBI even more challenging. The European Society of Intensive Care Medicine strongly recommends to consider PP in patients with concomitant ARDS and TBI, if ICP is stable . When PPSeveral factors may impair venous outflow from the brain, and elevated intra-abdominal pressure (IAP) is one of them. Significant increase in IAP closely corresponds to an increase in central venous pressure, jugular venous bulb pressure and low jugular venous bulb saturation in critically ill patients . It was  Dear Editor,2, 30% of whom (n = 3) had ICH during PP. The number of obese patients at risk of increased IAP was too small to conclude, and we agree with Dabrowski et al. that IAP plays a critical role in venous return changes during PP. The pressure in the right atrium, which drives cerebral blood outflow, is influence by cardiac output, intrathoracic pressure and to some extent by the venous pressure from other organs. PP is expected to improve thoracic compliance and thereby venous return; however, the increase in IAP may hinder this beneficial effect. For instance, during elective spine surgery the only frame that can reduce hemodynamic changes triggered by PP allows the abdomen to hang free [Dabrowski et al. published a letter in the journal about our work reporting data on the safety and efficacy of prone positioning (PP) in patients with acute brain injury and moderate-to-severe acute respiratory distress syndrome (ARDS) . They suang free  thereby ang free . IAP relang free . We agre


The world population is aging, and the prevalence of chronic kidney disease (CKD) is increasing. Whether this increase is also due to the methods currently being used to assess kidney function in the elderly is still a matter of discussion. We aimed to describe the actual referral pattern of CKD patients in a large nephrology unit and test whether the use of different formulae to estimate kidney function could affect the staging and the need for specialist care in the older subset of our population. In 2019, 1992 patients were referred to our center. Almost 28% of the patients were aged ≥80 and about 6% were ≥90 years old. Among the causes of kidney disease, glomerulonephritis displayed a higher prevalence in younger patients whereas hypertensive or diabetic kidney disease were more prevalent in older patients. The prevalence of referred patients in advanced CKD stages increased with age; estimated glomerular filtration rate (eGFR) decreased with age regardless of which equation was used (chronic kidney disease epidemiology collaboration (CKD-EPI), Lund–Malmö Revised (LMR), modification of diet in renal disease (MDRD), Full Age Spectrum (FAS), or Berlin Initiative Study 1 (BIS)). With CKD-EPI as a reference, MDRD and FAS underestimated the CKD stage while LMR overestimated it. The BIS showed the highest heterogeneity. Considering an eGFR threshold limit of 45 mL/min for defining “significant” CKD in patients over 65 years of age, the variability in CKD staging was 10% no matter which equation was used. Our study quantified the weight of “old” and “old-old” patients on follow-up in a large nephrology outpatient unit and suggested that with the current referral pattern, the type of formula used does not affect the need for CKD care within the context of a relatively late referral, particularly in elderly patients. The aging of the world’s population, particularly in high-income countries, has changed the profile of several specialties. This is true of nephrology. In the current clinical setting, in western countries, the main causes of chronic kidney disease (CKD) have switched from glomerulonephritis, typical of the young, to nephroangiosclerosis or diabetic nephropathy and multifactorial diseases, typical of elderly individuals . On the The definition of CKD as an eGFR below 60 mL/min for at least 3 months has challenged, in particular, the geriatrists, raising the question of whether this definition should be adapted to age, acknowledging the para-physiological decrease that is observed in older individuals . In factEven though the kidney diseases of the elderly frequently progress more slowly compared to diseases occurring in younger individuals, they are not always “benign”, and the median age of patients starting dialysis has increased from less than 50 years in the 1980s to over 70 years at present, while the definition of “old” kidney transplant recipients has increased from “above 50” in the late 1980s to “above 70” in the new millennium .As a result of an increasing prevalence of older patients, the definitions of “old” patients in nephrology, dialysis, and transplantation have changed over time, and several groups have been identified, although sometimes defined differently. These include the young-old ; the old-old ; and the older-old or oldest-old, a category usually encompassing those who are over 80 years of age ,13,14,15While these distinctions further add to the semantic conundrum, they indicate that “not all elderly patients are alike” and that the clinical and treatment problems faced by old patients deserve more-precise definition. One of the hot points in the discussion on CKD in the elderly resides in the problems of assessment of kidney function .There are good reasons for monitoring kidney function in the elderly. First of all, correctly estimating kidney function is fundamental if drug toxicity is to be avoided, guiding choice as well as dosage; and secondly, timely interventions may reduce the need for renal replacement therapy and avoid the difficult dilemma of whether or not to start dialysis in the oldest-old, in whom the start of renal replacement therapy is associated with a high risk of rapid impairment in terms of clinical condition and quality of life ,17,18.Finding a balance between a minimalist approach  and an interventionist one  is not simple, and the limited availability of nephrology care may further increase discrepancies in clinical management ,20.While the dialysis population is now monitored in most of the high-income countries and registries are being developed in medium-income settings, enabling the quantification of the burden of “elderly” patients on renal replacement therapy, less is known about the clinical burden and the main characteristics of elderly patients referred for nephrology care . Such daIt is against this background that the present study was designed to contribute to filling a major knowledge gap, by analyzing the main clinical characteristics and kidney function of elderly patients referred to a large non-university hospital in France, a country where CKD is eligible for fully reimbursed care. We employed the most commonly used formulae to estimate eGFR to highlight their effect, if any, on the staging employed in identifying a need for nephrology care and to assess the prevalence of the different categories of “old patients” referred to our units for nephrology follow-up.The present study was undertaken at Centre Hospitalier Le Mans (CHM), one of the largest non-university hospitals in France. CHM has a nephrology service with a network of outpatient-care facilities  and is the only hospital in the department of Sarthe with nephrology beds . The hospital is situated in the main city of the department, Le Mans, which has 143,325 inhabitants.All patients older than 18 who attended at least one consultation in 2019 in the nephrology outpatient clinics at CHM were included in the study. Patients on renal replacement therapy and kidney-transplant recipients were excluded. Patients’ data were retrieved from their electronic medical records (ORBIS). Kidney function was assessed by means of the following equations: chronic kidney disease-epidemiology collaboration (CKD-EPI), modification of diet in renal disease (MDRD), Lund—Malmö Revised (LMR), Full Age Spectrum (FAS), and Berlin Initiative Study 1 (BIS) ,24,25,26The following data were gathered: demographic characteristics (gender and age) and type of kidney disease. Causes of kidney disease were classified into 10 categories /obstructive/systemic disease/solitary kidney, polycystic kidney disease (ADPKD), isolated urinary abnormalities, multifactorial, postpartum-preeclampsia, renal stones, and other/not known/post-acute kidney injury (AKI)) in accordance with the diagnosis made by the attending nephrologist based on the patient’s medical history, the availability of a histologic assessment (kidney biopsy), and his/her expertise. All diagnoses were reviewed and confirmed by the senior nephrologist (G.B.P.).Statistical analyses were performed using SPSS Statistics version 23 . Quantitative data were expressed as median values (min–max), and qualitative data were presented as proportions and percentages.t-test was performed to compare two non-paired groups, otherwise the Wilcoxon rank sum test was used. Variance analysis was applied for additional group comparisons, otherwise the Kruskal–Wallis test was performed. Proportions were tested using the Chi-square or the Fisher exact test in case of a low subsample cohort size (<5). A two-sided alpha risk was set at 5%.The normality and homoscedasticity hypotheses were tested with the Shapiro–Wilk and Levene’s tests, respectively, for continuous series. The Student’s The study was conducted in accordance with the Declaration of Helsinki. The cross-sectional observational study involved the analysis of the clinical charts of patients who attended at least one consultation in a nephrology outpatient clinic in 2019; the anonymized database was built following the requirements of the regional health council, to assess the number of cases in CKD stages 4 and 5. The study was approved by the CHM ethical committee at its 24 September 2020 meeting.The demographic characteristics of the cohort of 1992 patients referred for at least one consultation to Centre Hospitalier Le Mans are reported in The highest prevalence was recorded in the 80- to 89-year-old age group (21.9%) while the oldest-old, aged 90 or older, accounted for 5.8% of the referred cases .In the context of this relatively old population, chronic kidney diseases varied significantly between age groups. While the prevalence of glomerulonephritis declined with age, the prevalence of three categories increased sharply. Multifactorial disease, nephroangiosclerosis, and kidney diseases associated with diabetes accounted for only 12.7% of the cases in the younger age group but for 80.7% in the 80- to 89-year-old age group and 84.6% in patients aged 90 or older .In keeping with a high prevalence of vascular nephropathies, which are usually non-proteinuric or characterized by mild proteinuria, the prevalence of the cases that displayed proteinuria over 1 g per day was low. It is worth noting that proteinuria was missing in several cases; the lack of regular control is partly a reflection of the fact that proteinuria had not been regularly checked in patients who were classified as having a vascular disease, and were known to have low or absent proteinuria in previous tests .Most kidney diseases were present in all age groups; the relatively high prevalence of cases with lithiasis or postpartum preeclampsia reflects specific referral patterns developed in the study center: for instance, younger patients with lithiasis are referred to the nephrologist for evaluation due to the higher probability of a genetic disease or a tubule-interstitial disorder, while older patients are usually followed up by urologists in the absence of an impairment of kidney function.In the population on follow-up, median serum creatinine steadily increased, and median eGFR consequently decreased with age, regardless of the formula employed .The highest median level of serum creatinine corresponded to 1.88 mg/dL at or above age 90. In line with these observations, the prevalence of CKD stages 4 and 5 increased. Only 1.7% of the patients aged 90 or older had a CKD stage of 1 or 2; over 60% of those in this age group were in CKD stages 4–5, versus 38.5% in the 80- to 89-year-old age group and only 8.3% of patients aged under 50 .The distribution of stages was different in different age groups . The latIn the context of good correlations between the most widely used formula (CKD-EPI); the classic MDRD formula; and other, more recent formulae targeted toward elderly patients, there were some differences in the results from the different equations . The higHowever, if we consider two broad groups of eGFR  were classifiable as “old” .Patients aged 60 or older accounted for about 70% of the overall cohort, and about one patient out of four was aged 80 or older (“old-old”); the most numerous subset was recorded in the 80- to 89-year-old age group (21.9%), while the extremely old patients, aged 90 or older, accounted for 5.8% of the cases .As for kidney diseases, the prevalence of multifactorial diseases, nephroangiosclerosis, and diabetes-associated kidney disease, particularly the variant with low proteinuria (diabetes-vascular), increased with age. These three diseases accounted for over 80% of the diagnoses in patients aged 80 or older at the time of our study . The diaSerum creatinine increased steadily with age in the study cohort . As a coThis distribution disproves the frequently reported concern that since the commonly used formulae are less reliable in the elderly, elderly patients are being over-referred, at levels of kidney function that do not represent “true kidney disease”. Hence, some authors suggest that the definition of CKD should start from <45 mL/min of eGFR in the elderly [While this present cross-sectional study did not allow us to analyze trajectories, there is little doubt that patients in CKD stages 4 and 5 are more fragile and prone to developing severe metabolic derangements; have a higher risk of death and a greater need to start renal replacement therapy; and should, therefore, be promptly identified ,28. The A strength of this study is that it is the only one recently carried out with the aim of assessing the burden of old, old-old, and extremely old patients followed up by nephrology units at a large general hospital. However, it has several limitations. First, it is a cross-sectional analysis, limited to one year only and without outcome data; second, even if the large majority of the patients had at least two data values for serum creatinine, thus allowing a diagnosis of CKD to be made, we considered only the latter value and did not analyze the frequency of variations during the year; and third, patients were followed up by five different nephrologists in two different macro-areas , and we did not attempt further analyses, for example, based on treatment or comorbidity. These points will be the subject of an in-depth analysis of the subset of patients more homogeneously followed up in the patient unit dedicated to advanced CKD stages.Notwithstanding these limitations, this first portrait of the elderly population followed up by a large nephrology unit suggests that elderly patients are not over-referred and that, on the contrary, they may even be under-referred, thus limiting the efficacy of actions aimed at preventing CKD progression and the start of dialysis. Furthermore, with the current relatively late recruitment, the choice of the formulae used only minimally affected the prevalence of patients with less than 45 mL/min of eGFR, and the differences among formulae were lower in “old” and “old-old” patients. This should serve to reassure us that, in contrast to large-population studies, the information used in daily practice is not subject to drastic changes according to the eGFR formula employed.Our study found that in a large nephrology outpatient unit a very high percentage of the patients were elderly, with a high prevalence of old-old and oldest-old cases. The current referral pattern is characterized by referrals of older patients with lower eGFR. In this setting, the use of different formulae does not lead to a relevant difference between patients with eGFR above or below 45 mL/min, the threshold now suggested for the definition of CKD in the elderly.


DISCUSSION/SIGNIFICANCE OF IMPACT: Here, we describe the relationship between renal structural changes and renal function and show that hypertension significantly modifies the relationship at a given eGFR. These data can be used to reasonably predict renal structural changes given clinical information without the need for renal biopsy and may provide prognostic value.OBJECTIVES/GOALS: Histopathological descriptions of kidney tissue provide more information about kidney disease severity and prognosis than serum measures, yet most patients with chronic kidney disease do not undergo kidney biopsy. We aim to develop a method to determine the degree of renal injury in patients with diabetes and hypertension without the need for biopsy. METHODS/STUDY POPULATION: Clinical data and renal tissue samples were collected from 864 patients undergoing tumor-associated nephrectomy in seven medical centers in the United States. Exclusion criteria included age < 18, presence of pyelonephritis or non-diabetic or hypertensive renal disease or incomplete clinical or histopathologic data. 19 histologic parameters were scored in a blinded manner by one renal pathologist. We examined the relationship between and functional variables (such as estimated glomerular filtration rate (eGFR)). Polynomial regression analysis was performed to model histopathologic variables and important clinical parameters such as eGFR RESULTS/ANTICIPATED RESULTS: 607 samples met inclusion criteria and were stratified as: control , hypertension alone (n = 224) and both diabetes and hypertension (n = 223). Interstitial fibrosis (IF) and glomerulosclerosis (GS) had the strongest correlations with eGFR. Regression analysis was used to model histopathologic score for a given eGFR. We found that diabetes and hypertension modified the relationship between tubulointerstitial fibrosis and eGFR. For example, while hypertensive patients without diabetes had 33% IF at an eGFR of 30 ml/min/1.73m


BackgroundDelayed graft function (DGF) is the most common early postoperative complication of renal transplantation. The occurrence of DGF can lead to both early and late devastating consequences on the allograft’s survival. The risk of developing this complication can increase with certain factors that are related to both the donor and the recipient. In the present study, we aimed to detect the incidence rate of DGF among patients attending a tertiary care hospital in Riyadh, Saudi Arabia, and to investigate potential predictors of DGF.Materials and methodsThis retrospective chart review was conducted at King Abdulaziz Medical City (KAMC), a tertiary care hospital in Riyadh, Saudi Arabia. The inclusion criteria were all patients, 18 years or older, who had renal transplantation from January 1, 2016, to March 31, 2020. Patients who had a second renal transplant, or renal transplantation in a different hospital and were followed up at KAMC were excluded. Patients’ medical records were accessed using the BESTCare electronic system to obtain the patients’ demographic data. A Chi-square test was used to test for the association between a predictor and a delay in graft function.ResultsA total of 344 patients were enrolled in the present study, approximately half of whom were males . Around one-half (49.4%) were aged between 40 and 64 years. The most common cause of renal failure was hypertension, which was found in 117 (35%) patients, followed by diabetes mellitus (DM) in 94 (28.1%) patients. Most organ donors 258 (77.2%) were alive. A total of 23 (6.9%) participants developed DGF. Mycophenolate mofetil (MMF) was found to be significantly associated with DGF (P < 0.001). Those who took MMF (5.9%) had a significantly lower rate of DGF compared to those who did not (36.4%). A significantly higher rate of DGF was seen in patients whose transplants were taken from deceased donors (15.5%) compared to living donor transplants (3.9%). Gender, age, body mass index (BMI), recipient blood type, donor blood type, and cause of renal failure were not associated with DGF.ConclusionsOnly 6.9% of the study’s participants exhibited DGF. The observed rate was lower than the ones detected in the literature. Those who took MMF had a significantly lower rate of DGF compared to those who did not. Transplants of deceased donors (15.5%) showed a significantly higher rate of DGF. Larger multicenter studies are required to further investigate DGF in a region with a high prevalence of organ failure and a higher need for transplantations, such as Saudi Arabia. Delayed graft function (DGF) is defined as failure of the renal transplant to function immediately, with the need for dialysis in the first post-transplantation week . It is t2 as underweight, 18.5-24.9 kg/m2 as normal, 25.0-29.9 kg/m2 as overweight, ≥30 kg/m2 as obese, and ≥35 kg/m2 as morbidly obese based on the World Health Organization (WHO) general population classification. The collected transplantation-related data were the cause of renal failure, donor blood type, donor condition, type of immunosuppressant used, and the occurrence of DGF.This retrospective chart review was conducted at King Abdulaziz Medical City (KAMC), a tertiary care hospital in Riyadh, Saudi Arabia. The inclusion criteria were all patients, 18 years or older, who had renal transplantation from January 1, 2016, to March 31, 2020. Patients who had a second renal transplant, or renal transplantation in a different hospital and were followed up at KAMC were excluded. Patients’ medical records were accessed using the BESTCare electronic system . The main outcome of the study was a delay in graft function. Demographic data including age, gender, body mass index (BMI), and blood type were obtained. The BMI of each patient was categorized into four groups: <18.5 kg/mThe figures were produced by Microsoft Excel 2019  and analyzed using the Statistical Package for the Social Sciences (SPSS) version 23.0 . For categorical variables, frequency and proportion were used. A Chi-square test was used to test for the association between a predictor and a delay in graft function. A p-value of ≤0.05 was deemed significant. Patients’ confidentiality was ensured by data anonymization using serial numbers instead of medical record numbers. The data were used by the research team members only.A total of 344 patients were enrolled in the present study, approximately half of whom were males 56.6%, n=189). In terms of the age at transplantation, 145 (43.4%) were aged between 18 and 39 years, 165 (49.4%) between 40 and 64 years, and 24 (7.2%) 65 years and older. Regarding the BMI, a small proportion of the participants  were underweight, 109 (32.6%) had a normal weight, 91 (27.2%) were overweight, 85 (25.4%) were obese, and 26 (7.8%) were morbidly obese. The most common blood type among recipients was O+ , followed by A+ , and AB+ . The socio-demographic profile of the participants is displayed in Table 89. In teThe most common cause of renal failure was hypertension, which was found in 117 (35%) patients, followed by DM in 94 28.1%) patients, and glomerular nephrotic syndrome in 26 (7.8%) patients. As for the blood type of donors, the most commonly reported blood types were O+ in 151 (45.2%) patients, followed by B+ in 51 (15.3%) patients, and A+ in 48 (14.4%) patients. Regarding the condition of organ donors, 258 (77.2%) were alive, 72 (21.6%) were deceased, and the condition of 4 (1.2%) organ donors was unknown. As for the post-transplantation immunosuppression therapy, 104 (31.1%) patients took prednisolone, 326 (97.6%) were given tacrolimus (Prograf), and 323 (96.7%) were given mycophenolate mofetil (MMF) (CellCept). A total of 23 (6.9%) participants documented DGF. The complete transplantation history of the patients is illustrated in Table 8.1% patiAs shown in Table It is known that aging can lead to a decrease in renal function through several mechanisms . With adEnd-stage renal disease (ESRD) occurs when CKD reaches an advanced state. In ESRD, the kidneys are no longer able to work as they should to meet the body's demands. Certain risk factors such as DM, hypertension, glomerulonephritis, and genetic diseases like adult polycystic kidney disease increase the likelihood of developing ESRD. Globally, the most common risk factor for ESRD is DM . In the Kidney transplant is the most appropriate renal replacement therapy for patients with ESRD in terms of survival and quality of life. Renal transplants are divided into living or deceased donor transplants . A livinMaintenance immunosuppressive therapy is administered to almost all renal transplant recipients to help prevent acute rejection and the loss of the renal allograft. Immunosuppressive agents are available in various combination regimens and include glucocorticoids , azathioprine, MMF, enteric-coated mycophenolate sodium (EC-MPS), cyclosporine, and tacrolimus . AccordiRegarding DGF, various studies used different definitions for DGF, such as the requirement for dialysis within one week of transplantation, an increase in serum creatinine in the first 24 hours by 43 mmol/L, or a decrease in urine output by 30 mL/hour in the first 24 hours . The mosIt is known that expanded criteria donors (ECDs), donors over the age of 60, contribute to the risk of DGF. In the present study, most donors were ECDs. Despite that, only 6.9% of the study’s participants exhibited DGF, and among the deceased donor category, only 15.5% of recipients exhibited DGF. A 2019 study of a similar sample size reported a 43.5% incidence rate of DGF among kidney recipients from ECDs who were deceased , it alsoThe present study showed a significant difference in the rate of developing DGF among living donor transplants when compared to deceased donor transplants. This result is not unexpected, given the large body of evidence supporting deceased donor transplants being a notable risk factor for DGF ,25. In aThere was no significant association in the present study between age and DGF among the study’s three designated age groups. While some studies recognized the effect of donor age on the risk of DGF; by probable way of being more susceptible to the damaging effect of CIT ,26, therThe present study did not reveal any significant association between any of the blood groups and DGF. It is notable to mention that all transplants in this study involved ABO compatible donors and recipients; transplant-related DGF by way of ABO incompatibility, therefore, could not be assessed. However, several studies shed light on ABO incompatibility as a risk for DGF rather than recipient blood group per se .It is well established in the literature that an increase in BMI is significantly associated with DGF . A 2011 Anti-thymocyte globulin (ATG) induction before transplantation, followed by a triple immunosuppressive regimen  post-transplantation is common practice at KAMC. Studies have shown the effectiveness of immunosuppressive therapy, encompassing triple therapy and IL-2 receptor antibody basiliximab in reducing the rates of DGF among kidney recipients, and though the induction used differs from that of KAMC, both ATG and basiliximab are safe and effective options . Triple There were some limitations to the present study. First, due to the retrospective nature of the study, associations were evaluated instead of causation in terms of the predictors of DGF. Second, the population size was relatively small compared to global multicenter studies. Although a significant association between MMF and the risk of DGF was found, this association may not be a true reflection of reality, given the limited number of participants in each group of the treatment regimens. Lastly, due to limitations in the BESTCare system, potential pre-operative predictors and baseline parameters such as creatinine levels and CIT were not collected.Although most donors were ECDs, only 6.9% of the study’s participants exhibited DGF. The observed rate was lower than the ones detected in the literature. Those who took MMF had a significantly lower rate of DGF compared to those who did not. Organ donor condition was significantly linked to DGF. A significantly higher rate of DGF was seen in patients whose transplants were taken from deceased donors (15.5%) compared to living donor transplants (3.9%). DGF remains a complex dilemma that is influenced by far more than the baseline predictors, which is evident by the conflicting reports in the literature. Larger multicenter studies are required to further investigate DGF in a region with a high prevalence of organ failure and a higher need for transplantations, such as Saudi Arabia.


Background: Traffic-related pollution is associated with the onset of asthma and the development of different phenotypes of asthma. Few studies have investigated the association between traffic proximity and late-onset of asthma (LOA) and early-onset asthma (EOA). This study was conducted to investigate the associations of LOA phenotypes with a function of the distance between residence and heavy traffic roads (HTRs).Methods: The study group consisted of 280 patients who were (LOA: 78.4%) recruited consecutively from a pay-for-performance asthma program to clarify the patient characteristics and proximity to HTRs within 1,000 m from their residences between EOA and LOA in three urban centers in Taiwan. The subsequent analysis focused on patients with LOA (n = 210) linking phenotypes and distance to HTRs.Results: Subjects with LOA tended to be older than those with EOA and had shorter asthma duration, poorer lung function, lower atopy, and less exposure to fumes or dust at home. Patients with LOA were more likely than those with EOA to live within 900 m of two or more HTRs . Among patients with LOA, minimum distance to an HTR was negatively associated with numbers of specific IgE as well as positively associated with the age of onset and body weight significantly. A higher proportion of patients with atopy  and anxiety/depression  and a trend of lower proportion of patients with obese  were found to be living within 900 m from HTRs.Conclusions: Late-onset of asthma (LOA) tended to live in areas of higher HTR density compared to EOAs. Among patients with LOA living close to HTRs, the interaction between traffic-related pollution, allergy sensitization, and mood status were the factors associated with asthma onset early. Obesity may be the factor for later onset who live far from HTRs. After an initial appearance in childhood, asthma may remain inactive for an extended period or reappear later in life. A number of recent studies have also described the onset of asthma during adulthood . Thus, eDespite the non-negligible incidence of adult-onset asthma, the causes have not been extensively investigated. Identifying the risk factors of LOA is crucial to understanding the underlying mechanisms and LOA was identified as the most significant independent risk factor for non-remission in patients with asthma . It shouIn the current study, we were interested in whether the traffic proximity was different in EOA and LOA. We sought to determine whether proximity or density of HTRs is associated with the LOA in the asthma cohort of an urban medical center. We also examined patient characteristics in order to identify factors significantly associated with traffic proximity in LOA.https://www.nhi.gov.tw/Content_List.aspx?=nEBDEAEDEC639490C&topn=5FE8C9FEAE863B46). Inclusion criteria included the diagnosis of asthma by a pulmonologist in accordance with ICD-10 code J45 at least twice within 90 days. Note that diagnoses were based on episodic respiratory symptoms , variable or persistent obstructive pulmonary function, and response to asthma therapy. All patients provided written informed consent. The study protocol was approved by the Chang Gung Medical Foundation Institutional Review Board (No. 201900211B0).This was a cross-sectional study of asthma patients recruited consecutively in a pay-for-performance program at Chang Gung Memorial Hospital, Linkou branch, which has been implemented by the National Health Insurance Administration (NHIA) in Taiwan since 2001 . CertifiAt the initial recruitment, we recorded the characteristics of the subjects based on questionnaires or medical records, including age at the time of asthma diagnosis by a physician, asthma control test (ACT) results, family history of asthma, the use of asthma medication, co-morbidities, childhood history of dyspnea, frequency of bronchitis, exposure to fumes or dust at home or work, smoking status, and current residence (in the last 6 months). Pulmonary function and allergy-related biomarkers, including eosinophils, eosinophil cation protein (ECP), immunoglobulin E (IgE), and specific IgE  were recorded. Patients with any positive specific IgE to allergens  were considered atopic. The tests above were done at physicians' discretion in real-world practice. For example, according to the regulation of Taiwan healthcare insurance, the reimbursement of specific IgE would not be offered unless the total IgE > 25 KU/L. Therefore, a test of specific IgE was not mandatory and the numbers of sIgE to check were based on the physicians' discretion.n = 58) and LOA (n = 210). This group of urban patients was subjected to further analysis to determine the proximity to HTRs within 1,000 m from their residences . Based on the geographic distribution of patients, we selected the ten busiest traffic monitoring sites, each of which had a daily mean bidirectional PCU exceeding 36,329 in 2018 (Heavy traffic roads (HTRs) were identified using open-data daily PCU (Passenger Car Unit) statistics from the Directorate General of Highways of Taiwan ( in 2018 .https://www.openstreetmap.org/export). Data covered the region between latitudes from 24.74 to 25.33 N and longitudes from 120.86 to 122.04 E. All map data other than roads and streets were excluded. Criteria for the selection of routing vectors were based on the Top-10 PCU routes. We sought to mitigate sphere projection bias by re-projecting the coronadite system of geometrics  from EPSG:4326  to EPSG:32651 (WGS 84 – UTM Zone 51N). This converted the spherical representation in radian units into a 2D flat surface presentation in meters, which is a convenient format for subsequent calculation. Geodata was processed using a custom script written in JavaScript under the NodeJS  runtime environment, and all exchangeable data formats were standardized according to GeoJSON format. The graphical representation of input variables and calculation results was handled using QGIS software .Geometric data were extracted from maps obtained from the open-data service – Open Street Map  was used to calculate the minimum distance between the domicile of each patient and the nearest HTR based on geometric data . We alsoSD or percentage. The Student's t-test was used to compare the means of continuous variables and normally distributed data; otherwise, the Mann-Whitney test was used. Categorical variables including patients with EOA and LOA living in ≥ 1 or 2 heavy-traffic roads within indicated distance were tested using the Chi-square test or Fisher exact test. For tests done by physicians' discretion, the numbers are tested were smaller than the total cohort. The analysis was done on the patients who were checked and the number of participants who provided information and the number of participants with positive results were specified. Unadjusted odds ratio (OR) and 95% CI were calculated for selective variables in geometric analysis during the Chi-square test. The association between the minimum distance to an HTR and patient factors was tested using the Spearman rank correlation because the distance was not normally distributed. All analysis was performed using IBM SPSS Statistics version 19. Armonk, NY: IBM Corp. Statistically significant results were defined as p ≤ 0.05.All data were expressed as mean ± 1) were lower in patients with LOA than in patients with EOA. As for allergic biomarkers, IgE levels were significantly higher in the EOA group than in the LOA group. The proportion of patients with ECP levels exceeding the normal range (18 μg/L) was higher in the EOA group than in the LOA group. The two groups were comparable in terms of eosinophil count. Patients with EOA tended to be more atopic and were also more susceptible to home dust mite (HDM), cat dander, and dog dander than patients with LOA  were LOA. with LOA .p = 0.07). We further analyzed the number of HTRs within regions that were measured from patient residences at set distances of up to 1,000 m. When patients resided with a distance of 900 m in the high-traffic road, more patients with LOA were living in multiple HTRs areas compared to patients with EOA , more positive atopic status , and a higher sensitivity to HDM .As shown in p = 0.025), BMI (p = 0.023) as well as negatively correlated with the numbers of positive specific IgEs (p = 0.005).To clarify the influence of high traffic density on patients with LOA, we conducted further analysis on the correlation between the distance to HTRs and patient characteristics in the LOA group . The minp = 0.001, unadjusted OR: 2.82, 95%CI: 1.519–5.235. p = 0.047, unadjusted OR: 1.81, 95%CI: 1.031–3.165. p = 0.075, unadjusted OR: 1.974, 95%CI: 0.936–4.165. For the binary variables and confirming the results of the correlation test, we compared the atopy, mood status, and obesity (BMI ≥ 30) of patients with LOA living within or beyond 900 m of HTRs . A higheOur analysis revealed that patients with LOA tended to be older than patients with EOA, to have had asthma for a shorter duration, were less likely to have a family history of asthma, were less exposed to fumes or dust in the home, were less likely to be atopic, were less sensitive to common inhaled allergens, and were more likely to have poor lung function. In urban areas, more patients with LOA had multiple HTRs (≥ 2 HTRs) within a distance of 900 m. Patients living within 900 m from multiple HTRs had a higher total IgE level, a more atopic status, and a higher sensitivity to HDM, compared to patients with ≥ 1 HTRs at a comparable distance. Among patients with LOA, the minimum distance to an HTR was positively associated with the age of onset and BMI and was negatively associated with atopy and mood status. Among patients with LOA, a higher proportion of atopic patients were living within 900 m from HTRs, a higher proportion of patients with anxiety or depression were living within 900 m from HTRs and a trend of a higher proportion of obese patients were living beyond 900 m from HTRs. To the best of our knowledge, this is the first study demonstrating the different traffic density between EOA and LOA and different phenotypes in LOA by geolocation, which showed the novel relation between asthma phenotypes and the urban environment.Correlation between TRAP and asthma is usually assessed in terms of pollutant concentration, such as nitrogen oxide and particulate matter (PM), or the distance to HTRs. Numerous cohort studies have demonstrated a positive association between exposure to TRAP and the risk of asthma , 29, 30;The patient profiles revealed by the subgroup analysis of patients living with multiple HTRs provided one of the possible mechanisms of asthma inception of LOA . PatientAnxiety and depression contribute to asthma symptoms and stressful life events have been shown as the risk factor of onset of asthma , 38. SomThe incidence of obesity in patients with LOA was higher among those living >900 m from HTRs than among those living <900 m from HTRs . This coThe study has several limitations. First, the cohort had a smaller patient number of EOA compared to LOA. This is because we recruited adult patients consecutively without selection in the pay-for-performance program to prevent selection bias. The higher ratio of LOA to EOA in our cohort is possible due to the remission rate of EOA being much higher than LOA and LOA is suggested to be more severe than EOA , 42. TheIn conclusion, the characteristics of patients with LOA were distinct from those of patients with EOA. By geolocation in urban centers, we discovered the correlation between asthma phenotypes and the urban environment in LOA. patients with LOA tended to live in areas of higher HTR density, which was associated with an elevated incidence of atopic symptoms, sensitivity to HDM, and mood disorder. Proximity to HTRs and obesity may be factors contributing to uncontrolled asthma in cases of LOA. The novel evidence of patient-environment interaction provides further explanation for asthma persistence in the modern world.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Chang Gung Medical Foundation Institutional Review Board (No. 201900211B0). The patients/participants provided their written informed consent to participate in this study.T-YL: conceptualization, data curation, investigation, formal analysis, and writing of the original draft. Y-SL: methodology, software, formal analysis, and visualization. H-CL: data curation, resources, and formal analysis. S-ML: data curation, resources supervision, formal analysis, and writing with review and editing. Y-LL, C-HW, P-JC, and C-YL: data curation and resources. All authors contributed to the article and approved the submitted version.Y-SL is employed by BalDr Strategic Consulting (Hong Kong) Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Building on lessons learnt from evidence-based community pharmacy asthma management models, a streamlined and technology supported Pharmacy Asthma Service (PAS) was developed to promote the integration of the service into routine practice.Objective: This study investigates the efficacy of the PAS in improving asthma symptom control and other health outcomes.Methods: A two-arm pragmatic cluster randomized controlled trial was implemented in 95 pharmacies across three Australian States. Participants were adults with poorly controlled asthma as per the Asthma Control Questionnaire (ACQ), with or without allergic rhinitis. Patients within the PAS arm engaged in four consultations with the pharmacist over a 12-month period. An evidence-based algorithm guided pharmacies, via a trial specific software, to deliver a series of interventions targeting three issues underpinning uncontrolled asthma  to patient clinical asthma status and patient need. Comparator arm patients received a minimal intervention likened to usual practice involving referral of eligible patients to the GP and two follow-up consultations with their pharmacist to collect comparative data.Results: In total, 143 of 221 PAS patients (65%) and 111 of 160 comparator patients (69%) completed the trial. Improvements in asthma control were achieved in both the PAS (mean difference (MD) in ACQ from baseline = −1.10, p <.0001) and comparator  arms at the trial end; however, there were no significant differences between the two arms . Patients’ quality of life in the PAS arm improved significantly when compared with the comparator arm  = −0.52, 95% CI −0.89 to −0.14, p = 0.0079).Conclusion: Despite the PAS achieving a greater improvement in patients’ quality of life, the pharmacist-led service and usual practice arm produced comparable improvements in asthma control. These results ask us to reflect on current standards of usual care, as it appears the standard of asthma care in usual practice has evolved beyond what is reported in the literature. Optimal management of asthma is known to save lives; however, suboptimal asthma control within the community is globally evident and is often underpinned by ineffective use of effective medicines . ConsequResearch within Australia and elsewhere over the past two decades has demonstrated that structured pharmacy-based, pharmacist-delivered, patient-centered asthma management services can cost-effectively improve a range of patient outcomes . DespiteIn response to feedback from pharmacists in earlier trials  and to iThe objective of this study was to measure the relative efficacy of the PAS when compared to a minimal intervention  in a randomized controlled trial (RCT) design. The main outcome measured was asthma control.A cluster RCT design was used, with pharmacies the unit of cluster and patients the unit of analysis. All pharmacists and patients provided written or electronic informed consent. Recruitment commenced in July 2018 and the trial was completed in February 2020.Pharmacists from regional and metropolitan areas in New South Wales (NSW), Western Australia (WA), and Tasmania were invited to nominate their pharmacy via an online expression of interest form sent out by The Pharmacy Guild of Australia.To participate, pharmacies were required to: be approved to dispense Pharmaceutical Benefits Scheme (PBS) medicines as part of the National Health Scheme defined in Section 90 of the National Health Act 1953 (Section 90 pharmacy); have an area physically separated from the retail trading floor to ensure privacy during consultations; and have a minimum of two pharmacists on duty at times when the service was to be delivered.To ensure that rural and urban pharmacies were representative of the distribution of the Australian population in NSW, WA, and Tasmania, randomization was stratified according to State and remoteness index using the Pharmacy Access/Remoteness Index of Australia (PhARIA)  and randPharmacists were offered remuneration for their participation, with PAS pharmacists receiving AU$120 per completed patient and comparator pharmacists receiving AU$35 per completed patient. These payments were considered compensation for professional time.Prior to implementation, pharmacists in the PAS arm were required to pass both theoretical and skills-based training for assurance of the advanced clinical knowledge and skills required to deliver the PAS and compliance with the trial protocol . DetailsUpon completion of required training, pharmacies in both arms were asked to recruit a minimum of seven patients each. The sample size was based on feasibility established in previous studies, to account for predicted pharmacy and patient withdrawal rates, and the numbers required to show statistically significant change in asthma control .The primary inclusion criterion for patients was uncontrolled asthma as determined by a score ≥1.5 in the Asthma Control Questionnaire (ACQ) . AdditioPatients were excluded from the study if they had a high dependence on medical care , were unable to manage their own medicines (as determined by the pharmacist), and/or had a confirmed diagnosis of chronic obstructive pulmonary disorder (as reported by the patient) or a terminal illness.Depending on the pharmacy in which they were recruited, patients proceeded into the PAS or comparator arm pathway. The PAS was a pharmacist-led 12-month program conducted in the regular pharmacy of the recruited asthma patient. To deliver the service, the pharmacist undertook three private face-to-face consultations with the individual over a period of 12 months: at baseline, month 1 and month 12, with one additional telephone follow-up at month 6 to monitor progress and identify potential risks. After screening and identifying patients with uncontrolled asthma, patients underwent a baseline consultation consisting of education and counselling-based interventions centered on patient knowledge, beliefs of disease and medicines, and determining possible causes of poor control by addressing patient adherence, inhaler technique, and relevant co-morbidities such as allergic rhinitis. Pharmacists were also encouraged to refer patients with uncontrolled asthma control with unknown causes/complex issues to their GP.The comparator was a minimal intervention active control arm designed to mimic usual pharmacy practice whilst being structurally equivalent to the PAS arm for non-specific factors including format and data collection time points . PatientThe project utilized GuildPath, a web-based, study-specific data collection software, to integrate data collection into routine pharmacy practice. GuildPath was integrated with GuildCare NG™, professional services software operating in over 5000 pharmacies in Australia . All valPatient characteristics, including self-reported age of asthma symptom onset, smoking status, demographic data, including age, sex, location, education status and work status were collected at the beginning of the trial for patients in both arms.To evaluate the efficacy of the PAS relative to comparator arm, the following outcome measures were assessed.The primary outcome was asthma symptom control, as assessed via the ACQ  at all cPatient quality of life was evaluated via the Impact of Asthma on Quality of Life Questionnaire (IAQLQ)  at baselThe self-reported number of hospitalizations and emergency department presentations in the preceding 12 months, and whether a patient recalled receiving a lung function test in the preceding 12 months, were recorded at baseline and month 12 for patients in both arms. Medicare Benefits Schedule (MBS)Australia Medicines Handbook,  have you used each day?] /device(s), against National Asthma Council Australia device-specific checklists . PatientPatients in both arms who had comorbid allergic rhinitis completed the Rhinitis Control Assessment Test (RCAT) at baseline, month 1 and month 12 . Based oAsthma action plan possession was recorded only upon completion of the trial at month 12 in both PAS and comparator arms. Pharmacists were asked to refer patients without a current plan to their GP.A sample size of 80 pharmacies (40 per arm), each recruiting seven patients  had 90% power to detect a 20% absolute improvement in the proportion of patients with controlled asthma at 12 months, assuming that no more than 30% would have controlled asthma in the comparator group. This assumed an intra-cluster correlation of 0.1 and allowed for 20 and 15% of patient and pharmacy withdrawal, respectively.The proportion of patients who had controlled asthma at 12 months were analyzed using a repeated measure mixed logistic regression including both the month 1 and month 12 values as dependent variables. Fixed effects included the random group allocation, the visit (month 1 or month 12), the interaction between the arm allocation and the visit and the baseline value of the ACQ score as a continuous variable. A random intercept per cluster was included to account for intra-cluster correlation. The main effect of the PAS was estimated as the odds-ratio (PAS vs comparator) together with its 95% confidence interval. The model was rerun after adjusting for the following baseline patient covariates: age, whether the patient had a lung function test within 12 months of baseline, smoking status, work status and presence of co-morbid allergic rhinitis. Missing data for ACQ scores at month 1 and month 12 were imputed using a multiple imputation technique  as part of the sensitivity analysis. The imputation model included random group allocation, the visit (month 1 or month 12), baseline value of the ACQ score and cluster variable along with the following baseline variables: IAQLQ score, age, sex, work status, education status, age since diagnosis, history of lung function test, smoking status and allergic rhinitis status. A subgroup analysis was also performed by adding a subgroup variable as well as its interaction term to the model used for the primary outcome analysis. Following variables were analyzed: Age , sex, pharmacy state and pharmacy remoteness.Dichotomous secondary outcomes were analyzed using the same method as for the primary outcome, while continuous secondary outcomes were analyzed using a similar approach with a linear model instead of a logistic one. No adjusted or subgroup analyses were applied to the secondary outcomes.i) Month 1–20 to 50 days included;ii) Month 6–160 to 220 days included; andiii) Month 12–330 to 420 days included.All data pertaining to a trial consultation, regardless of the exact timing in which the consultation was conducted, was included in the analysis. To account for variability in timing in which some consultations were conducted, a sensitivity analysis was performed. The sensitivity analysis involved re-running the primary outcome analysis model including only sessions conducted within the following time frames:Individual participants were excluded from the sensitivity analysis if their visits fell outside the specified time windows.p <0.05 was used for all statistical procedures. Process variables were computed in SPSS Version 25. Analyses were performed primarily using SAS software  in accordance with the pre-determined statistical analysis plan , WA (n = 21) and Tasmania (n = 11) participated and recruited 381 patients into the trial. The mean number of patients recruited per pharmacy was four, ranging from one to 16 patients per pharmacy. Sixteen pharmacies (17%) withdrew from the study after recruiting patients into the trial (nine PAS pharmacies and seven comparator pharmacies).In total, 95 community pharmacies (51 PAS and 44 comparator) across NSW  completed the trial by attending all consultations during the 12-months. Patient engagement throughout the trial is depicted in p = 0.0050), their asthma impacted their quality of life negatively to a greater extent (p = 0.0004), had poorer asthma control (p = 0.0029), and were recruited from highly accessible metropolitan pharmacies (p <0.001) and from NSW (p = 0.0089).Of the non-completing patients, 41.7% were successfully contacted at month 12. The mean ACQ score reported by these patients at month 12 was 1.7 (±1.0), and 60.4% had uncontrolled asthma at that point in time, as indicated by their ACQ score. When patients who completed the full 12-month trial were compared to those who did not, the two groups were overall quite comparable; however, those who did not complete were less likely to have a history of allergic rhinitis  and comparator arms (p <.001) (p = 0.1669). Results from the sensitivity analyses involving analysis on restricted timeframes, missing data imputation as well as the subgroup analyses were consistent with the main analysis.Asthma control significantly improved over the 12-month period of the trial in both the PAS (p <.001) . Howeverp = 0.0079)  .p = 0.0115). There was a significant increase in GP visits in the comparator arm during the trial (p = 0.0110). There were no significant differences between self-reported emergency department visits (p = 0.0620), hospital admissions (p = 0.0532) or MBS recorded GP visits (p = 0.1770) when the two arms were compared.In the PAS arm, there was a significant decrease in the mean number of self-reported emergency department presentations during the 12 months of the trial compared with the 12 months prior to the trial (n = 381), 378 patients consented to the collection of their PBS data, and 345 were able to be linked to complete PBS data collection: 205 (93%) patients from the PAS arm and 140 (86%) from the comparator arm. For patients who had their study data successfully paired with PBS data 12 months prior to baseline as well as 12 months during the trial, there were no significant differences  when comparing adherence between the two trial arms at month 12.Of the total sample .Using patient p = 0.034) and the comparator arm (p = 0.009) (p = 0.3872).Self-reported reliever use in the preceding 7 days decreased significantly over time when figures were compared in the PAS arm (= 0.009)  with no p = 0.0035). Additionally, the number of puffs required to obtain relief decreased amongst PAS patients over the 7 days preceding baseline (three puffs) to the 7 days preceding month 12 consultations (2 puffs) (p <.0001).PAS patients reported that in the 7 days prior to baseline, they used their reliever on average 15 times (ranging from zero to 140 times in that week). There was a significant reduction in self-reported reliever use by the end of the intervention; PAS patients reported using their reliever inhalers on average nine times in the 7 days preceding month 12 consultation , dry-powder inhalers, and soft-mist inhaler devices, respectively, had mastery. Almost all patients using a pMDI (97%) and a dry-powder inhaler (97%) achieved device mastery after training (baseline), and mastery was sustained by over half the patients by month 12 .n = 12).For patients using a soft-mist inhaler, device mastery was achieved by all and was sustained by 67% of patients by month 12; however, numbers were small (p <.0001) and comparator arms (p = 0.0122)  . Howeverp = 0.862). Oral antihistamines, although not recommended for first-line treatment, were the patient’s treatment of choice with 84% reporting use at baseline. This significantly decreased to 64% at month 1 (p = 0.003).Regarding allergic rhinitis management, at baseline, 86% of patients with allergic rhinitis in the PAS arm accepted a new recommendation by the pharmacist to help manage their allergic rhinitis (there were none prescribed for the comparator arm). Compared to baseline (50%), a higher proportion of patients were treating their allergic rhinitis symptoms at month 1 (66%). Only 42.0% of patients were taking the first-line recommended treatment at baseline  . This imp = 0.20).At month 12, 39% of PAS patients and 49% of comparator patients were in possession of a current Asthma Action Plan. This difference was not significant   at the tLiterature shows that patient expectations of their pharmacists change after having participated in a pharmacy-based health service . Thus, iAsthma is a chronic condition that cannot be cured, so steps towards minimizing patient burden, enhancing their emotional well-being, and improving their ability to wholly participate in work, social and school life unrestricted by asthma are key . Humanisself-reported adherence, measured in the PAS arm, showed significant improvements in the use of their asthma medications, including an increase in preventer use and a decrease in reliever use over the 12 months of the study. This is not surprising, as patients are likely to report to the pharmacist that they are using their medications. In addition, the pharmacists only asked patients about the previous 7 days, whereas the PBS analyzed a 12-month period where use may be intermittent.There was no significant improvement in patient adherence to preventer medication in PAS or comparator arms during the trial when measured using PBS records. At month 12, in both the PAS and comparator arms, adherence was approximately 50%, which suggests only half the patients were having their asthma medications dispensed at appropriate intervals. Despite the known benefits of regular preventer use on symptomatic control of asthma and reducing long term risks, asthma patients are known to not take their preventer therapy regularly . Rather,The lack of a change in adherence may seem surprising. In previous studies using similar interventions, we have observed an improvement in adherence . For theDespite this apparent lack of improvement in preventer medication use, the proportion of people with asthma who were using an inappropriate level of reliever medication was significantly reduced over the duration of the study in both the PAS and comparator arms. Inappropriate reliever overuse has been associated with tolerance, reduced benefit, increased risk of exacerbations and asthma death . On averThe proportion of patients with device mastery at baseline is consistent with the published literature and what we would expect in a community sample of people with asthma . The almFor allergic rhinitis, symptom control improved in both arms. In the PAS arm, pharmacists were required to undertake a detailed and structured assessment of symptoms and medication taking, using an evidence-based algorithm. Allergic rhinitis medication recommendations are part of routine clinical practice in pharmacy and may explain why allergic rhinitis symptom control improved in the comparator arm as well, where no structured intervention took place.An earlier study had included an active referral to a GP for every asthma patient who did not have a current asthma action plan at baseline . In the What is made clear by the trial is that for a PAS to be efficacious and routinised into practice further research on an ideal level of service is needed. A balance is yet to be achieved between complexity, implementability and efficacy. In the past, more complex interventions were more effective but less implementable . The curThe trial experienced a higher proportion of patient loss to follow up (33%), and subsequent pharmacy discontinuation (17%) than sample size calculations had allowed for .It is important when studying a sample of pharmacies that the results are generalizable. Participating pharmacies came from three states of Australia, were randomly allocated to either intervention or comparator arm and stratified according rurality to be representative of the spread of the Australian population. We thus believe we have a representative sample.Recruitment ran over 7 months ; as such, we cannot discount the effects of seasonality on asthma control, rhinitis control and medication use. However, any possible effects of seasons were the same for both arms. External climatic factors including dust storms and major bush fires which occurred during the trial are likely to have impacted negatively on patient control of their asthma. The air quality in many regions deteriorated during the bush fire season, and people with asthma were advised by health officials to stay indoors . The effComparable improvements in asthma control were experienced in both the PAS and minimal intervention, usual practice arm. However, the PAS was associated with greater improvements in patient quality of life. This research provides evidence that harnessing the skills of pharmacists and allowing them to contribute to their patients’ asthma management improves therapeutic and humanistic outcomes for patients. Further, it prompts reflection on current standards of usual care, as it appears the standard of asthma care in usual practice has evolved beyond that reported in the literature.


PurposeTo investigate any possible relationship between the central corneal thickness and the radial peripapillary capillary density detected by optical coherence tomography (OCT) angiography in eyes with ocular hypertension.Materials and methodsIn this observational study, 135 eyes were examined. OCT angiography of the optic disc (4.5 mm) and ultrasound corneal pachymetry were performed in all cases. Age, medical treatment for ocular hypertension, sex, and retinal nerve fiber layer thickness were evaluated. The main indices of blood flow were also examined. Spearman correlation coefficients were used to explore the association between two continuous variables.ResultsA directly proportional significance regarding the correlation between central corneal thickness and radial peripapillary network was indicated in eyes with ocular hypertension (p = .036).ConclusionsCentral corneal thickness and radial peripapillary capillary density constitute two essential screening parameters for patients with ocular hypertension. Ocular hypertension (OH) is defined as a condition in which the intraocular pressure (IOP) is greater than 21 mmHg in one or both eyes, with no evident glaucomatous defect. Its prevalence in people older than 40 years is estimated to range from 3% to 10% -11. The In this study, 135 eyes with ocular hypertension were examined. Data were collected prospectively during one year. All subjects were adults over 18 years of age. Patients (eyes) with the following conditions were excluded from the study: anti-glaucoma treatment with more than one pharmaceutical agent, any type of treatment for ocular diseases, dense cataracts, conditions consistent with abnormal macular findings, signs of uveitis, previous complicated cataract surgery, previous vitreoretinal interventions, previous refractive operations, and selective laser trabeculoplasty procedures.The same protocol was applied to all the cases. First, all patients were carefully examined clinically. They underwent medical history recording, visual acuity evaluation, slit-lamp examination, tonometry, and fundus examination. Afterwards, OCT-A of the optic disc (4.5 mm program) and ultrasound corneal pachymetry were performed in all eyes. AngioVue HD  software was used for all angiography measurements.With regards to the applied statistical analysis, normally distributed variables were expressed as means (standard deviation), while variables with skewed distribution were expressed as median (interquartile range). Qualitative variables were expressed as absolute and relative frequencies. Spearman correlation coefficients were used to explore the association between two continuous variables. All reported p-values were two-tailed. Statistical significance was set at p < 0.05, and analyses were conducted using SPSS statistical software version 22.0 .All methods were carried out in accordance with the relevant existing guidelines and medical regulations. All experimental protocols involved in the study included the actualization of clinical and screening examinations. Ethical approval was obtained from the General Assembly of Medicine School of National and Kapodistrian University of Athens, after evaluation by the Scientific Committee for Research Ethics of Athens Medicine School. Written informed consent was obtained from all participants.The sample consisted of 135 patients with a mean age of 62.1 years +/-13.1 SD Table . The C/DOH has been an essential field of study. In the United States, its prevalence in non-Hispanic Whites over 40 years accounts for 4.5 percent, and increases up to 7.7 percent in 75- to 79-year-olds. In Latinos, the prevalence across ages is similar .Risk factors and conditions related to OH have been meticulously studied. The Ocular Hypertension Treatment Study (OHTS), a multicenter randomized trial, remains the principal guiding light for all scientific approaches towards new immersive data. Its purpose was to evaluate the safety and efficacy of topical ocular hypotensive medical agents in delaying or preventing the onset of primary open-angle glaucoma (POAG) in individuals with elevated intraocular pressure (IOP) and no detectable glaucomatous damage.The latest update of the OHTS indicates the baseline factors that predict the evolution of primary open-angle glaucoma. These include older age, race (African American), sex , larger vertical cup-disc ratio, larger horizontal cup-disc ratio, increased intraocular pressure, higher Humphrey visual field pattern standard deviation, heart disease, and thinner central cornea (CCT) , 18-20.Additionally, the RNFL assessment is widely used to weigh the amount of structural loss in OH and glaucoma, since the retinal thickness measurements present significant thinner change in patients suspected for glaucomatous conditions -19.However, ocular blood flow changes have been considered to play a key role in the onset and development of different retinovascular and optic nerve diseases. Thus, not only RNFL thickness but also the density of RPCs network may also be associated with optic nerve head parameters and possible glaucomatous damage .FurtherIn our study, after the evaluation of all parameters, significant interconnection between two essential parameters for the diagnostic algorithm of ocular hypertension parameters was encountered. There is an important correlation between CCT and RPC density. Moreover, after individually approaching the collected data, the low percentage of RPC density in eyes with OH was statistically significant. Specifically, a lower proportion of RPC density in the inferior hemi-quadrant of the optic nerve head in these eyes could potentially be associated with parallel or future structural changes. As a result, the possibility of conversion to primary open-angle glaucoma would be enhanced as the “ISNT” rim pattern  could be verified ,11,18-22In light of the above, the CCT and RPC density constitute two essential screening parameters for patients with ocular hypertension. After having taken all the aforementioned aspects into consideration, we can clearly conclude that the CCT and RPC density constitutes two associated parameters. We could assume that the newly introduced value of RPC density could be considered as an additional risk factor to those described in the OHTS. However, it would be interesting to examine this factor over a long-term period and with reference to scientific studies concerning primary open-angle glaucoma.


The optimal gas conditioning strategy during helmet NIV remains to be established.There is growing interest towards the use of helmet noninvasive ventilation (NIV) for the management of acute hypoxemic respiratory failure. Gas conditioning through heat and moisture exchangers (HME) or heated humidifiers (HHs) is needed during facemask NIV to provide a minimum level of humidity in the inspired gas (15 mg H2/FiO2 < 300 mmHg) underwent consecutive 1-h periods of helmet NIV  with four humidification settings, applied in a random order: double-tube circuit with HHs and temperature set at 34 °C (HH34) and 37 °C (HH37); Y-piece circuit with HME; double-tube circuit with no humidification (NoH). Temperature and humidity of inhaled gas were measured through a capacitive hygrometer. Arterial blood gases, discomfort and dyspnea through visual analog scales (VAS), esophageal pressure swings (ΔPES) and simplified pressure–time product (PTPES), dynamic transpulmonary driving pressure (ΔPL) and asynchrony index were measured in each step.Twenty patients with acute hypoxemic respiratory failure (PaO2O/L) 16 [12–19] vs. 28 [23–31] vs. 28 [24–31] vs. 33 [29–38], p < 0.001; temperature (°C) 29 [28–30] vs. 30 [29–31] vs. 31 [29–32] vs 32. [31–33], p < 0.001; VAS discomfort 4 [2–6] vs. 6 [2–7] vs. 7 [4–8] vs. 8 [4–10], p = 0.03. VAS discomfort increased with higher absolute humidity (p < 0.01) and temperature (p = 0.007). Higher VAS discomfort was associated with increased VAS dyspnea (p = 0.001). Arterial blood gases, respiratory rate, ΔPES, PTPES and ΔPL were similar in all conditions. Overall asynchrony index was similar in all steps, but autotriggering rate was lower during NoH and HME (p = 0.03).Median [IqR] absolute humidity, temperature and VAS discomfort were significantly lower during NoH vs. HME, HH34 and HH37: absolute humidity  on August 23rd, 2016. The ongoing COVID-19 pandemic dramatically highlighted the role of noninvasive management of acute hypoxemic respiratory failure . In hypo2 from the high device-related dead space . Ordinal qualitative variables and non-normal quantitative variables distributions in the four study step were compared with the Wilcoxon/Kruskal–Wallis sum of rank test. Paired comparisons between steps were performed with the Wilcoxon test. All analysis was performed applying a bilateral hypothesis and results with Twenty patients were included. Patients’ demographic and baseline most relevant clinical features are shown in Table 2/FiO2 ratio at enrollment was 169 mmHg [112–279]. No differences in PaO2/FiO2, PaCO2, pH, heart rate and mean arterial pressure were detected between the study steps (Table Median [interquartile range] PaOp < 0.001), displaying an increasing trend from the steps NoH to HME to HH34 to HH37. Median absolute humidity was above 15 mgH2O/L in all steps, notably being 16 [12–19] mgH2O/L in the NoH step.These results are shown in Table p = 0.03 and p < 0.001, respectively). VAS dyspnea was not significantly different between the study steps (p = 0.46). Across all study steps , VAS discomfort increased at raising levels of absolute humidity (p < 0.001) and temperature (p = 0.007), as displayed in Fig. p = 0.001—Fig. These results are shown in Table ps p = 0.6. Acrossp = 0.99 and p = 0.43, respectively). Total minute ventilation  was slightly higher in HH34 and HH37 when compared to the non-actively humidified steps (p = 0.009). The analyzed work of breathing indices  along with ΔPL did not differ between steps.These results are displayed in Table p = 0.78), with a median asynchrony index of 16% [4–40%]. Overall, the most represented asynchrony was premature expiratory cycling, with an index of 4% when all measurements were taken into account [0–16%]. The rate of autotriggering, albeit low in all steps, was significantly higher in HH34 and HH37 steps (p = 0.03).As shown in Table 2O/L, which has been described as the minimum required humidification during NIV [Levels of humidity and temperature are significantly lower when no external gas conditioning is applied, when compared with the use of HME or HHs. Even with a NoH strategy, most patients are above the absolute humidity threshold of 15 mgHring NIV .Subjective discomfort is lower when a double-tube circuit with no humidification is used, as it is the formation of fog effect inside the interface.2O/L. Increasing levels of discomfort appear to be related to worsening dyspnea in these patients.Overall, discomfort increased at raising levels of humidity and temperature, provided that the great majority of measurements above or around the abovementioned safety margin of 15 mgHThe gas conditioning strategy does not appear to influence overall patient–ventilator synchrony, with the exception of an increased rate of autotriggering when HHs are used.Respiratory rate, inspiratory effort, dynamic transpulmonary driving pressure and work of breathing are not affected by the gas conditioning strategy used. A slightly increased total helmet minute ventilation is seen when heated humidification is applied.The main results of this randomized cross-over physiological study on gas conditioning during helmet pressure-support NIV can be summarized as follows:−1) with a PEEP valve [−1, which is the minimum value of fresh gas flow suggested to avoid CO2 retention in the interface and significant rebreathing [Two studies addressed the issue of gas conditioning during helmet continuous positive airway pressure (CPAP), and showed that humidification and comfort were optimal when no gas conditioning strategy was used during ventilator-delivered CPAP, while the application of a HH was needed at high continuous fresh gas flows  when compared to high-flow CPAP, where usual flows range around 50 L/min: this allows the helmet interface to efficiently work as a mixing chamber where patient’s expired air directly contributes to the heating and humidification of ventilator-delivered dry inspired gas, without being massively washed-out as in high-flow CPAP : in our The gas conditioning strategy does not appear to influence gas exchange, work of breathing and overall patient–ventilator interaction (as measured by the asynchrony index). When individual asynchronies were analyzed, a small increase in the autotriggering rate with heated humidifiers was apparent, likely due to increased water condensation in the inspiratory limb of the circuit .Despite the physiological nature of the study, our results may have relevant clinical implications. During helmet pressure-support noninvasive ventilation in hypoxemic patients, a double-tube circuit with no external humidification applied may be an acceptable gas conditioning strategy, since it does not affect work of breathing and oxygenation and appears to improve patient’s comfort and patient–ventilator interaction.The duration of each study step was limited to 1 h, which may preclude generalizability of the results to patients subjected to longer NIV treatments. Specifically, such a limited time could be insufficient to accurately assess respiratory discomfort directly related to higher airway dryness in case of under-humidification. However, study measurements were taken at the end of the 60-min periods after ensuring stability of physiological data, and the randomized cross-over design with 60-min consecutive periods of the present investigation is consistent with previous studies comparing different gas conditioning systems during CPAP or NIV with similar physiological endpoints –30, 49. The small sample size may have precluded the possibility to draw specific conclusions on secondary outcome measures and particularly subgroup analyses. Nevertheless, similar sample sizes have been selected for physiological studies focusing on similar outcomes, and results on the primary outcomes show a strong statistical significance.2/FiO2 ratio, albeit below 300 mmHg, varies significantly between patients, with a relevant proportion of patients exhibiting mild hypoxemia (PaO2/FiO2 between 200 and 300). This may have diluted the sample of moderate-to-severe patients, which are expected to display higher inspiratory effort and total minute ventilation: it is possible that a sample of more severe patients with higher helmet minute ventilation could reach higher median washout flows, possibly exceeding 30–40 L/min and thus physiologically resembling the abovementioned condition of high-flow CPAP [PaOOur study has limitations:During helmet pressure support NIV, a double-tube circuit with no external gas conditioning ensures adequate humidity and heat of the inspired gas, improves comfort and patient–ventilator interaction. Use of HHs or HME in this setting may generate excessive humidity and heat in the interface, finally increasing discomfort, which is associated to worse dyspnea.


Clinical practice guidelines recommend sodium-glucose co-transporter 2 inhibitors (SGLT2is) to mitigate adverse kidney and cardiovascular outcomes in patients with type 2 diabetes (T2D), including patients with comorbid chronic kidney disease (CKD), also referred to as diabetic kidney disease (DKD), who are at even higher risk. In this study, we sought to identify predictors of cardio-kidney events, cardio-kidney complications, and treatment failure  after new initiation of SGLT2is in patients with CKD and T2D (DKD).In this retrospective cohort study, we identified adult patients with DKD who initiated SGLT2is between April 1, 2012, and June 30, 2019, in Optum claims data. Outcome rates per 1000 person-years (PY) are reported with 95% confidence intervals (CIs). Cox proportional hazards regression identified patient characteristics associated with each outcome.The study population consisted of 6389 initiators of SGLT2is. The rate of CV hospitalization was 26.0  per 1000 PY. Baseline characteristics associated with higher risk of CV hospitalization included age, atrial fibrillation, peripheral vascular disease (PVD), and cancer. The rate of kidney hospitalization was 12.0  per 1000 PY. The risk increased significantly with baseline evidence of heart failure, hyperkalemia, respiratory failure, depression, and use of loop diuretics. In total, 55.0% of all SGLT2i initiators discontinued treatment during the follow-up period. The rate of treatment failure was 510.5  per 1000 PY. Analysis of key time-dependent SGLT2i-associated adverse events showed that experiencing diabetic ketoacidosis and volume depletion were associated with risk of treatment failure.Our study demonstrated high rates of residual cardio-kidney outcomes and treatment failure in patients with DKD treated with SGLT2is. Patients with high baseline CV risk and the presence of certain conditions, such as atrial fibrillation, PVD, and heart failure, were at higher risk for cardio-kidney events. Further research is needed to assess the potential relationship between adverse events and SGLT2i treatment failure.The online version contains supplementary material available at 10.1186/s12916-021-02191-2. Chronic kidney disease (CKD) is a serious complication of type 2 diabetes (T2D) that afflicts between 25 and 40% of all diagnosed patients . CKD proProlonged, unmanaged CKD in T2D, also referred to as diabetic kidney disease (DKD), often leads to end-stage kidney disease (ESKD), which requires dialysis and/or need for kidney transplantation , 7. ThesThere is an increasing need for new therapeutic agents that may slow or halt the progression of DKD and reduce the high morbidity and mortality in this population. Sodium-glucose co-transporter 2 inhibitors (SGLT2is), the most recently approved class of glucose-lowering agents for T2D in the US in March 2013, have later shown beneficial effects on kidney and cardiovascular outcomes and are recommended in clinical practice guidelines , 10. NotThis retrospective observational cohort study was conducted using Optum Clinformatics™ Data Mart (CDM) between April 1, 2012, to June 30, 2019, to identify predictors of cardio-kidney events and predictors of treatment failure among initiators of SGLT2i with DKD. The data source is an administrative health claims database with longitudinal data of patients enrolled in a commercial and Medicare Advantage health plan data in the US. The data contain demographic, medical encounters from inpatient and outpatient settings, pharmacy dispensing, and laboratory results for a subset of patients. The data contain approximately 63 million unique members and are considered representative of the commercially insured US population.. Follow-up period began 1 day after the index date and ended on the earliest occurrence of the outcome, disenrollment, death, and the end of data on 30 June 2019 (or SGLT2i discontinuation for cardio-kidney outcomes only)  and 30 June 2019 was considered the index datePatient demographic characteristics were assessed on index date. Comorbidities, laboratory values , and medication use (cardiovascular and antiglycemic agents) were assessed during the 365-day baseline period.Cardio-kidney events and their predictors were evaluated separately in the study population during the follow-up period. These included CV hospitalization , kidney hospitalization defined by CKD diagnosis, and AKI hospitalization. Treatment failure was also evaluated during follow-up, defined as the occurrence of discontinuation of SGLT2i or switch from SGLT2i to another T2D medication class; or addition of another T2D medication class not used in baseline; or initiation of insulin  and medians  were reported for continuous characteristics. Baseline medication use of patients was described according to proportion of patients with at least one dispensation of a drug of interest. Event rates of each outcome per 1000 person-years (PY) were reported, and 95% confidence intervals (CIs) were estimated using Poisson regression with a Normal approximation. For the rate calculations, the numerator consisted of the total number of first occurrences in the population and the denominator included the total person-time (in years) from 1 day after the index date to the date of the outcome or the end of follow-up.p values were reported with a pre-specified alpha (ɑ) level of 0.05. Backward selection methods were used to identify a subset of covariates associated with each outcome , the provider being a general practitioner or internist [HR 2.79 ], and the number of outpatient encounters [HR 1.02  per additional encounter]. The risk also increased significantly with baseline evidence of heart failure, hyperkalemia, respiratory failure, and depression, as well as the baseline use of loop diuretics  events per 1000 PY, captured over a mean follow-up time of 293.5 (SD 330.0) days. AKI hospitalization risk significantly increased with being a Medicare beneficiary [HR 1.66 ], having baseline evidence of atrial fibrillation [HR 2.74 ], PVD [HR 1.63 ], or cancer excluding NMSC [HR 1.77 ], and the use of loop acting diuretics  days.N = 4802) was attributed to SGLT2i discontinuation or a switch from SGLT2is to another antidiabetic drug class. One-third (31.1%) of treatment failure events were due to the addition of another antidiabetic drug class to therapy, which was not previously used in baseline  events per 1000 PY over an average of 361.5 (SD 366.0) days of follow-up. The reason for treatment failure in more than half (63.6%) of all treatment failure events in follow-up ] and non-significantly with outpatient facility providers [HR 1.31 ]. In contrast, the risk of treatment failure was significantly decreased with baseline use of statins [HR 0.9 ], GLP1ra [HR 0.8 ], basal insulin [HR 0.79 ], or concurrent use of both [HR 0.77 ]  related to SGLT2is.Among our study population, very few patients were at a late stage of CKD (stages G4 or G5), while a high proportion of patients had mild to moderate decreased eGFR (CKD stage G3) at the time of SGLT2i initiation, conforming with indications during the study period for this drug class. During follow-up, we observed high cardio-kidney events rates, particularly in patients with moderate to high CV risk, or prior CV comorbidities, such as atrial fibrillation and PVD; or patients with evidence of frequently reported side effect, such as hyperkalemia, or depression , 22. AddOur results reflect physician adherence with current drug recommendations for SGLT2i initiation in kidney impaired T2D patients . SGLT2isThe discontinuation rates found in our study population were slightly higher than existing research on discontinuation of SGLT2i among T2D patients , 25, whiUltimately, the residual risk, combined with the observed high treatment discontinuation rates of SGLT2is, reveals suboptimal treatment in a significant proportion of this vulnerable population and suggests the need for additional cardio- and renoprotective interventions . The cliOur study had several limitations. First, administrative claims data carries a potential for misclassification of patients’ diagnoses, since the presence of a diagnosis code may not indicate the presence of a disease, but a rule out code in some instances. To address this limitation in identifying DKD, validated algorithms for identification of T2D patients from inpatient, outpatient, and prescription claims, as well as two laboratory values indicating kidney disease to identify CKD patients, were used. Nonetheless, DKD can only be accurately defined by histopathologic screening of the kidney . Second,Our study demonstrated a high unmet need with high rates of cardio-kidney outcomes among patients with DKD treated with SGLT2is in clinical practice and high rates of SGLT2i treatment failure. Patients with high baseline CV risk and the presence of certain conditions, such as atrial fibrillation, PVD, and heart failure, were at higher risk for cardio-kidney events and might particularly benefit from further treatment options. Further research is needed to assess the potential relationship between adverse events and SGLT2i treatment failure.Additional file 1: Table S1. Definitions of all variables used or explored in this study. Table S2: Overall Multivariate Time Dependent Assessment of Factors Associated with Treatment Failure among SGLT2i initiators with DKD and stratified by insurance. Table S3: Adverse Events of Interest over Follow-upAdditional file 2: Figure S1. CV Hospitalization outcome among subgroups. Figure S2. Renal Hospitalization among subgroups. Figure S3. AKI Hospitalization among subgroups. Figure S4. Treatment Failure among subgroups