This cohort study investigates the association of early physician follow-up with readmission among patients hospitalized with acute myocardial infarction, congestive heart failure, or chronic obstructive pulmonary disease. Is early physician follow-up after discharge associated with 30- and 90-day readmission rates among patients hospitalized with acute myocardial infarction (AMI), congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD) in Canada?In this retrospective cohort study of 450 746 patients with AMI, CHF, or COPD, among individuals with CHF or COPD, those who had early follow-up had lower rates of unplanned readmissions at 90 days. Among patients with COPD, those with early follow-up had lower rates of COPD-related readmissions at 90 days, and among patients with CHF, those with early follow-up had lower 90-day mortality.These findings suggest that early follow-up in conjunction with a comprehensive transitional care strategy for hospitalized patients with medically complex conditions coupled with ongoing effective chronic disease management may be associated with reduced 90-day readmissions. A better understanding of the association between early physician follow-up after discharge and adverse outcomes among hospitalized patients may inform interventions aimed at reducing readmission for common chronic conditions.To assess whether hospitalized patients with early physician follow-up after discharge had lower rates of overall and condition-specific readmissions within 30 days and 90 days of discharge.This cohort study was conducted among Ontario, Canada, adults with first admission for acute myocardial infarction (AMI), congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD) during 2005 to 2019. The exposure was follow-up visit with a primary care physician or relevant specialist within 7 days of discharge. Cox proportional hazards models were used to compare patients with vs without early follow-up, adjusting for sociodemographic factors and comorbidities, weighting by propensity score–based overlap weights. Data were analyzed from January through July 2021.Primary outcomes were 30-day and 90-day readmissions, cardiac readmissions  for patients with cardiac conditions, and COPD-related readmissions for patients with COPD. Mortality at 30 days and 90 days was a secondary outcome. All percentages reported in Results are unweighted.The study cohort comprised 450 746 patients, including 198 854 patients with AMI, 133 058 patients with CHF, and 118 834 patients with COPD; the median (IQR) age was 66 (56-77) years for AMI, 78 (68-85) years for CHF, and 73 (64-81) years for COPD, and there were 64 339 (32.35%) women, 62 575 (47.03%) women, and 59 179 (49.80%) women, respectively. There were 91 182 patients (45.85%), 56 491 patients (42.46%), and 40 159 patients (33.79%), respectively, who received an early follow-up visit. Overall, patients with early follow-up had higher rates of collaborative care  and visits to a specialist within 30 days . Those with early follow-up had lower 90-day readmission rates among patients with CHF  and among those with COPD . Among patients with COPD, those with early follow-up had lower 90-day COPD-related readmission rates , and among patients with CHF, those with early follow-up had lower 90-day mortality rates . There were no significant benefits at 30 days or for patients with AMI.These findings suggest that early follow-up in conjunction with a comprehensive transitional care strategy for hospitalized patients with medically complex conditions coupled with ongoing effective chronic disease management may be associated with reduced 90-day readmissions. In Canada, approximately 9.4% of patients are readmitted to the hospital within 30 days of discharge, with the highest readmission rates among patients with congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD).10 An early study11 found that early physician follow-up among patients with CHF after discharge was associated with reduced 30-day readmissions, leading to early physician follow-up becoming a standard of care.17 Early follow-up is an opportunity for clinicians to assess the patient’s condition, comorbidities, medications, and therapies; clarify discharge instructions; and develop a plan if symptoms persist.18The days immediately after hospital discharge are a period of increased risk for patients. Because of stressors and deconditioning occurring during hospitalization and lingering illness effects, optimal transitions between hospital and ambulatory sectors are key to improving health and reducing readmissions.20 There have been attempts to standardize the discharge process through medication reconciliation, patient education, communication between hospital and community clinicians, and creation of quality standards21 Other efforts have focused on building integrated health care systems in Ontario and the US for treating patients with high levels of need by reorganizing health delivery and payment systems to incentivize coordinated care across hospitals and clinicians, engagement of multidisciplinary teams of primary care and specialists across sectors, and promotion of collective accountability.26Good hospital-community transitions may be associated with decreased medication errors, adverse drug events, and readmissions.Our objectives were to assess whether hospitalized patients in Ontario with acute myocardial infarction (AMI), CHF, or COPD who had physician follow-up within 7 days after discharge had lower rates of readmission at 30 and 90 days given that these patients have medically complex conditions, often have unrelated comorbidities, and may be cared for by multiple physicians. We reasoned that 30-day readmissions likely reflect transitional care while 90-day readmissions capture ongoing chronic disease management, although both are a necessary part of care for patients with medically complex conditions.STROBE) reporting guideline for observational studies.This cohort study used data from ICES, which is a prescribed entity under Ontario’s Personal Health Information Protection Act (PHIPA). Section 45 of PHIPA authorizes ICES to collect personal health information without consent for the purpose of analysis or compiling statistical information with respect to management, evaluation, or monitoring of the allocation of resources to or planning for all or part of the health system. Projects that use data collected by ICES under section 45 of PHIPA and use no other data are exempt from research ethics board review. Use of the data in this project is authorized under section 45 and approved by the ICES Privacy and Legal Office. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology  admission for AMI, CHF, or COPD to an Ontario acute care hospital between April 1, 2005, and December 15, 2019, restricting the population to adults aged 20 to 105 years. We excluded patients who died before discharge and patients who were admitted from or discharged to long-term care, complex continuing care, or rehabilitation because our study context was integration between hospital and community sectors. To reliably assess comorbidities, we excluded patients who were ineligible for Ontario health care during the prior 3 years. We created an index episode of care beginning at initial admission and ending at final discharge, incorporating transfers. We lastly excluded patients who died or were readmitted for any cause within 7 days of discharge among those who survived to discharge but were otherwise eligible  to allow a window of opportunity to be seen by a physician .The exposure was an ambulatory visit or telephone call with a primary care (PC) physician  or relevant specialist within 7 days of discharge. Relevant specialists were cardiologists for AMI and CHF, respirologists for COPD, and general internal medicine specialists for all cohorts.27 In post hoc analyses, we restricted analyses to frail elderly adults (ages ≥75 years), low-income groups (lowest 3 income quintiles), patients with any comorbidity, and rural patients to investigate whether early physician follow-up had a differential association among these subgroups with increased risks.Patients were followed up for readmissions and mortality for 90 days after index episode discharge date. Primary outcomes were 30-day and 90-day unplanned all-cause and condition-specific readmission after index admission discharge. Cardiac readmission was defined as readmission for AMI, CHF, or angina. For COPD, we reported readmission for COPD or a COPD-related condition. Mortality was a secondary outcome. Planned subgroup analyses assessed whether findings differed by sex, recency (2005-2012 vs 2013-2019), or length of index hospital stay  because readmission risk is associated with LOS.29; visit with relevant specialist within 30 days; medication reconciliation within 30 days of discharge  for hospital admissions, procedures, and transfers, which includes the most responsible diagnosis for LOS, secondary diagnosis codes, comorbidities present upon admission, complications occurring during the hospital stay, and attending physician identifier; Ontario Health Insurance Plan for physician billings, which includes diagnosis codes and procedures and location of visit; Ontario Drug Benefit for medication reconciliation and outpatient drug prescriptions for individuals older than age 65 years; and Registered Persons Database for patient demographic information and deaths. PC models were grouped as family health teams (FHT) , non-FHT models (blended fee-for-service or blended capitation models), or no usual PC physician.31 results suggest the validity and reliability of Ontario’s health administrative data. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision Canada (ICD-10-CA) diagnosis codes and Canadian Classification of Interventions procedure codes are reported in eTable 2 in the 32Cause of admission was determined using the most responsible diagnosis, excluding complications occurring during the index hospital episode. Comorbidities were identified using secondary DAD diagnosis fields. Previous study34 PS, defined as the probability of receiving vs not receiving an early follow-up visit, was estimated separately for each cohort using multivariable random-effects logistic regression and included covariates associated with receipt of an early follow-up visit.36 Covariates included age group , sex, condition-specific comorbidities at admission ,30 admission for the same condition in the previous 5 years, and individual Charlson comorbidities in the previous 5 years. PS models for AMI and CHF also included history of CHF or angina in the previous 5 years (AMI) and history of AMI or angina in the previous 5 years (CHF). The PS model for COPD also included the presence of another chronic respiratory disease at admission (eTable 5 in the 35We used propensity score (PS)–based overlap weights to create cohorts that were balanced across baseline characteristics.33 Overlap weights give larger weights to patients who have a high probability of receiving either exposure, targeting patients who have the greatest overlap in observed covariates and are therefore most in equipoise and downweighting patients in the extremes of the distribution, the reverse of inverse probability treatment weights.34 Overlap weights achieve perfect balance for covariates included in the PS and produce the smallest standard errors among all balancing-weight approaches.39Each patient was then weighted according to the patient’s overlap weight, defined as the probability of being assigned to the opposite exposure group based on PS.40 We used cause-specific competing risk models to analyze readmissions, treating mortality as a competing risk.41 We controlled for covariates included in the propensity model, as well as year of discharge, discharge physician specialty, cardiac revascularization (coronary artery bypass graft surgery or percutaneous coronary intervention) during index admission or in the previous 5 years (AMI), and receipt of implantable cardioverter defibrillator or permanent pacemaker in the previous 3 years (CHF).38 Statistical tests were 2-sided and performed at the 5% level of significance. Analyses were performed using SAS Enterprise Guide version 7.15 on SAS statistical software version 9.4.5 (SAS Institute).42 Data were analyzed from January through July 2021.We used Cox proportional hazard regression models, weighting by overlap weights, to estimate adjusted hazard ratios (aHRs) between patients who did vs did not receive an early follow-up visit and included a robust variance estimator to account for weighting.A total of 450 746 patients, including 198 854 patients with AMI, 133 058 patients with CHF, and 118 834 patients with COPD, were eligible for inclusion in the study . The medPatients who received a 7-day physician follow-up visit were more than 2-fold as likely to receive collaborative care  within 30 days  and up to 43% more likely to see a relevant specialist within 30 days  compared with patients without a 7-day follow-up. They were more likely to receive medication reconciliation  and be prescribed evidence-based medications within 90 days  . PatientAmong patients with CHF and COPD, those with 7-day follow-up had fewer readmissions within 90 days  compared with those without 7-day follow-up . Among pThis population-based retrospective cohort study found that early follow-up with a PC physician or relevant specialist was associated with fewer readmissions for patients with CHF or COPD, fewer COPD-related readmissions for patients with COPD, and lower mortality for patients with CHF, all within 90 days of discharge, but that there was no demonstrable benefit at 30 days or for patients with AMI. Less than half of patients discharged from an Ontario hospital after an admission did not see a physician within 7 days, and the percentages did not change over 15 years despite the importance of early follow-up.This study’s strengths are the large population-based cohort examining outcomes after early physician follow-up across 3 serious conditions. The study was conducted in a single-payer health care system with few financial barriers to care, used rigorous methods, and included comprehensive measures of health care use, outcomes, and performance on factors associated with process.43The finding that there were no associations at 30 days may be associated with study patients being healthier than the overall discharged patient population because we excluded 6.13% of patients with AMI, 6.85% of patients with CHF, and 6.10% of patients with COPD who died or were readmitted within 7 days of discharge. It may take more than 30 days for the occurrence of outcomes associated with interventions begun at the 7-day follow-up visit. Several factors may explain the small effect sizes. Patients in groups with and without 7-day follow-up received high levels of evidence-based care, including medications, home care, and testing, and had high continuity of care with their usual PC physicians, and most patients not seeing a physician within 7 days had a visit within 14 days, which may have attenuated associations. It is also possible that patients may require follow-up earlier than 7 days. Randomized clinical trials are underway to evaluate whether early (72-hour) cardiology follow-up, risk stratification, and systematized outpatient care can reduce readmissions among patients with CHF who present to the emergency department.46 findings suggest that care including a multilevel discharge planning approach and care coordination in predischarge , postdischarge , and transitional settings may be optimal and associated with reduced readmissions and patient improvement. Meta-analyses48 of randomized clinical trials of patients with CHF found that comprehensive discharge planning with postdischarge support, multidisciplinary heart failure–management clinics, structured telephone support, and nurse home-visiting programs was associated with reduced readmissions and mortality.Most importantly, early physician visits are only 1 component of a large set of collaborative efforts required for better patient care. In our study, patients with early follow-up also had higher rates of collaborative care, visits with a relevant specialist, guideline-directed medical therapy, and medication reconciliation, and patients with CHF had higher rates of cardiac functional assessment and evaluation for myocardial ischemia, all of which may have been associated with improvement, suggesting that early physician visits may provide the opportunity to develop a plan of care and ongoing chronic disease management. AMI care pathways may also be more standardized and responsive to acute management than those for chronic diseases like CHF and COPD. Systematic review49 Guidance and tool kits have been developed to address multiple chronic conditions, including by providing appropriate medication management and care integration, while optimizing quality of life.50Reasons for readmission are multifactorial. In our study, the rate of all-cause readmissions was 2-fold that of condition-specific readmissions, which suggests that these patients may have also had unrelated comorbid conditions. Multimorbidity is associated with increased risk of adverse events and requires a multidisciplinary approach to care.51 have found comparable results. In Ontario, early physician follow-up of patients with CHF after discharge from the emergency department was associated with lower readmission rates and reduced mortality at 90 days, although the decrease in mortality was not statistically significant. Patients with CHF who had US Medicare and were discharged from hospitals with higher rates of physician follow-up within 7 days had lower risk of 30-day readmission,52 but this was not true among patients with AMI.53 Among patients with COPD who had US Medicare and had a follow-up physician visit within 30 days of discharge, there was a reduced risk of 30-day readmission.54 A randomized clinical trial of patients with CHF across 10 Canadian hospitals55 found that after a transitional care intervention, including physician follow-up within 1 week of discharge, the composite outcome of readmission or emergency department visit within 30 days was lower , although this difference was not statistically significant.Other studiesThis study has several limitations. A lack of clinical data prevented us from understanding the care patients received, including the content and quality of physician visits and the extent of communication between discharge and community physicians or PC physicians and specialists. As in all studies using administrative data, our data on patient clinical presentation were limited to recorded diagnoses. Thus, findings may be biased owing to lack of information on unmeasured risk factors, such as smoking status, disease severity, adherence to recommendations, self-efficacy in disease management, and social risk. Additionally, our findings are limited to Ontario and so may not generalize to other jurisdictions; however, given Ontario’s size and diversity, these findings may be likely to reflect trends in the rest of the country.These findings may have implications for performance measurement and practice improvement. Early postdischarge physician visits may be important to maximize the reduction in adverse events associated with treatment for patients with medically complex conditions. However, these visits need to be part of a comprehensive transitional care strategy coupled with ongoing effective chronic disease management encompassing care coordination among multiple sectors of the health care system and providing comprehensive, patient-centered care that addresses coexisting illness. Early physician follow-up and readmission rates did not change in 15 years, despite performance measurement and reporting, suggesting the need to better develop, implement, and evaluate comprehensive models of care that address factors associated with readmission, along with implementation strategies associated with improvement.


Drug-drug interaction is one of the causes of adverse drug reactions. Generally, drug-drug interaction is common in multidrug therapy. Diabetic patients, particularly due to associated comorbidities tend to have various drug-drug interactions due to the effect of multiple drugs. The objective of this study was to find out the prevalence of drug-drug interactions in diabetic patients.It was a descriptive cross-sectional study that was conducted among previously diagnosed diabetic patients visiting the outpatient department of medicine at a tertiary care hospital between March 2021 and August 2021. Ethical approval was taken from the institutional review committee (Ref no: 030-076/077). Data was collected from diabetic patients presenting to the outpatient department of medicine using a preformed self-constructed questionnaire. Convenient sampling was done. Statistical Package for Social Sciences version 16 and Microsoft Excel were used for data analysis. Point estimate at 95% confidence interval was calculated along with frequency and proportion for binary data.The prevalence of drug-drug interaction between hypoglycemic and non-hypoglycemic medication was seen in 56 (44.1%)  of the patients out of which at least one drug-drug interaction was seen in 48 (37.8%) of the patients.Our study showed the prevalence of drug-drug interactions in diabetic patients to be higher than other studies done in similar settings. Based on the severity, we observed two types of drug-drug interactions; close monitoring drug-drug interactions and minor drug-drug interactions. Multidrug therapy is seen among diabetic patients having numerous comorbidities.The objective of the study is to find the prevalence of drug-drug interactions between hypoglycemic and non-hypoglycemic medications in diabetic patients.It was a descriptive cross-sectional study conducted among previously diagnosed diabetic patients visiting the outpatient department of medicine at Nepal Medical College and Teaching Hospital. The study was commenced from March 2021 to August 2021 for 6 months. Ethical approval was taken from the NMCTH (Ref no: 030-076/077). Written informed consent was taken from each patient. Diabetic patients with comorbidities who are exposed to at least two drugs (one hypoglycemic and other nonhypoglycemic) and wish to participate in the study were included. Diabetic patients who were admitted in the ward, patients who were on monotherapy with hypoglycemic drugs, drug-drug interactions among hypoglycemic medication, and interactions among non-hypoglycemic medications were excluded in this study. Drugs not included in the Medscape database were also excluded.The sample size was calculated as follows,2 × p × q / e2n = Z2 × 0.5 × (1-0.5) / 0.092  = 1.96  = 119where,n= required sample size,Z= 1.96 at 95% Confidence Interval (CI),p= prevalence taken as 50% for maximum sample size,q= (1-p)e= margin of error, 9%The required sample size will be 119 for the study. However, 127 patients were studied and the sampling method used was convenience sampling.5 for various drug-drug interactions and entered in SPSS 16 for descriptive statistical analysis. Medscape contains a separate tool for detecting DDIs known as a multi-drug-drug interaction checker tool. The drugs were entered into the tool to identify potential DDI and classified them based on severity as contraindicated, serious , significant , use with caution, monitor closely, and minor (non-significant interaction).6Data on patient's details and medications profile was collected from the outpatient department (OPD) of medicine by the researchers themselves by interviewing individually through the preformed self-constructed questionnaire. Pretesting was done in 10% of the sample population. The questionnaire was modified as per subject expert. Reliability of the questionnaire was maintained. Self-reported sociodemographic details, diagnosis, comorbidities, and different medications were noted by the investigator. The drug names were entered in the Medscape drug-drug interaction checker toolData entry and analysis was done using the Statistical Package for the Social Sciences version 16. Point estimate at 95% CI was calculated along with frequency and percentage for binary data.The data was collected by interviewing 127 patients who visited the outpatient department of medicine. The prevalence of drug-drug interaction between hypoglycemic and non-hypoglycemic medication was 56 (44.1%)  of the patients out of which at least one DDI was seen in 48 (37.8%) of the patients. Out of a total of 56 patients, 22 (39.28%) patients were males and 34 (60.71%) patients were females.The Medscape tool for checking drug-drug interaction classified the drug-drug interactions observed in our study into two categories: monitored closely and minor .The commonly used medications for the management of diabetes were metformin (85.8%), glimepiride (26.8%), and insulin (18.9%). The common nondiabetic medications used for the management of various comorbidities associated with diabetes were amlodipine (33.10%), atorvastatin (29.10%), and losartan (26.80%) .7 DDI is characterized as a clinical event that occurs when the effect and/or toxicity of a drug are altered by the presence of another drug. The result of DDI may be positive (enhanced effectiveness) or negative , they are generally unpredictable and undesirable in pharmacotherapy.4 We observed drug-drug interaction between hypoglycemic and nonhypoglycemic medication in 44.1% of the patients. Among the 44.1% of the patients, most of the drug-drug interaction was single drug-drug interaction (37.8%) i.e. one hypoglycemic agent having drug-drug interaction with one non-hypoglycemic drug. Most of the drug-drug interactions that were observed in our study required close monitoring while few drug-drug interactions were minor (non-significant interaction). DDI that require close monitoring demonstrate that the specified agents may interact with each other in a clinically significant manner. The benefits of concomitant use of these two medications usually outweigh the risks. An appropriate monitoring plan should be implemented to identify potential negative effects. Dosage adjustments of one or both agents may be needed. DDI that were minor or non-significant indicate that the specified agents may interact with each other, but there is little to no evidence of clinical concern resulting from their concomitant use.7The study aimed to identify potential drug-drug interactions (DDI) between hypoglycemic and nonhypoglycemic medications in diabetic patients with comorbidities. Drug-drug interactions (DDIs) are defined as two or more drugs interacting in such a manner that the effectiveness or toxicity of one or more drugs is altered on administration of the other.5 Metformin when given along with thyroxine decreases the effects of metformin by pharmacodynamic antagonism. It can lead to hypoglycemia on withdrawal of thyroxine.5 Metformin when given along with enalapril increases toxicity of metformin by unspecified mechanism. There is increased risk for hypoglycemia and lactic acidosis.5 Glimepiride when given with aspirin increases the effect of glimepiride by plasma protein binding competition leading to the risk of hypoglycemia.5 Insulin when given along with telmisartan increases the effect of insulin by pharmacodynamic synergism.5 Insulin when given along with losartan increases the effect of insulin by pharmacodynamic synergism.5 Repaglinide when given along with atorvastatin increases toxicity of atorvastatin i.e. Increased risk of myopathy.5 Metformin when given along with furosemide decreases the effect of furosemide while furosemide increases the effect of metformin by unspecified interaction.5 Metformin when given along with hydrochlorothiazide decreases the effect of metformin by pharmacodynamic antagonism and hydrochlorothiazide will increase the level of metformin by competing for renal tubular clearance.5 Glimepiride when given along with hydrochlorothiazide decreases the effect of glimepiride by pharmacodynamic antagonism.5 Metformin when given along with budesonide decreases the effects of metformin by pharmacodynamic antagonism.5Drug-drug interaction between metformin-amlodipine, metformin-thyroid hormone was common (>10%) while drug-drug interactions between metformin-enalapril, glimepiride-aspirin, insulin-telmisartan, insulin-losartan, repaglinide-atorvastatin, metformin-furosemide, metformin-hydrochlorothiazide, glimepiride-hydrochlorothiazide, and metformin-budesonide were less common (<10%). Metformin when given along with amlodipine decreases the effects of metformin by pharmacodynamic antagonism. It can lead to hypoglycemia on withdrawal of amlodipine.We also observed that metformin, glibenclamide, and insulin were among the common hypoglycemic medications that were used for the management of diabetes. They were also the common medication to have a drug-drug interaction with other medications that were prescribed for comorbid conditions associated with diabetes. We observed amlodipine (33.10%), atorvastatin (29.10%), losartan (26.80%), and rosuvastatin (23.60%) as common medication used for management of common comorbidities like hypertension (55.90%), hyperlipidemia (52.8%), and hypothyroidism (13.4%).13 In such conditions one cannot assume that the effect of the single drug would remain the same when it is combined with the others. Some interactions can produce toxicity or inhibit the drug's efficacy or therapeutic benefit. In another study conducted by Dobrica EC concluded that polypharmacy should be an area of serious concern as diabetic patients received more drugs than their non-diabetic counterparts and were exposed to more drug-drug interactions.14 Drug-drug interaction should always be considered when adverse effects are seen. A study concluded that potential drug-drug interaction should be carefully investigated.4 Another study also reported that in a survey conducted among 1601 subjects, 46% had at least one clinically significant drug-drug interaction and 10% of those interactions were considered as highly serious.15 The drug-drug interaction may be pharmacokinetic (the delivery of the drug to its site of action is hampered by other drugs) or pharmacodynamic (response of the drug target is modified by the second drug). The common drug-drug interaction observed in our study was mostly pharmacodynamic interaction. Although not analyzed in this study but interaction of food with the drug also increases the risk of a food-drug interaction.16 The drug-drug interactions that were observed in our study need to be monitored closely. Some of the drug-drug interactions were minor or non-significant interactions. We did not observe any life-threatening, serious, or significant drug-drug interaction in our study. A study conducted by Sankar V et al17 had screened 50 prescriptions out of which nine drug-drug interactions were between hypoglycemic and non-hypoglycemic medication17 which was approximately 18%. In another study conducted by Prado M et al interviewed 1517 individuals reported 119 drug-drug interactions between hypoglycemic and non-hypoglycemic medication4 which is approximately 7.8%. These records indicate that drug-drug interactions were much higher in our study.The drugs are often used in combination to achieve a synergistic or additive action. Moreover, multidrug therapy is used when multiple disease conditions have to be treated. A study conducted by Indu R et al concluded that diabetic patients suffer from several comorbid conditions due to which the level of multidrug therapy was high.17 reported the drug-drug interactions between various hypoglycemic and non-hypoglycemic drugs. The interactions between the drugs were as follows: glibenclamidediclofenac, glibenclamide-ranitidine, glibenclamidehydrocortisone, glimepiride-budesonide, glimepiride-aspirin, metformin-budesonide, insulin-aspirin, insulin-levofloxacin, and insulin-metoprolol. The study had reported cases of infection in diabetic patients following which antibiotics were used.17 In our study, patients have not reported the use of antibiotics therefore we have not come across such drug-drug interaction between hypoglycemic medication and antibiotics. In another study conducted by Prado M et al reported drug-drug interaction between glibenclamide-hydrochlorothiazide, glibenclamideaspirin, insulin-aspirin, metformin-propranolol, metformin-atenolol, metformin-enalapril.4 In our study, drug-drug interaction between metformin and amlodipine (27.6%) was the commonest. A study that was conducted on rabbits concluded that amlodipine causes hyperglycemia in normal rabbits and its use with metformin increases the hypoglycemic effect of metformin. Therefore, it should be used cautiously in diabetic patients.18 Similarly, another common interaction (>10%) seen in our study was between metformin and thyroxine. Metformin enhances the effect of thyroxine which is to increases blood glucose.19 This can lead to decreased efficacy of metformin. Other drug-drug interactions that were observed in our study were less common and some were non-significant. A study conducted by Upadhyay DK et al, reported that metformin was the anti-diabetic drug with the greatest risk of DDI and the most common drug-drug interaction observed was between metformin and enalapril. Metformin was also found to have a drug-drug interaction with atenolol and ranitidine.2 Antidiabetic drug gliclazide was found to have DDI with atenolol while glibenclamide was found to have DDI with atenolol and aspirin.2 Contradicting to the above study, another study conducted by May M concluded that metformin has very low interaction potential but caution should be taken when other drugs that impair the renal function are used. However, incretin mimetic  and sodium-glucose co-transporter-2  inhibitors comprise of very low interaction potential and are therefore recommended as an ideal combination partner from a clinical-pharmacological point of view. A study conducted by Sheen A concluded that inhibitors of sodium-glucose cotransporter-2 were not influenced by concomitant administration of other glucose-lowering drugs or cardiovascular agents commonly used in type 2 diabetes.20The study conducted by Sankar V et al9 Another limitation is the selection of patients. Diabetic patients who were admitted in the ward or even diabetic patients who had come for dialysis were not enrolled in this study which is a source for potential bias. However, the inclusion of dialysis patients might not represent usual diabetic patients. Another limitation of this study was that drug-drug interaction between two hypoglycemic drugs was not included as its use is intended for additive or synergistic action.We came across certain limitations in this study. The soul of this study is the Medscape drug interaction checker tool. Although Medscape is a popular application as well as a popular webpage among health professionals, some drugs were not listed in Medscape database but prescribed to the patients. Interaction between such drugs and hypoglycemic medication could not be looked into. Also, interaction between drugs that patients could not recall at the time of the consultation was missed. The advantage of Medscape is that it is a free application. Another application for monitoring drug-drug interaction is IBM Micromedex drug interaction.Our study showed the prevalence of drug-drug interactions in diabetic patients to be higher than other studies done in similar settings. Based on the severity, we observed two types of drug-drug interactions; close monitoring drug-drug interactions and minor drug-drug interactions. We did not observe any serious or life-threatening drug-drug interaction between hypoglycemic and non-hypoglycemic medication.


Dendrimers are highly branched macromolecules tailorable at will to fulfil precise requirements. They have generated a great many expectations and a huge number of publications and patents in relation to medicine, including in relation to personalized medicine, but have resulted in very poor clinical translation up to now. As clinical trials are the first steps in view of developing new compounds for  medicine, this review focusses on the clinical trials carried out with dendrimers. Many of these clinical trials have been recently posted (2020–2022); thus, only very few concern phase 3. The safety and efficiency of essentially two main types of dendrimers, based on polylysine and polyamidoamide scaffolds, have been assessed up to now. These dendrimers were tested with the aim of treating mainly bacterial vaginosis, cancers, and COVID-19. Dendrimers  are a spClinicalTrials.gov” (accessed on 2 August 2022) [ClinicalTrials.gov (accessed on 2 August 2022) (USA) and in part from clinicaltrialsregister.eu (European Union) [It must be said that these synthetic macromolecules, which do not resemble anything natural or biological, arouse a certain number of fears. The very first dendrimers were synthesized in 1978 , and then Union) . It shouThe very first large dendrimers synthesized and patented were based on poly-L-lysine , and the®, has been tested in at least 13 clinical trials for assessing first the safety, tolerability, PK, and acceptability of vaginal administration. The first conclusion of a randomized, double-blind, placebo-controlled, dose-escalation trial conducted in 2004 at the Royal Adelaide Hospital  was that VivaGel® applied vaginally once daily for 7 days at concentrations of 0.5% to 3% was safe and well-tolerated in women, with no evidence of systemic toxicity or absorption [® was generally well-tolerated and comparable with the placebo although there was a higher incidence of low-grade related genital adverse effects, as in the previous study [A second example of poly-L-lysine dendrimer was proposed by Starpharma  as an active ingredient in gels against sexually transmitted diseases, as it has antiviral properties and is able to block bacteria when formulated as a mucoadhesive gel . It is bsorption . Anothersorption . It was sorption . Anotherus study . Anotherus study . The tolus study  and its us study .®.The antiviral effects were early assessed, in particular against genital herpes  and against HIV  . However® is now available in different countries under different names, as gel against BV, and also as lubricant for condoms, as it has been shown in laboratory studies to inactivate HIV, herpes simplex virus (HSV), and human papillomavirus (HPV) [TM [VivaGelus (HPV) . A recenHPV) [TM . Tests wHPV) [TM .2100 molecules and 32 molecules of a dual Bcl-2/Bcl-xL inhibitor (anti-tumor agent) named AZD4320, attached through the linker X = N-Me . Other different linkers have been used to modify the release rate of the drug   . The sloIn view of these interesting pre-clinical results in mice, at least three clinical trials are presently underway with AZD0466. NCT04214093 (30 December 2019) is a phase 1, first in human study in patients with advanced solid tumors, lymphoma, multiple myeloma, or hematologic malignancies. NCT04865419 (29 April 2021) is a phase 1  and phase 2 (AZD0466 in combination with the drug voriconazole) study in patients with hematological malignancies. NCT05205161 (25 January 2022) is a phase 1/phase 2 in patients with non-Hodgkin lymphoma.The same concept of dually functionalized polylysine dendrimers was also applied to the docetaxel-dendrimer conjugate SPL8783, tested in the phase 1 clinical trial EudraCT Number 2016-000877-19 (13 July 2016) in patients with advanced solid tumors . Another188Re  dendrimers  are the l trials . Neverthl trials . All werIt was shown that this compound OP-101 has anti-inflammatory and anti-oxidant activity in microglia cells . The firA second example of PAMAM hydroxyl dendrimers stochastically functionalized concerned the grafting of known drugs suitable for treating diverse eye diseases. A recent paper published this concept using triamcinolone-acetonide as drug conjugated to the dendrimer and tested in models of age-related macular degeneration . However18F, for specific positron emission tomography (PET) imaging and radiotherapy, with the aim of detecting inflammatory sites or tumors [A third example of PAMAM-hydroxyl dendrimer concerns the stochastic grafting of a few radionuclides, in particular r tumors . This spAnother clinical trial with PAMAM dendrimers is NCT04262076 (10 February 2020), which concerns the use of a PAMAM dendrimer with Pulpine for the remineralization of carious-affected dentin. However, the generation and the type of surface functions of the PAMAM dendrimer used are unknown in this study carried out by the Al-Azhar University (Egypt). No result has been posted.®. Trial number NCT05208996 (26 January 2022) is a phase 1 clinical trial to assess the safety and tolerability of siCoV/KK46 in healthy volunteers. Trial number NCT05184127 (11 January 2022) is a phase 2 clinical trial to assess the efficacy and safety of MIR 19® via 14 days of treatment of hospitalized patients with symptomatic moderate COVID-19.Two clinical trials against COVID-19 are currently on-going, both based on the same cationic peptide dendritic structure having lysine as branching elements, named KK-46, whose structure is shown in ® ; thus, most of them concern phase 1 assays. The only dendrimer under phase 3 clinical trials is the polylysine used as an active ingredient of VivaGel® B to trea®RD concerns the simultaneous detection of 10 bacteria commonly involved in respiratory infections. DendrisCHIP®OA allows the detection of 10 bacteria responsible for deep and osteoarticular infections [®DP is dedicated to the identification of fungi involved in dermatophytosis, whereas DendrisCHIP®SD is dedicated to the identification of 10 pathogens  responsible for sexually transmitted infections [However, dendrimers have already found application in personalized medicine to enhance the efficiency of diagnosis tools . They arfections . Dendrisfections .per se or as carriers of drugs should have generated breakthrough in medicine, including in personalized medicine. However, this is not the case, with two exceptions that are bioassays for the specific detection of diseases and gels for the local treatment of bacterial vaginosis. The hope of expanding the number of dendrimers actually used in human health lies in the phase 1 clinical trials carried out recently and on others that are planned. One can cite in particular ongoing and future assays against influenza A and B virus; against COVID-19 [The huge number of dendrimers already synthesized and the even larger number of dendrimers that could be synthesized as active COVID-19 ; againstCOVID-19 ; and to COVID-19 ,63. The


As hypothesised, adaptive actions increased alongside reductions in depression and anxiety symptoms from baseline to post-treatment. Treatment effects were consistent when the intervention was provided with regular weekly therapist support or with optional weekly therapist support, and some  types of adaptive actions had a mediating effect on change in depressive symptoms. The present findings support further work examining adaptive actions as a mechanism of change in psychotherapy, as well as the utility and scalability of Internet-delivered treatments to target and increase adaptive actions with the aim of improving mental health.Adaptive actions, including healthy thinking and meaningful activities, have been associated with emotional wellbeing. The Things You Do Questionnaire—21 item (TYDQ-21) has recently been created to measure the frequency of such actions. A study using the TYDQ-21 found that adaptive actions increased across Internet-delivered therapy for symptoms of depression and anxiety, and higher TYDQ-21 scores were associated with lower psychological distress at post-treatment. The current study examined the relationships between adaptive actions and psychological distress among adults ( An important body of work has previously demonstrated that our thoughts and behaviours, that is, “actions”, can have a significant impact on our psychological health ,2,3. MorThe Things You Do Questionnaire—21-item (TYDQ-21) was developed to capture adaptive  actions most strongly associated with psychological health . Across In an extension of this work, a subsequent study examined whether the frequency of these actions changed during Internet-delivered psychological treatment and whether these changes were associated with changes in symptoms . InterneNotably, all participants in that trial received optional therapist guidance—that is, guidance was provided based on participant preference and clinical need. As previous meta-analyses have identified that psychological treatments with ongoing, regular therapist support are more effective than self-guided treatments ,18, the The primary aim of the current study was to extend previous psychometric validations of the TYDQ-21 in Australian samples ,12 to a The secondary aim of the current paper was to examine the contribution of increased frequency of adaptive actions to reductions in psychological symptoms across treatment using mediation. Although not to be taken as conclusive evidence of causality, mediation analyses are an important step towards determining whether a particular variable is a mechanism of treatment change ,24.Observational data were collected as part of routine care at the Online Therapy Unit, funded by the Saskatchewan government to provide transdiagnostic ICBT to Saskatchewan residents. The collection of observational data received ethics approval from the University of Regina, and informed consent was obtained from all participants involved in the study.www.onlinetherapyuser.ca, accessed on 1 September 2022) and completed an initial assessment via REDCap. Eligibility was then confirmed during a brief telephone screening interview. Participants were considered eligible if they: (1) were 18 or older; (2) endorsed symptoms of depression and/or anxiety; (3) were Saskatchewan residents and would be in the province for at least 8 weeks; (4) reported access to a computer and the Internet; (5) provided a medical contact for emergency purposes; and (6) had interest in and consented to ICBT. Exclusion criteria included: (1) recent hospitalization, high crisis service involvement, or high risk of suicide; (2) severe alcohol or drug problems; (3) concurrent weekly mental health treatment; (4) seeking help for a different mental health condition; or (5) self-reported medical condition which would interfere with participation. Ineligible applicants were referred to community mental health services in their area.Participants were recruited between 17 December 2020 and 16 December 2021. Interested persons were directed to the study website (n = 1114) who reported clinically significant symptoms on the depression or anxiety measure (as defined below), completed pre-treatment questionnaires, and began Lesson 1. Participant flow is provided in During the recruitment period, 2127 individuals expressed interest and completed an initial assessment, of which 1874 applicants met initial inclusion criteria. The telephone interview was completed by 1660 applicants, and 1435 individuals were accepted into the trial. The current study utilized a subsample of these participants . This 8As the current study examined the influence of therapist guidance level on treatment outcome, only those participants with clinical symptoms were included in the current sample to eliminate potential confounds. The level of therapist guidance depended on the participant’s preference, whereby participants chose between ‘optional support’ and ‘standard support’ (see  for furtThings You Do Questionnaire 21-item (TYDQ-21). The 21-item version of the TYDQ-21 described in Study 2 of Titov et al.  was usedPatient Health Questionnaire 9-item (PHQ-9). The PHQ-9 is a measure of DSM-IV-congruent depressive symptoms over the past two weeks ,28. The Generalized Anxiety Disorder 7-item (GAD-7). The GAD-7 is a measure of general anxiety symptoms over the past two weeks, designed to detect DSM-IV-congruent generalized anxiety, social anxiety, and panic disorder . The GADConfirmatory factor analyses were conducted in IBM SPSS Amos version 26 and tested the five-factor structure of the TYDQ-21 identified by Titov et al. . Model fn = 1114) was used for treatment outcome and adherence analyses. Missing data at post-treatment were handled using multiple imputation, accounting for baseline symptom severity and lesson completion [d effect sizes and 95% confidence intervals were calculated based on estimated marginal means. One-way ANOVAs were used to compare depression and anxiety symptoms between participants based on the frequency of adaptive actions .All other analyses were conducted using IBM SPSS version 27. The intent-to-treat sample . Supplementary analyses did not find a significant interaction between time, therapist support level, and TYDQ21 scores for change in depression symptoms (p = 0.59) or anxiety symptoms (p = 0.52). Given the similarities in the two treatment samples, and given the opportunity to increase statistical power, the two therapist support groups were treated as a single group in mediation analyses. Prior to analysis, all variables were log-transformed to ensure that mediation models reflected the percentage change in the dependent variable which was explained by a one-unit percentage increase in the predictor variable . Log-trression, . In the p > 0.05). Approximately half were in paid employment (52.1%), and not currently taking medication for their mental health (57.3%), with no differences between guidance conditions (ps > 0.05).Participant demographics and symptom severity are presented in In the standard support group, therapists sent an average of 8.35 (SD = 1.61) emails and received an average of 3.01 emails (SD = 2.73) per participant. In the optional support group, therapists sent an average of 4.37 (SD = 2.22) emails and received an average of 2.26 emails (SD = 3.00) per participant.CFAs were used to test the goodness-of-fit of the five-factor model of the TYDQ-21 identified by Titov et al.  at pre-tp > 0.05).Participants completed an average of 3.90 (SD = 1.41) lessons in the standard support group and 4.08 (SD = 1.28) lessons in the optional support group, with no significant difference . Consistent with this main effect, there were significant differences in TYDQ-21 scores at pre-treatment (p = 0.021) and post-treatment (p = 0.04) according to guidance. There was no difference in how TYDQ-21 scores changed from pre- to post-treatment based on guidance condition .TYDQ-21 Total Score. Overall, participants reported a 29% increase  in the frequency of adaptive actions measured by the TYDQ-21 from pre- to post-treatment , Meaningful Activities (d = 0.50), and Goals and Plans (d = 0.48). Smaller effect sizes were observed for Healthy Habits (d = 0.27) and Social Connection (d = 0.28). Across timepoints, those participants who received standard support reported lower scores on Healthy Thinking , Meaningful Activities (p = 0.03), and Goals and Plans (p = 0.045), but not Healthy Habits or Social Connections , whereby scores were significantly different between support conditions at pre-treatment (p < 0.001) and post-treatment (p < 0.001). There was no difference in treatment outcome according to guidance level .Depressive Symptoms (PHQ-9). Participants experienced a significant reduction in depressive symptoms from pre- to post-treatment .Those participants who reported engaging in adaptive actions over half the days each week, on average, reported lower depressive symptoms. This was the case for the TYDQ-21 total score and each of the five domains  and post-treatment (p = 0.001). There were no differences in change in anxiety symptoms over the course of treatment based on the level of support received . Participants in the standard support group reported an average reduction of 40%, while those in the optional support group reported an average reduction of 44% in anxiety symptoms, with similar within-group effect sizes (d range 1.01–1.08).Anxiety Symptoms (GAD-7). Participants reported a significant decrease in anxiety symptoms on the GAD-7 from pre- to post-treatment irrespective of guidance condition .As was observed for depressive symptoms, those participants who reported engaging in adaptive actions over half the days each week, on average, reported lower anxiety symptoms. This was the case for the TYDQ-21 total score and each of the five domains  in depressive and anxiety symptoms as well as small to medium increases  in the frequency of adaptive actions. Then, adaptive actions were examined as a mediator of treatment change in depressive and anxiety symptoms—we found that some, but not all, types of daily actions mediated change in depressive symptoms from baseline to post-treatment, but not anxiety symptoms. Taken together, these findings suggest that changes in the frequency of adaptive actions across treatment were related to improvements in psychological distress, and that change in adaptive actions were not related to the amount of therapist support received.The frequency of adaptive actions captured by the TYDQ-21 increased across treatment, as anticipated. However, a novel finding of the current study was that similar increases in adaptive actions were observed whether participants received regular therapist guidance or only the option of guidance. This was consistent with past work examining the role of therapist guidance in Internet-delivered therapy which report no differences in treatment adherence or outcomes between participants who choose to receive optional or standard guidance ,21,22. NThe current study also found that participants who reported engaging in adaptive actions most of the time  reported lower depressive and anxiety symptoms. This pattern of findings was consistent for the total TYDQ-21 score as well as each of the five domains of actions, potentially suggesting that all domains of adaptive activity  are associated with emotional wellbeing. Unexpectedly, the magnitude of change in adaptive actions was smaller than previously seen in a different study which examined changes in the TYDQ-21 during the same ICBT course. For example, Bisby et al.  reportedA mediating effect of Healthy Thinking, Meaningful Activities, and Goals and Plans were found on the change in depressive symptoms from pre- to post-treatment. This effect was not observed for anxiety symptoms, suggesting that the adaptive actions captured by the TYDQ-21 domains are more relevant for reductions in depressive, rather than anxiety, symptoms during treatment, at least in this sample. An increase in the frequency of the adaptive actions captured by the Healthy Thinking domain is consistent with the use of key strategies taught in cognitive therapies, such as challenging unhelpful/unrealistic thoughts and treating oneself in a fair and reasonable way ,44. SimiThe current finding of a mediating effect of increased adaptive actions on treatment-related change in depressive symptoms is supportive of further experimental investigations into this relationship. Several converging lines of evidence are required to determine if a given variable is a mechanism of treatment change, including mediation, experimental manipulation, a dose–response relationship, and temporality ,49,50. FThe findings of the current study should be considered in light of several limitations. First, by virtue of being an observational study from a routine care digital mental health service, no control group was included in the current study. As a result, we could not determine whether the increase in frequency of adaptive actions was treatment-related or would have occurred in the absence of treatment. Future research examining change in adaptive actions over time in a no-treatment control group is warranted. Second, mediation analyses were only conducted on the completer sample due to constraints with data analysis. Considering that 33% of post-treatment data were missing , and missingness is more likely in participants who do not complete treatment or report high baseline symptoms , it is pOverall, it is important to note that this study used data collected during 2021, and is likely influenced by the ongoing impacts of the COVID-19 pandemic in Canada at that time. As the current study was conducted within a digital mental health service, data collection was not impeded due to the pandemic. However, the data collected during this period do appear to have been somewhat impacted. Indeed, the within-group changes in depression symptoms were smaller in the current sample than previously observed using the same treatment program ,41,51. TThe present findings speak to the potential for adaptive actions as a mechanism and as a target in psychological treatment. Such actions could form the basis of a brief and self-guided treatments focused on promoting the frequency of these actions to reduce psychological distress, and particularly depression. There is substantial public health potential for developing interventions and treatments with simple, practical messages such as increasing how often individuals perform actions during the week—including doing things they find meaningful and fun, and practicing taking perspective. This approach mirrors that which has been taken by governments worldwide to promote physical health, such as eating fruit and vegetables and participating in regular exercise. Future work which develops and rigorously evaluates such treatments within randomised controlled trials offers both theoretical and pragmatic value.


Overall, the average TTT in the trial cohort (N = 114) was 10.1 days faster (p < 0.05) than the control (N = 114), leading to a 25% reduction in TTT. For patients treated based on EGFR positivity, the mean TTT was 16.8 days faster (p < 0.05) in the trial cohort (N = 33) than the control cohort (N = 28), leading to a 48% reduction in TTT. Conclusion: Using the Idylla EGFR test as part of the molecular testing repertoire in advanced-stage NSCLC patients could significantly reduce TTT. Introduction: Patients with advanced-stage non-small cell lung cancer (NSCLC) may benefit from a short time-to-treatment (TTT). Predictive biomarker testing is performed prior to treatment, as recommended by various international expert consensus bodies. Genetic testing is more time-intensive than immunohistochemistry (IHC) and commonly contributes to prolonged TTT. For epidermal growth factor receptor-positive patients (EGFR+), further genetic testing may not be required due to the mutual exclusivity of actionable mutations. Methods: The trial cohort (N = 238) received both BC Cancer NGS panel (Oncopanel) and Idylla EGFR testing. Data were also collected for a control cohort (N = 220) that received Oncopanel testing. For each patient, the time that the lab received the sample, the time taken to report the NGS and Idylla tests, the time of first treatment, and the final treatment regimen were recorded. Results: A concordance frequency of 98.7% (232/235) was observed between the Idylla and NGS panel. The lab turnaround time (TAT) was faster for the Idylla test by an average of 12.4 days (N = 235,  EGFR, ALK, ROS1, BRAF, MET, NTRK, KRAS, etc.) and PD-L1  days) than the Oncopanel lab TAT (N = 235) (The lab TAT of the Idylla EGFR test was faster by an average of 12.4 days (N = 235) . The meap < 0.05, 95% CI:  days), a 25% reduction in TTT , a 48% reduction in TTT (p = 0.89) was observed between patients treated based on PD-L1 ≥ 50% in the trial (N = 19) and control (N = 24) cohorts  was 30.7 days, whereas the control (N = 114) cohort was 40.8  of EGFR-positive patients, treatment was initiated after receiving the Idylla test result but before the Oncopanel result. The TTT was 8.2 days on average for these patients. In patients who had a PD-L1 TPS of ≥ 50%, only 5% (1/19) had treatment initiated after the Idylla test result and before the Oncopanel results.EGFR test to improve TTT in advanced-stage NSCLC patients, and thus, patient outcomes. Our findings of a 98.7% concordance frequency between the Idylla EGFR test and the Oncopanel adheres with the previously established concordant rates of 94% to 100% [EGFR test is positive, no further genetic testing would be required because all positive Idylla results were correct and EGFR mutations are, in practice, mutually exclusive with other oncogenic drivers [EGFR mutation is negative would Oncopanel testing be required, for two specific reasons. First, the Idylla EGFR test covers a limited variety of EGFR mutations and does not detect rarer EGFR mutations that would otherwise be detected by more comprehensive EGFR gene coverage (performed by NGS testing). Second, it is important to perform genetic testing to check for other targetable oncogenic drivers if EGFR is negative. The EGFR mutation rate of the Canadian NSCLC population is about 15%; however, we observed an overall EGFR positivity rate that is closer to 20% [These results shed light on the possibility of using an ultra-rapid  to 100% ,24,25,26 drivers ,16,17,18EGFR testing as compared with the Oncopanel allows for a faster completion of molecular testing in EGFR-positive patients. Our data demonstrate that the Idylla test was, on average, 12 days faster than the NGS Oncopanel results, which is similar to the finding of a study by Petiteau et al. where Idylla EGFR testing was, on average, 9 days faster than NGS [EGFR mutations, the pre-test probability of harbouring an EGFR-mutation-positive tumor is higher in certain patient populations such as non-smokers. The true value of ultra-rapid EGFR testing in these patient subsets is the prompt identification of a targetable mutation and subsequent quick match to the appropriate treatment.The lower laboratory TAT for ultra-rapid than NGS . Therefothan NGS . AlthougThe use of one common source of tumor material for both tests by means of evaluating extracted DNA allowed for a side-by-side comparison of both assays. This would not be possible in instances where NGS testing is frequently conducted on extracted material while Idylla testing is performed directly on FFPE tissue. This also helps quantify and determine optimal Idylla load amounts based on tumor content and cellularity. Furthermore, this enables best triage of tumor material to the appropriate assays without the risk of under- or overloading.EGFR testing are an important addition to the limited body of literature on this topic. There is an impactful decrease in TTT in the EGFR-mutation-positive patients, a population that makes up a large portion of advanced-stage NSCLC patients [EGFR-mutation-positive patients is what drove the decrease in TTT in the overall cohort because, in both cases, a larger density of patients has a TTT of approximately 10 days in the trial group. The decrease in TTT has the potential to improve patient outcomes but further studies on this topic are warranted. Furthermore, the high proportion (17/33) of patients in the trial group who received EGFR-TKI treatment with genetic results only from the Idylla test, implies that many oncologists trust the result of the Idylla test and consider an EGFR single-gene test sufficient to initiate treatment. However, when patients were EGFR-negative, rarely did clinicians treat without Oncopanel results (14/205). It was expected that the patients who were treated based on being PD-L1-high would have a lower TTT if they had received Idylla EGFR testing; however, this was not observed. The oncologists treating patients in the trial cohort were likely waiting for the Oncopanel results for other oncogenic drivers prior to initiating treatment. This is reflected in that only one (1/19) of the PD-L1-high patients in the trial cohort were treated before Oncopanel results were received. Another reason for this observation may be that unlike EGFR-TKI, which is a per oral treatment that patients can begin immediately after a treatment decision is made, initiation of immunotherapy relies on hospital scheduling for IV administration and has more factors affecting TTT. Despite a homologous TTT between the trial and control groups in our study, using the Idylla EGFR test can rule out treating EGFR-mutation-positive patients with immunotherapy. This is critical because there can be severe consequences of administering immunotherapy in EGFR-mutation-positive patients due to the suboptimal efficacy of immunotherapy in this population and the toxicities associated with switching to EGFR TKI treatment [EGFR-negative did not benefit from Idylla EGFR testing as these cases would follow the routine workflow. Since there are still other targetable alterations that could be detected by the Oncopanel, it is likely that clinicians found it best to wait for Oncopanel results prior to starting therapy.Our findings of an improved TTT using ultra-rapid patients . It is lreatment ,29,30,31EGFR assays help quickly identify patients that can start on targeted therapy without significantly altering testing workflow. For the patients that tested negative by single-gene testing, a more comprehensive testing strategy can be pursued from the same source tumor material. Alternatively, prompt single-gene tests can be performed at the originating sites/hospitals and those that tested negative can then be sent over to the central lab for additional/expanded testing. Both strategies could theoretically lead to faster and cheaper lung cancer molecular testing on average, with potential TTT savings. Based on our results, benefits would most likely be in EGFR-positive patients. Nevertheless, if comprehensive testing is delayed while waiting for EGFR single-gene testing results, EGFR-negative patients may have a longer TTT. The main pitfall of this approach is that in many instances for lung cancer specimens, the source material is scant permitting only one test. In this scenario, it may be prudent to do an assay with broader coverage so that material is not depleted by attempting the ultra-rapid EGFR assay.There is value to a tiered-testing approach in a setting where a centralized genomics laboratory does mutational testing for lung cancer from many different sites or hospitals. As outlined, ultra-rapid EGFR-positive and PD-L1 ≥ 50% cohorts were small. While oncologists use patient demographics to determine the likelihood of a patient being EGFR-mutation-positive to expedite treatment, this study did not include patient demographics as part of the analysis. Our study utilized a historical control group, causing our comparison to be prone to confounding factors such as change in clinical or laboratory practices. Additionally, cohorts were studied during the COVID-19 pandemic; therefore, outcomes may have been impacted by policy changes at our institution.When stratifying patients to analyze TTT, the sample sizes of the Future studies may investigate how the improved TTT affects patient outcomes. Similar studies should be conducted on different oncogenic drivers as TKI treatment becomes available for more NSCLC-causing mutations. More research is needed to analyze the cost-effectiveness of using Idylla single-gene testing. Each cartridge of the Idylla EGFR test is expensive, but with certain workflows it may save costs.EGFR testing as part of the molecular testing repertoire in advanced-stage NSCLC patients with lung AC reduced their TTT. Genetic testing with the Idylla EGFR test may be sufficient if a positive result is obtained. Follow-up testing by a more expansive panel is needed if negative. Furthermore, this study demonstrates that, on average, TTT from molecular testing initiation can be reduced by 48% in EGFR-positive NSCLC patients. As cartridge-based molecular testing expands to hotspots in other genes and targets, a large population of NSCLC patients may see a meaningful reduction in TTT. This study shows how this paradigm could work for EGFR mutations, the most prevalent actionable biomarker.Using the Idylla platform for ultra-rapid


To evaluate the association between cumulative fentanyl dose during neonatal intensive care and 5-year neurodevelopmental and socioemotional outcomes in very preterm infants.p < 0.1). Linear regression models related outcome measures to the log of cumulative fentanyl dose adjusted for covariates.Patient demographics and clinical factors during the perinatal and neonatal course were collected in 84 patients born between 23- and 30-weeks gestational age (GA). Cumulative fentanyl dose during neonatal intensive care was calculated. Developmental testing at age 5 years included the Wechsler Preschool and Primary Scale of Intelligence Full-Scale Intelligence Quotient, Third Edition, Clinical Evaluation of Language Fundamentals-Preschool, Second Edition, Movement Assessment Battery for Children, Second Edition (MABC-2), and Shape School Assessment. Socioemotional outcomes were assessed via caregiver's responses on the Child Behavior Checklist/1.5-5 (CBCL/1.5-5.5) and Social Responsiveness Scale, Second Edition (SRS-2). Covariates were identified on bivariate analysis (p < 0.01). Cumulative fentanyl dose did not correlate with composite intelligence quotient, language, or executive function. The Clinical Risk Index for Babies score, log of mechanical ventilation, inotrope, and anesthesia duration, and log of cumulative midazolam and hydrocortisone dose were also associated with MABC-2 scores (p < 0.1). Cumulative fentanyl dose was not associated with composite MABC-2 scores on multiple linear regression. Higher cumulative fentanyl dose was associated with decreased socioemotional problems based on caregiver's response on CBCL/1.5-5.5 t-scores driven by fewer symptoms of depression. The McMaster Family Assessment Device general functioning scale score, maternal age, GA, log of total parenteral nutrition days, patent ductus arteriosus requiring treatment, and log of inotrope hours were also associated with CBCL/1.5-5.5 t-scores (p < 0.1). Cumulative fentanyl dose (p = 0.039) and family dysfunction score (p = 0.002) remained significant after controlling for covariates on multiple linear regression.Higher cumulative fentanyl dose was associated with lower composite motor scores on bivariate analysis (Cumulative fentanyl dose during neonatal intensive care did not correlate with 5-year motor, cognitive, or language outcomes after controlling for other variables. Fentanyl dose was associated with caregiver reported total socioemotional problems on the CBCL/1.5-5.5 on multivariate modeling. Additional long-term studies are needed to fully elucidate the safety of fentanyl in very preterm neonates. Very preterm infants are uniquely susceptible to the sensation of pain due to immature descending pain modulatory pathways in comparison to more mature ascending pain perception pathways . NeonataMorphine is a natural opioid; its administration has been associated with clinically significant hypotension in very preterm infants, which may contribute to an increased risk of cerebral ischemia resulting in IVH and PVL. Large randomized controlled trials have assessed the short- and long-term neurological outcomes of morphine administration in mechanically ventilated very preterm infants reporting subtle and mixed long-term outcomes –12. In oFentanyl is a synthetic opioid that is hypothesized to have a lesser propensity for hypotension in very preterm infants , 18. FenPreclinical models utilizing neonatal mice have demonstrated that prolonged opioid exposure significantly reduces brain volume with long-term consequences including motor delays . Long-teThis observational cohort study included very preterm infants born between 23- and 30-weeks gestational age (GA) that were enrolled at birth following admission to the NICU at St. Louis Children's Hospital between April 2007 and June 2010. Infants with known congenital anomalies, cardiorespiratory failure (>80% FiO2 for 6 h and/or ≥2 inotropic drugs), or severe IVH (Grade III and IV) in the first 24 h of life were excluded. Cumulative doses of all analgesia and sedatives from birth until term equivalent age or prior to NICU discharge were collected from the electronic medication administration records. Patient demographics , perinatal course , and neParticipants underwent developmental assessments of cognition, language, motor skills, and executive function at 5 years of age conducted by highly experienced psychometricians at the Washington University Intellectual and Developmental Disabilities Research Center. Child socioemotional problems were assessed through questionnaires completed by the child's primary caregiver. Contact with families of all surviving children was attempted, regardless of participation in the 2-year follow-up wave of this longitudinal study. The Wechsler Preschool and Primary Scale of Intelligence Full-Scale Intelligence Quotient, Third Edition (WPPSI-III) was used to assess cognition . The Clip < 0.1 was used to identify potential covariates on bivariate analysis to more comprehensively assess the complement of factors that may contribute to neurodevelopmental and socioemotional outcomes in very preterm infants. Multivariate linear regression models were utilized to relate outcome measures to the log of cumulative fentanyl dose, after adjusting for potential covariates with p < 0.05 utilized to identify significant associations. For multivariate models, collinearity diagnostics were reviewed and all variance inflation factor (VIF) and tolerance values were found to be within or close to the acceptable range (VIF <5).Statistical analyses were performed in SPSS 25 . Variables with skewed distribution were log transformed for statistical analysis. Association between log of cumulative fentanyl dose during the NICU stay and neurodevelopmental and socioemotional outcomes were assessed using linear regression models. The composite scores from the WPPSI-III, CELF-P2, and MABC-2 were used to assess cognitive, motor, and language outcomes, respectively. The CBCL/1.5-5.5 and SRS-2 were assessed as both composite and subscale scores. The Shape School Task was assessed via subscale scores. Potential covariates [maternal age, antenatal steroids, GA, birthweight, sex, 5-min APGAR score, CRIB score, log ventilation days, log TPN days, patent ductus arteriosus (PDA) requiring treatment, necrotizing enterocolitis, retinopathy of prematurity, chronic lung disease, IVH on cranial ultrasound using the Volpe grading system , PVL on Eighty-four patients  were assessed at 5-year follow-up between August 2012 and March 2016 . Patientp < 0.1)  . Birth wp < 0.1) .Socioemotional outcomes were obtained for 79 children . Cumulative fentanyl dose did not correlate with autistic traits on the SRS-2 t-score, or either subscale including the Social Communication and Interaction t-score and RBR t-score. Cumulative fentanyl dose was associated with total socioemotional problems on caregiver reported CBCL/1.5-5 t-scores, driven primarily by higher levels of depressive symptoms in patients with low or no fentanyl exposure . AdditioThis is the first report of a cohort of very preterm children evaluating the association between cumulative neonatal fentanyl dose and neurodevelopmental and socioemotional outcomes at early school age. At 5 years of age in our cohort, cumulative fentanyl dose during NICU care was associated with motor delays on bivariate linear regression, but significance was not maintained on multivariate analysis. No other neurodevelopmental outcomes were associated with cumulative fentanyl dose. Cumulative fentanyl dose and family dysfunction were associated with total socioemotional problems via caregiver report on the CBCL/1.5-5.5, which remained significant after adjusting for covariate factors.While inadequate analgesia in very preterm infants may have neurological consequences, opioids used to treat pain are not without risk. Opioid exposure during neonatal intensive care of very preterm infants has been associated with reduced brain growth and impaired long-term developmental outcomes. One previous study has reported a negative impact of morphine infusion during invasive mechanical ventilation on neurological outcomes at 8–9 years of age . PreclinLong-term follow-up of motor performance is vital in cohorts of children born prematurely. Motor performance assessments have been validated in the first 2 years of life, but task performance can be affected by unintentional or abnormal motor signs commonly observed in very preterm infants in this age range. Furthermore, transient early dystonia may not preclude the development of typical long-term motor function in premature children . In thisCumulative fentanyl dose during the NICU stay was associated with motor delays in a dose-dependent manner on bivariate linear regression at 5 years of age in our cohort. However, it is important to understand the limitations of the observational nature of this study with the implicit challenges of the co-associations with cumulative fentanyl dose that may have neurological impact. This was apparent when the bivariate findings did not remain significant following adjustment for the many other covariates. On multiple linear regression accounting for the effects of identified covariates, the association between cumulative fentanyl dose and reduced composite MABC-2 scores was attenuated. In fact, no additional covariate factors that were associated with reduced composite MABC-2 scores in bivariate analyses maintained statistical significance in multiple linear regression analysis. These findings highlight the multifactorial and complex processes, that are often co-bedded, underlying neurodevelopmental outcomes in very preterm infants. Our findings are consistent with the current literature regarding neonatal fentanyl exposure and long-term neurodevelopmental outcomes , 24, 25.Cumulative fentanyl dose was independently associated with decreased socioemotional problems via caregiver report on the CBCL/1.5-5.5, and this finding persisted after adjusting for covariate factors. Very preterm infants are at a greater risk of developing socioemotional problems compared to term born infants, particularly in the domains of inattention-hyperactivity, anxiety, emotional disturbance, and social difficulties . MorphinCumulative fentanyl dose was not independently associated with full scale intelligence quotients, language ability, or executive function skills at 5 years in our cohort which is consistent with previous findings , 24, 25.Our study is limited by its observational nature and relatively small size. Additionally, we recognize that current pain management protocols in the NICU have evolved since the time in which patients were enrolled, which may limit the generalizability of our findings. While we were able to detect correlations, we cannot directly attribute cumulative fentanyl dose causatively to our findings. We acknowledge that pain scores were not collected as part of routine clinical care in our NICU at the time of fentanyl administration, so we are unable to assess the appropriateness of fentanyl administration in the setting of pain. Furthermore, cumulative fentanyl dose may have been a surrogate marker for the severity of illness and could be confounded by indication. Therefore, we do not feel the results of our study should encourage or discourage utilization of fentanyl in clinical practice and refer readers to previous topical reviews . Our patCumulative fentanyl dose at term corrected age did not correlate with 5-year neurodevelopmental outcomes when adjusting for other variables. Cumulative fentanyl dose and family dysfunction were associated with caregiver reports of socioemotional problems on composite CBCL/1.5-5 Total Problem scores, which persisted after adjusting for covariate factors. Large, prospective studies and/or randomized controlled trials of analgesic and sedative exposure with long-term follow-up are warranted to better understand the safety of analgesia in very preterm infants.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Washington University Institutional Review Board Washington University School of Medicine in St. Louis. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.CS, TI, CR, and CM designed the study. RL and CM organized the database. KM performed the statistical analysis and wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.Support by the National Institute of Health , the Intellectual and Developmental Disabilities Research Center at Washington University (NIH/NICHD P50 HD103525), and the Doris Duke Charitable Foundation.The 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.