Potential adverse drug event (PADE) is a medication error with the potential to cause associate degree injury however that does not cause any injury, either due to specific circumstances, chance, or as a result of the error being intercepted and corrected. This study aimed to assess the incidence, contributing factors, predictors, severity, and preventability of PADEs among hospitalized adult patients at Jimma Medical Center. A prospective observational study was conducted among hospitalized adult patients at a tertiary hospital in Ethiopia. Logistic regression was performed to identify factors predicting PADE occurrence. P-value < 0.05 was considered for statistical significance. A total of 319 patients were included. About 50.5% of them were females. The mean ± SD age of the participants was 43 ± 17.6 years. Ninety-four PADEs were identified. Number of medications , anticoagulants , anti-seizures , anti-tuberculosis , and Elixhauser comorbidity Index ≤ 15  were independent predictors of PADEs occurrence. About one-third of patients admitted to the hospital experienced PADEs. The third Global Patient Safety Challenge seeks the commitment of health-care workers, regulatory agencies, researchers, pharmaceutical corporations, and higher institutions. Its goal will be to “reduce the level of severe, avoidable harm related to medications by 50% over 5 years, globally”2.The World Health Organization (WHO) announced the third Global Patient Safety Challenge as “medication without harm”3. Medication errors are a significant health burden causative to over half of all ADEs among hospitalized patients4. Globally, the price related to medication errors has been 42 billion $/year, not considering lost wages, productivity, or health care prices5.National coordinating council for medication error reporting and prevention defines a medication error as “any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional and patient”6. It has been reported that PADEs constitute over 17 million emergency department visits and 8 million hospital admissions per year in the United States7. The incidence of PADEs was estimated to be 13.8 per hundred admissions in Saudi Hospital8.Potential adverse drug event (PADE) is a medication error with the potential to cause associate degree injury however that does not cause any injury, either due to specific circumstances, chance, or as a result of the error is intercepted and corrected9.Among the 52 medication errors reported in Morocco, 53.8% result in clinically significant potential harm and 46.2% result in actual patient harm. According to this report, there were 7.7 medication errors for a thousand patient-days. The preventable event occurrence was higher in the ordering (71.1%), followed by the administration (21.2%) and transcribing stage (5.7%)10. Of all medication errors, the prescribing and monitoring were the most common error stages10. Seventy-one percent of the potentially harmful medication error occurrence was found to be at the ordering stage of the medication-use process11. Non-psychiatric drugs were three times as likely to cause ADEs compared to psychiatric drugs10.The incidence of medication errors per thousand patient-days ranges from 7.7 to 40.913. Medication administration errors in a University Hospital in Egypt, about 5531 errors were observed with 2.67 errors per observation and the overall error rate was 37.68%14.The total prescribing error rate was 40.9% with 1.3% significant errors, in Nigeria. Duration of treatment omission and abbreviations which can lead to serious errors was the most common15, 40 per 100 orders16 and 52.5%17 were reported. Wrong drug combination , wrong frequency (15.5%17), omission errors (42.89%16) and wrong dose  were the common medication ordering errors. The medication administration errors were found to be 51.8%; wrong timing (30.3%) and missed doses (18.3%) were the common administration errors18. The errors ranged from 16.8 to 28.6% for non-intravenous medications and from 20.6 to 33.4% for intravenous medications19.In our country, medication error incidence of 56.4%Hospitalized patients are more likely exposed to polypharmacy. This, in turn, is a concern for PADEs. Patients who have PADEs are likely to have a longer hospital stay, reduced quality of life, increased overall health care cost, and an increased risk of morbidity and mortality. To our knowledge, in Ethiopia, there is no prospective observational study that followed patients admitted in the ward to identity the incidence, severity, preventability of PADEs. Therefore, this study aimed to determine the incidence, contributing factors, predictors, severity, and preventability of PADEs among hospitalized adult patients at Jimma Medical Center.20.The study was conducted among hospitalized patients at the medical ward of Jimma Medical Center (JMC), the only medical center in the south–west part of the country with 800 active bedsA prospective observational study was conducted among adult patients admitted to inpatient medical wards or units.20. PADEs during/before admission were not included in the calculated incidence.Participant's eligibility and inclusion were performed according to previous study report20. The proportion of PADE occurrence (P) = 0.525 was taken from a study done in JMC18.The sample size equals 319 was calculated based on the assumption detailed in the previous article23. Patient medical chart review, patient interview, and direct observation was performed to obtain the data20. PADEs were identified on the conditions that medication errors that can cause clinically serious harm in advance3. Drug-drug interaction was assessed as per Lexicomp drug interaction classification since Lexicomp Interactions scored highest in scope and completeness compared to seven drug information resources25. Drug-drug interaction with major severity levels; contra-indicated (avoid combination) and consider therapy modification were considered. The severity of PADEs was classified according to the National coordinating council for medication error reporting and prevention (NCCMERP) severity category modified definition21 and according to the stage in the medication use stages, they have occurred as prescribing (ordering), dispensing, administering, transcribing and monitoring. The training was given to data collectors on the data collection procedure and research objectives. Before exporting to SPSS, data was checked and cleared in EpiData to exclude ambiguous, incomplete, and erroneous data.A semi-structured questionnaire was designed by reviewing different literature for important variablesPADE occurrence.Patient-related: Age, sex, educational status, residence, marital status, occupation, cigarette smoking, and alcohol consumption. Disease-related: History of previous ADRs, comorbidity (Charlson’s comorbidity index), admission diagnosis, length of hospital stay, previous hospitalization, and previous medical condition. Medication-related: Drug category, number of drugs, traditional medicine use, and history of medication use.20. The patient’s medical chart and documents such as the progress note, laboratory result, prescriber’s orders, and drug administration chart were assessed20.In the current study, methods used for detecting PADEs include a chart review, patient interview, and direct observationStatistical Package for Social Sciences (SPSS) version 24 and Microsoft Excel (2010) were used for analysis. Multivariate logistic regression was performed to identify independent predictors of PADE occurrence. A p-value of < 0.05 was considered to be statistically significant.“PADEs incidence per 100 admissions: The total number of PADEs identified, divided by the total number of admissions; multiplied by 100”“PADEs incidence per 1000 patient-days: The total number of PADEs identified, divided by the total number of patient- days multiplied by 1,000”“PADEs incidence per 100 medication orders: The total number of PADEs identified, divided by the sum of medications ordered multiplied by 100”The outcome of the study was reported as PADEs incidence per 100 admissions, per 1000 patient-days, and per 100 medication orders; severity of PADEs; the percentage of PADEs in stages of medication use .Ethical clearance & approval was obtained from the institutional review board (IRB) of Jimma University with the reference number of IHRPGD/550/19. It was based on the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Before the start of the study, written informed consent was requested and received from the patient. Informed consent was obtained from all individual participants included in the study.26.Medication errors: “Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional and patient”3.PADE: “A medication error with the potential to cause an injury but which does not actually cause any injury, either because of specific circumstances, chance, or because the error is intercepted and corrected”Educated: Participants who had primary, secondary, or tertiary education.From a total of 319 participants, 158 (49.5%) of them were males. The mean ± SD age of the participants was 43 ± 17.6 years. Most of the participants, 225 (70.5%) were from a rural area. About 27.3% of study participants drunk alcohol and 14 (4.4%) patients had used traditional medicine. The mean ± SD and the total length of hospital stay of the patients were 17.8 ± 14.5 days and 5667 patient-days respectively. Comorbidities were determined by weighted Elixhauser Comorbidity Index (ECI) and the mean ± SD of ECI was 5.7 ± 5.8. The mean ± SD number of medications prescribed for the study participants was 4.4 ± 2 -10 codes. Most of the patients were diagnosed with diseases of the circulatory system (53%), infectious and parasitic diseases (34.5%), and diseases of the genitourinary system 28.5%). The diagnosis category most commonly associated with PADEs were diseases of the circulatory system (51.1%) and infectious and parasitic diseases (46.8%)  had a previous medical condition. Diseases of the circulatory system 88 (51.46%), infectious and parasitic diseases 48 (28.07%), and endocrine, nutritional and metabolic diseases 25 (14.62%) were the common previous medical condition of the patients , cardiovascular medicines 48.3%), gastrointestinal medicines (35.7%), and analgesics (28.2%). Medication classes most commonly associated with PADEs were antibiotics (55.3%) followed by gastrointestinal medicines (43.6%) and cardiovascular medicines (39.4)  patients had a history of medication use in the 3 months before the study period. One hundred eight patients were on medication during admission. Most of the patients were on cardiovascular medicines 79 (73.15%), antibiotics 28 (25.93%), and antiviral agents 28 (25.93%)  per 100 admissions, 16.59 (95% CI: 13.55–20.3) per 1000 person-days, and 6.74 (95% CI: 5.45–8.25) per 100 medication orders. PADEs were occurred at prescribing 63 (67%), administration 16 (17%), and monitoring 15 (16%) stages . Patients with ECI ≤ 15 were 6.2 times more likely to experience PADEs compared to patients with ECI > 15. Patients who were on anticoagulants were about 2.5 times more likely to develop PADEs than those who were not on anticoagulants . Patients receiving anti TB were 2.2 times more likely to develop PADEs than who were not on anti TB . Patients who were on anti-seizure were 22 times more likely to develop PADEs than those who were not on anti-seizures  (Table Area under the receiver operating characteristics (AUROC) = 80.2% (95%CI: 74.9%- 85.4%) Fig. .Figure 327. Health care systems should design specific programs of action for improving patient safety in each of four medication use stages, developing strategies, plans, and tools to ensure that the medication process has the safety of patients, monitoring medication-related harm, and producing a strategy for setting out research priorities2.Medication errors may occur at any medication use stages  and can result in severe harm, disability, and even death which are avoidable harm28, 16.9 (95% CI 15.7 to 18.3) per 100 admissions, 21.8 (95% CI 20.2 to 23.5) per 1000 person-days. The higher incidence rate was observed in the current study compared to 5.5 PADEs per 100 admissions reported by Bates and colleagues29.In present study, the incidence of PADEs were 29.47 (95% CI 23.8–36.06) per 100 admissions (crude rate), 16.59 (95% CI 13.55–20.3) per 1000 person-days and 6.74 (95% CI 5.45–8.25) per 100 medication orders. This is comparable with a study in Saudi ArabiaMultivariate analysis indicated that the number of medications the patient was receiving, ECI, anti-seizures, anti-TB agents, and anticoagulants were independent predictors of PADE occurrence. The ability of these variables to predict PADE occurrence was assessed using AUROC, which is 80.2% (95% CI: 74.9–85.4%); thus the model demonstrated excellent performance.30 reported an increased number of prescribed medications were significantly associated with all adverse events. Using multiple drugs concurrently, ADEs result from alterations of the pharmacokinetics parameters31.Patients who received greater than or equal to 7 medications had higher odds of experiencing PADEs among the study participants. In line with this, Diaz and colleagues32. Besides, anticoagulants have a narrow therapeutic index, and pharmacokinetics or pharmacodynamics interactions with other drugs may result in PADEs33.Anticoagulants were independently associated with the occurrence of PADEs. In anticoagulant therapy, the thrombotic and hemorrhagic risk is easily affected by factors such as age, co-morbidities, and concomitant medications. PADEs of anticoagulants are influenced by the types of anticoagulant agents, therapeutic versus prophylactic therapy, and duration of treatment34.Anti-seizures were significantly associated with the occurrence of PADEs. When other drugs combined with anti-seizures to treat intercurrent illness, there is a probability of PADEs, because anti-seizures are commonly given for prolonged time, have a narrow therapeutic window, and little alterations in their pharmacokinetics can result in toxic effects. Carbamazepine, phenytoin, valproic acid, and phenobarbital greatly alter liver enzymes and can affect the metabolism of other combined medications35.Anti-TB was also found to have a significant association with the occurrence of PADEs. Rifampin, isoniazid, and pyrazinamide are hepatotoxic and their interaction with other drugs will increase the risk of PADEs. Genetic causes, advanced age, malnutrition, high dosage, and multiple comorbidities are predisposing factors for PADEs of anti-TB agents36 noted a significant number of PADEs of antiviral agents, leading to severe PADEs. Anwikar and colleagues37 observed a highly significant association between the use of zidovudine and anemia.Patients who were receiving antiviral agents were more likely to experience PADEs than patients who were not receiving these agents. Mok and colleaguesThe incidence of PADEs was 29.47 per 100 admissions, 16.59 per 1000 person-days, and 6.74 per 100 medication orders. The most common stage of the medication use process at which PADEs occurred was at the prescribing stage. The number of medications, ECI, anti-seizures, anti-TB agents, and anticoagulants were independent predictors of the occurrence of PADEs.


Aim was to study the effect of sarcopenia on the survival in patients with HCC. 2/m2 for women and ≤50 cm2/m2 for men. we included 262 patients and were followed up for 12 months. Sarcopenia was calculated by skeletal muscle index (SMI). Sarcopenia was defined by SMI ≤39 cmpatients with sarcopenia  were older, mainly males, Child-Pugh class B and smokers. Patients with sarcopenia had lower survival than those without (10.09 vs. 11.72 months). Survival was also lower in Barcelona clinic liver cancer stage C than B and A (9.02 vs. 11.21 vs. 11.89 months). Age and sarcopenia were hazardous of mortality (p<0.05). There was statistically significant difference of serial SMI in patients without baseline sarcopenia unlike patients with baseline sarcopenia. On follow up patients with sarcopenia had higher incidence of ascites (45% vs. 20.4%), spontaneous bacterial peritonitis (21.7% vs. 11.6%), hepatic encephalopathy (28% vs. 11.5%) and bleeding (22.9% vs. 12.7%). Totally patients with sarcopenia had higher incidence of progressive HCC (39% vs. 25.5%). Sarcopenia is associated with lack of response to therapy, liver decompensation and higher mortality in hepatocellular carcinoma patients. Hepatocellular carcinoma (HCC) is a dreadful complication of the liver cirrhosis that is associated with short survival. In men, HCC is the fifth malignancy meanwhile in the women, it is the eighth malignancy .The generalized loss of both the function and the mass of muscles, is called sarcopenia. Sarcopenia may be due to aging or secondary to medical disease like liver cirrhosis . There are multiple factors that cause malnutrition and subsequent sarcopenia in patients with cirrhosis. Decreased nutrient intake is common owing to anorexia, protein restriction, disturbed conscious state and taste change. The energy metabolism is altered due to hypercatabolic state and altered metabolism for carbohydrates, proteins, and fat. Maldigestion is common. Another factor is repeated fasting with bleeding, encephalopathy and before procedures .).There are various methods for the diagnosis of sarcopenia such as the hand grip, anthropometry, bioelectrical impedance, dual-energy X-ray absorptiometry and computerized tomography (CT). In CT sarcopenia is diagnosed by measuring the skeletal muscle cross sectional at the third lumbar vertebra normalized to the height .There are various consequences of malnutrition and sarcopenia in pateints with cirrhosis. There is increased incidence of hepatic encephalopathy and decreased quality of life. Bacterial complications are common with shortened survival. The decreased physical activity predisposes to peri or post-operative complications. HCC patients with sarcopenia suffer from increased treatment induced complications and decreased overall survival. Sarcopenia affects liver transplantation badly where there is increased waitlist mortality, peri/post-operative mortality with decreased survival . A recent review article mentioned the role of sarcopenia with all the modalities of HCC treatment and the effect on the survival .The aim of the study was to assess the effect of sarcopenia on the survival in patients with HCC.Patients and MethodsThis study included 262 patients diagnosed to have HCC recently within 4 weeks without any management as regards the focal lesions. Hepatocellular carcinoma was diagnosed by triphasic CT in which the focal lesion showed arterial enhancement followed by portal and venous washout . These patients were Barcelona clinic liver cancer (BCLC) stage A through C as patients with BCLC D were excluded from the beginning and those who were willing for liver transplantation.All the patients underwent complete history taking and physical examination. The following investigations were done: liver function tests, kidney function tests, complete blood picture, INR and alfa-fetoprotein. The patients were followed up for 12 months.2) of the muscles measured by CT at level of the third lumbar vertebrate that was normalized to the height of the patient. Sarcopenia was defined by SMI ≤39 cm2/m2 for women and ≤50 cm2/m2 for men .Sarcopenia was diagnosed radiologically by the calculation of the skeletal muscle index (SMI). The SMI was defined as the cross-sectional area . These morphological changes are the mean of the right and the left short to long axis of the psoas muscle . Sarcopenia was assessed at inclusion (baseline) then after 1, 3, 6 and 12 months. At these time points patients were assessed also as regard the response to management and the occurrence of liver decompensation .The management of the hepatocellular carcinoma was determined by the decision of the multidisciplinary HCC team which included hepatologist, radiologist and a hepatobiliary surgeon. The management included liver resection, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, trans-arterial chemoembolization, oral sorafenib and the best supportive care.This study was conducted in National Liver Institute hospitals, Menoufia University, Egypt. Patients were recruited from the outpatient hepatocellular carcinoma clinic. Approval from the institutional review board was obtained and the patients signed an informed signed consent before enrollment.Statistical Analysisχ2) and Fisher exact test for categorical data analysis. Repeated measure ANOVA or Friedman test was used for testing serial changing variables. The survival as assessed by Kaplan-Meier survival. Comparison of survival curves was done by Logrank test. The Cox proportional-hazards regression was used to detect the predictors of mortality. Data were statistically analyzed using IBM® SPSS® Statistics® version 21 for Windows. Data were presented as mean ±standard deviation for normally distributed data and number (column percentage) for the categorical data. All p-values are 2 tailed where values <0.05 considered statistically significant. Comparisons between two groups were performed using the Student’s t-test for normally distributed. CHI-squared test ; age , BMI , serum bilirubin , serum albumin , CTP B , BCLC B , BCLC C  and sarcopenia .Longitudinal follow up of patients with and without sarcopeniaOn follow up of patients with and without baseline sarcopenia after 1, 3, 6 and 12 months we found that the percentages of grade 2 and 3 sarcopenia were higher in patients with baseline sarcopenia, in these different time points .2/m2) was statistically higher than the 1, 3, 6 and 12 months . On pairwise comparison of the different time points there was a statistically significant difference (p=0.001) between all of them except the value at 6 and 12 months which were comparable (p >0.005).On tracing the SMI  from the2/m2; p =0.407).In patients with baseline sarcopenia, there was no statistically significant difference between the baseline and 1, 3, 6 and 12 months (44.12 ±5.34 vs. 43.85 ±5.77 vs. 43.90 ±5.45 vs. 43.52 ±5.31 vs. 45.72 ±13.23 cm2/m2) in patients without baseline sarcopenia (52.78 ±8.32 vs. 44.12 ±5.34), (51.80 ±8.41 vs. 43.85 ±5.77), (50.34 ±8.12 vs. 43.9 ±5.45), (49.54 ±8.28 vs. 43.52 ±5.31) and (49.28 ±8.29 vs. 45.72 ±13.23).On pairwise comparison of patients with and without sarcopenia in the different time points; there was a statistically significant difference (p =0.001) with higher values  higher percentage of ascites development in the first (34.5% vs. 12.1%), third (46% vs. 23.5%) and the sixth months (58.3% vs. 22.6%). On the end of the study as shown in Patients with baseline sarcopenia had a statistically (p =0.01) higher percentage of spontaneous bacterial peritonitis in the first (10.9%vs. 0.7%), third (39.9% vs. 12.8%) and the sixth months (32.4% vs. 6.1%). On the end of the study the percentage was comparable .th months (40.7% vs. 15.9%). On the third months the percentage were comparable Patients with baseline sarcopenia had a statistically (p =0.01) higher percentage of hepatic encephalopathy in the first (13.3% vs. 1.3%), sixth (44.4% vs. 17.8%) and the 12th months (18.6% vs. 5.8%). The percentage was comparable in the first  and the sixth month .Patients with baseline sarcopenia had a statistically (p =0.01) higher percentage of upper gastrointestinal bleeding in the third (30.1% vs. 14.1%) and the 12Totally patients with sarcopenia compared to those without had higher (p =0.001) percentage of ascites (45% vs. 20.4%), spontaneous bacterial peritonitis (21.7% vs. 11.6%), upper gastrointestinal bleeding (22.9% vs. 12.7%) and hepatic encephalopathy (28% vs. 11.5%).Relationship between sarcopenia and response to treatmentPatients with baseline sarcopenia compared to those without, had higher percentage of progressive HCC despite intervention in the first , third , sixth  and the 12th months .Totally patients with sarcopenia compared to those without had higher (p =0.001) total percentage of progressive HCC (39% vs. 25.5%).HCC is an ominous complication of liver cirrhosis. It is associated with high mortality . Recently sarcopenia was found to be a risk factor for decreased the overall survival in HCC patients . In patients who underwent trans-arterial chemoembolization; the presence of baseline sarcopenia was associated with decreased overall survival  unlike other studies who did not found difference . A recent study reported that the presence of sarcopenia is associated with high mortality and does not affect locoregional therapy safety .Harimoto et al., (2013) reported that patients who underwent resection with pre-operative sarcopenia had statistically lower survival and recurrence-free survival. This was confirmed by other studies .Sarcopenia is associated with higher incidence of recurrence following surgical resection and radiofrequency ablation of HCC .In the different studies by Hiraoka et al.,(2017), Nishikawa et al., (2017) and Takada et al.,(2018) conducted on sorafenib treatment in HCC patients; about ~60% of the patients had sarcopenia. The overall survival was significantly less in patients with pretreatment sarcopenia.AFP >100 mg/dL is a predictor of sarcopenia in HCC patients who are prepared for liver transplantation . In the patients who were transplanted beyond the Milan, the HCC recurrence was higher in patients with pretransplant sarcopenia .In our study, patients with sarcopenia were older and having advanced BCLC stage. The overall survival was less in patients with baseline sarcopenia in accord with other studies  and in contrast to other studies . Moreover, the survival was higher in BCLC A patients. Patients with baseline sarcopenia had higher incidence of liver decompensation e.g. ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, upper gastrointestinal bleeding during the study.Furthermore, the baseline sarcopenia was associated with lack of response to intervention and progressive HCC.On tracing of the skeletal muscle index, we found comparable values at the different time points of the study for patient with baseline sarcopenia. In contrast, the skeletal muscle index was decreasing from the baseline in patients without baseline sarcopenia. It may be due to the fact that most treatments are not curative till now for HCC.In conclusion, Sarcopenia is associated with lack of response to therapy, liver decompensation and higher mortality in hepatocellular carcinoma patients.


To clarify whether in adults with a nonobstructive spirometry a reduced FEF25-75% is associated with a positive methacholine challenge test (MCT).  Data was collected for all the patients who had a MCT done between April 2014 and January 2020 but had nonobstructive baseline spirometry. Logistic regression was utilized to estimate the log odds of a positive methacholine test as a function of FEF25-75% and also for age, gender, BMI, FEV1, and FEV1/FVC. p < 0.001). Mean FEF25-75% was lower in MCT positive (3.12 ± 0.99 L/s) vs. MCT negative (3.39 ± 0.97 L/s) patients, p = 0.003. Logistic regression results suggest that MCT outcome is inversely related to FEF25-75%, age, and gender. Specifically, as FEF25-75% percentage of predicted value increases, the log odds of a positive MCT decrease (odds ratio (OR) = 0.90, 95% confidence intervals (CI) = 0.84‐0.96, p = 0.002). Also, as age increases, the log odds of a positive MCT decrease .  Out of 496 patients, 187 (38%) had a positive MCT. Baseline characteristics in two groups were similar except that patients with positive MCT were younger (32 ± 11.57 vs. 38 ± 13.25 years, respectively,  Reduced FEF25-75% in adults with nonobstructive spirometry can predict a positive response to MCT in younger patients. However, this relationship becomes weaker with increasing age. Asthma remains one of the most prevalent chronic respiratory illnesses and carries a high clinical and socioeconomic burden . An accuThe majority of mild asthma patients are managed in primary care facilities where bronchial challenge testing is not readily available, and simple spirometry is the only diagnostic tool at hand. This raises the question of whether other spirometry-derived parameters can help identify patients who could have airway hyperresponsiveness and would benefit from either further testing to confirm the diagnosis of asthma, or in whom a trial of treatment with inhaled corticosteroids is warranted.Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC are the usual measurements of interest in patients with obstructive airway disease. Forced expiratory flow 25–75 (FEF25-75%) is also routinely measured and reported on spirometry. It is defined as “forced expiratory flow over the middle one-half of the FVC; the average flow from the point at which 25% of the FVC has been exhaled to the point at which 75% of the FVC has been exhaled.” A reduced FEF25-75% is thought to be a marker of small airway obstruction , and theOur study is aimed at investigating whether a reduced FEF25-75% is associated with increased airway hyperresponsiveness as demonstrated by a positive methacholine challenge test, in adults with asthma-like symptoms and a nonobstructive spirogram .In this retrospective observational study, we identified and reviewed the electronic medical records of all adult patients who underwent a methacholine challenge test between April 2014 and January 2020, having presented to our respiratory clinic with asthma-like symptoms , and had at least one baseline spirometry assessment which ruled out airflow obstruction. Patients with a prior confirmed diagnosis of asthma and those with alternate diagnoses that could explain their symptoms were excluded from the study.We recorded absolute values as well as % predicted values for FEV1, FEV1/FVC, and FEF25-75% for all participants. Only the tests that met the American Thoracic Society (ATS) criteria for spirometry were included in the study, and Global Lung Function Initiative (GLI) reference values were used to determine the % predicted values. The results of methacholine challenge results were recorded as positive or negative. As per the ATS guidelines [nd and 3rd degree polynomial terms for continuous variables were all examined. Model reduction was performed in a stepwise fashion by removing interaction and higher-order polynomial terms that failed to reach statistical significant at the 0.05 level. Main effects were retained in the final model in all instances; however, all nonsignificant (p > 0.05) main effects were grand-mean centered to facilitate model interpretation. Proportions were used as descriptive statistics for categorical variables, and data are expressed as the mean ± standard deviation (SD). Comparisons of values between groups were performed by using Student's t-test, and p < 0.05 was considered statistically significant.Logistic regression was utilized to estimate the log odds of a positive methacholine test as a function of patient age, gender, BMI, FEF25-75%, FEV1, and FEV1/FVC. As a first step in the model building process, main effects, two-way interactions between clinical variables, and 2p < 0.001. There was no significant difference between the two groups in terms of BMI. Mean FEF25-75% was significantly lower in MCT positive (3.12 ± 0.99 L/s) vs. MCT negative (3.39 ± 0.97 L/s) patients, p = 0.003. This effect was more pronounced on comparison of FEF25-75% percentage of predicted values, 88.29 ± 22.05% for MCT positive vs. 100.13 ± 22.85% for negative patients, p < 0.001. Prebronchodilator FEV1 and FEV1% predicted values were not significantly different between the two patient groups. Baseline characteristics and outcomes are listed in Four hundred and ninety-six patients had a methacholine challenge test between April 2014 and January 2020 and met the inclusion criteria for the study including 186 (37.5%) men and 310 (62.5%) women. MCT was positive in 187 (38%) and negative in 309 (62%) patients. Mean age of the study subjects was 36 ± 12.97 years. Patients with positive MCT were significantly younger, mean age 32 ± 11.57 vs. 38 ± 13.25 years, respectively, p = 0.002), though the associated 2nd degree polynomial term indicates that the rate of this decrease lessens as FEF25-75% predicted values increase . Similarly, as age increases, the log odds of a positive MCT also decrease . Finally, we found that males have lower odds of a positive MCT relative to females .The final logistic regression model along with odds ratio point estimate results is provided in x-axis and y-axis represent FEF25-75% percentage of predicted value and age, respectively, while the contour lines represent the probability of a positive test.Next, the estimated log odds based on age and FEF25-75%% predicted values were transformed into probabilities. A contour graph was then constructed to show how the probability of a positive MCT changes as a function of age and FEF25-75% percentage of predicted values—see The Receiver Operating Characteristic (ROC) curve resulting from the final model is shown in Our study shows reduced midexpiratory flow rates as evidenced by a low FEF25-75% in patients with nonobstructive spirometry, but asthma-like symptoms can predict a positive response to MCT in younger patients. However, this relationship becomes weaker with increasing age. Hence, it is perhaps unsurprising that the association between FEF25-75% and asthma has been more established in pediatric than the adult populations.Boggs et al. were one of the earliest groups to look at FEF25-75% in asthmatics . In 1982The Severe Asthma Research Program (SARP) looked at 829 severe adult asthmatics and noted that FEF25-75% was an independent predictor of severe asthma symptoms after controlling for FEV1, FEV1/FVC, and demographic variables . Their r20 < 16 mg/mL). A significant moderate positive correlation between bronchial hyperresponsiveness and FEF25-75%  was noted. However, the authors did not look at differences in bronchial hyperresponsiveness based upon the age of patients. Additionally, patients with lower FEF25-75% were noted to have higher fractional exhaled nitric oxide (FeNO) levels and sputum eosinophils. In a separate study, Raji and colleagues also looked at FEF25-75% values in 234 patients with normal FEV1 and FEV1/FVC ratios with asthma-like symptoms who went for bronchial hyperresponsiveness testing [p < 0.001). However, they were unable to determine an optimal discrimination threshold of FEF25-75% that could be used as a cut-off for predicting bronchial hyperresponsiveness. Drewek and colleagues also looked at a pediatric population of 532 children aged 4-18 years and observed that those patients with a positive methacholine challenge test were more likely to have reduced FEF25-75% [Malerba et al. looked at the association between impairment in FEF25-75% and bronchial hyperresponsiveness through methacholine challenge testing in adults . They foEF25-75% . They alMost recently, Hou et al. performed a multicenter retrospective cross-sectional study of 846 Chinese adults with suspected asthma and FEV1 ≥ 80% predicted and found that FEF25-75% values were significantly lower and FENO values significantly higher in patients with a positive methacholine challenge test. Combining these two values gave an area under the curve (AUC) of 0.865 (95% CI: 0.833-0.893). They observed that the optimal cut-off for predicting a positive methacholine results to be FEF25-75% of less than 74.9% predicted in patients younger than 55 years of age and less than 62.9% in patients > 55 years of age .FEF25-75% also has certain limitations due to the fact that it is directly dependent on FVC maneuver. Hence, if the FVC is reduced due to the patient effort during the test, then the FEF25-75% will also be reduced. This error can be minimized by making sure that the patient understands the test instructions and that the ATS criteria for spirometry performance are followed and met. Secondly, the FVC and can also be reduced due to a disease process which in turn will affect the FEF25-75%. For this reason, we only included the patients without preexisting lung disease in our study .Our study is unique as it demonstrates a variable relationship between FEF25-75% and a positive MCT depending on the age of the subjects as it shows that younger patients with a reduced FEF25-75% were more likely to have a positive MCT as compared to an older patient with the same degree of midrange airflow limitation. The use of The limitations of our study include the fact that it is a retrospective one and most of the patients were of a single (Arab) ethnic group; hence, there is a need to validate our age-based threshold cut-off findings in a prospective manner and test these thresholds cut-offs in different ethnicities. Also, since most of the MCTs and the data collection was done prior to the European Respiratory Society's guidance on technical standards for bronchial challenge testing , the MCTIn conclusion, this study shows an age-related correlation between the midrange flow limitation and presence of bronchial hyperresponsiveness in adult patients, meaning that younger patients had a much higher likelihood of a positive MCT if they had reduced FEF25-75% which in turn could be a marker of undiagnosed asthma and a predictor of BHR positivity in a select group of younger patients.


D3 or complete mesocolic excision (CME) surgery has become a common surgical procedure for the treatment of colon cancer metastasis. Clinical misuse and overuse of lymph node dissection bring unnecessary burdens to patients. A detailed guidance for lymph node dissection in patients with T3 and T4 stage right colon cancer at different locations is urgently needed.A retrospective study was performed. Patients received D3 or CME surgery were divided into ileocecal group, ascending colon group, and hepatic flexure group according to the 9th edition of the Japanese Society for Cancer of the Colon and Rectum guidelines. The distributions of lymph node metastases were analyzed according to tumor infiltration depth (T stage) and tumor location.χ2 = 7.955, p = 0.019) and degree of differentiation , and terminal ileum lymph node metastasis is related to tumor location . Patients with T3/T4 hepatic flexure cancer received radical right hemicolectomy in addition to No.206 lymph node dissection.The incidence of metastases in the paracolic area (or station), intermediate area, and main  area was 38.4% (139/362), 12.7% (46/362), and 9.7% (35/362), respectively. The proportion of patients having No.206 and terminal ileum lymph nodes metastases was 7.7% (14/181) and 3.7% (9/244), respectively. No.206 lymph node metastasis is related to tumor location (Radical right hemicolectomy and No.206 group lymph node dissection are necessary for T3 and T4 stage colon cancer therapy. Selection of a reasonable surgical strategy is directly related to the incidence of surgical complications, postoperative recovery, and 5-year survival rate of patients with advanced right colon cancer , 2. The At present, complete mesocolic excision (CME) could not only remove the lymph nodes beside the colon, but also further remove the lymph nodes that feed the roots of blood vessels, increasing the rate of lymph node acquisition , 10. HowThis study was approved by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University. A total of 390 patients diagnosed with right colon cancer and performed D3 or CME surgery by the same group of colorectal surgeons in the First Affiliated Hospital of Fujian Medical University from January 2010 to December 2017 were collected, and a total of 362 cases were screened. Inclusion criteria are as follows: (1) primary stage I, II, and III right colon cancer; (2) D3 radical resection or CME + R0 resection; and (3) the number of lymph nodes submitted for each case was 12 or more. Exclusion criteria are as follows: (1) patients with multiple primary colon cancer, familial adenomatous polyposis (FAP), other malignant tumors at the same time or in the past, recurrence or metastasis after colon cancer surgery and (2) neoadjuvant therapy before surgery.Patients with T1 and T2 stages of right colon cancer were treated with D2 dissection, and patients with T3 and T4 stages were treated with D3 dissection. D3 dissection of the right colon for the treatment of ileocecal cancer included No.203 and No.213. D3 dissection and radical resection of the right colon for the treatment of ascending colon cancer and hepatic flexure colon cancer included No.203, No.213 and No.223. T3 + T4 stage hepatic flexure cancer of the colon was treated with radical right hemicolectomy, and the lymph nodes in group No.206 were included in the radical right hemicolectomy.After the operation, the surgeon in the operation team dissected the gross specimen to find, separate, and locate the lymph nodes, a small part of which was obtained by the pathologist. All the obtained lymph nodes were immersed and fixed in formalin solution, and stained with standard HE, and were identified by 2–3 experienced pathologists.The statistics and labeling of the colorectal lymph nodes and the classification of ileocecal group, ascending colon group, and hepatic flexure group were carried out in accordance with the 9th edition of the Japanese Society for Cancer of the Colon and Rectum guidelines . The tumNo.206 lymph nodes are lymph nodes distributed along the proximal end of the right gastroepiploic artery. No.206 lymph nodes are mainly distributed along the inferior pyloric artery down to the confluence of the right gastroepiploic vein and the superior anterior pancreaticoduodenal vein. Metastasis lymph nodes that appear in these areas were defined as #206 metastases. No.212 lymph nodes are intermediate lymph nodes in the right colic artery. Only these metastasis lymph nodes were defined as #212 metastases.p < 0.05 indicate an accepted statistical significance. The single factor analysis method (chi-square test) was initially applied. The chi-square segmentation method (a' = a/[k(k − 1)/2 + 1], k = number of groups) was used for pairwise comparisons. Small sample Fisher exact probability calculation method can be used. Fisher’s exact probability calculation method was used for small samples. Then, the significant related factors in the single factor analysis (p < 0.05) were screened for logistic multivariate regression analysis, with a = 0.05 as the significance level.SPSS 20.0 statistical software and chi-square test were used to perform statistical analysis, and n = 155) was 42.8%. The overall number of dissected lymph nodes was 11892, of which 619 (5.2%) were metastatic. The proportion of patients who possess lymph nodes metastases in the region paracolic area was 38.4% (139/362). Among them, the total number of lymph nodes was 1601, and the metastatic lymph nodes were 252, with a degree of metastasis of 15.7%. The incidence of metastases in the intermediate area was 12.7% (46/362), and 6.5% lymph nodes (34/525) were metastatic. The proportion of patients who possess lymph nodes metastases in the main area was 9.7% (35/362). Among them, the total number of dissected lymph nodes was 786, and the metastatic lymph nodes were 37, with a degree of metastasis of 4.7%. Accordingly, the incidence of metastases in the paracolic area, the intermediate area, and the main area was 38.4% (139/362), 12.7% (46/362), and 9.7% (35/362), respectively. The difference was statistically significant . The distribution of lymph nodes metastases in proximal regions along the bowel (paracolic area) was 43.5% (40/92), 40% (54/135), and 33.3% (45/135), respectively, and the difference was not statistically significant . No.222 and No.223 lymph node metastasis was not found in the ileocecal group, and no.202 and No.203 lymph node metastasis was not found in the hepatic flexure colon group.As shown in Table χ2 = 16.629, p = 0.000). Among them, No.202 is significantly higher than No.222 (12.0% vs 0); the difference is statistically significant . In addition, the lymph node metastasis rate in No.203, No.213, and No.223 was 6.5%, 2.2%, and 0.0%, respectively. The difference between groups in main area was statistically significant . Our results suggest that in the ileocecal group, metastases dominated by the ileocolic, right colic, and middle colic arteries.In ileocecal group Table , lymph nχ2 = 0.415, p = 0.375). In addition, the lymph node metastasis rate in No.203, No.213, and No.223 was 2.2%, 4.4%, and 3.0%, respectively. The difference between groups in main area was not statistically significant. Among them, No.202 is similar to No.212 (6.7% vs 3.0%), No.212 is similar to No.222 (3.0% vs 4.4%), No.203 is similar to No.213 (2.2% vs 4.4%), and No.213 is similar to No.223 (4.4% vs 6.7%). The difference is not statistically significant , indicating that cancer in the ascending colon group could metastasize to the ileocolic, right colic, and middle colic arteriesIn the ascending colon group, lymph node metastasis rate in No.202, No.212, and No.222 was 6.7%, 3.0%, and 4.4%, respectively. The difference between groups in intermediate area region was not statistically significant . In addition, the lymph node metastasis rate in No.203, No.213, and No.223 was 0%, 6.7%, and 5.9%, respectively. The difference between groups in main area was not statistically significant . Among them, No.212 is similar to No.222 (4.4% vs 6.7%), No.213 is similar to No.223 (6.7% vs 5.9%), and the difference is not statistically significant , indicating that cancer in the ascending colon group could metastasize to the ileocolic, right colic, and middle colic arteries.In the hepatic flexure colon group, lymph node metastasis rate in No.202, No.212, and No.222 was 0%, 4.4%, and 6.7%, respectively. The difference between groups in intermediate area was not statistically significant . Only N1 lymph node metastasis was found in both T1 and T2, which was 11.1% and 14.3% respectively. N1, N2, and N3 in T3 and T4 groups all had lymph node metastasis, with metastasis rates of 38.2%, 11.6%, and 7.9% and 63.9%, 26.5%, and 25.3%, respectively. We found that there were statistical differences in the metastasis rates of T1, T2, T3, and T4 at paracolic area, intermediate area, and main area , indicating that the depth of invasion were associated with the rate of total lymph node metastasis in right colon cancer  and degree of differentiation .The proportion of patients having No.206 lymph nodes metastases was 7.7% (14/181). The overall number of dissected No.206 lymph nodes was 432, of which 14 (3.2%) were metastatic. As shown in Table χ2 = 6.273, p = 0.043).The proportion of patients having terminal ileum lymph nodes metastases was 3.7% (9/244). The overall number of dissected terminal ileum lymph nodes was 253, of which 17 6.7%) were metastatic. As shown in Table .7% were The therapeutic effect of colon cancer is far from that of rectal cancer. The main reason is that the widespread implementation of total mesorectal excision is of great significance for reducing the recurrence rate and improving the survival rate of patients . In 2009χ2 = 7.955, p = 0.019). The metastasis rate in the hepatic flexure colon group was significantly higher than that in the ascending colon group and the ileocecal group. In addition, the lymph node metastasis of No.206 group all occurred in T3 + T4 stage . Our data show that the lymph node metastasis in right colon cancer patients first appear in the bowel axis lymph nodes, and then to the central lymph nodes. Colon tumor cells tend to metastasize to lymph nodes close to the axis of the bowel [χ2 = 29.6555, p = 0.000). With the deepening of colon cancer infiltration depth, the metastasis rate of bowel axis and central lymph node increased significantly, similar to domestic and foreign studies [For the distribution of lymph node metastases by tumor location, we found that the lymph node metastasis rates of the paracolic area (or station), intermediate area, and main  area were 38.4%, 12.7%, and 9.7%, respectively. It suggested that the metastatic ability of cancer cells was significantly correlated with the distance between the lymph nodes . The research progress shows that lymph node metastasis follows the supporting blood vessels. The distal ileum is the ileum fed by the branches of the ileocolonic artery, and it is also a possible area for lymphatic metastasis of right colon cancer [The vascular anatomy of the right colon has showed several significant changes, including the absence of some branches (lack of RCA in 27.4% of cases), extra branches, common trunk, and posterior superior mesenteric vein routes . Therefon cancer . The disn cancer . Howevern cancer . Kang SIIn conclusion, we demonstrated that radical right hemicolectomy and dissection of No.206 lymph nodes are necessary for T3 and T4 stage colon cancer. The dissection of peri-ileal LNs should be prioritized to the preservation of function. We also found that T2/T1 right colon cancer should be treated with D2 radical resection: T3/T4 ileocecal cancer should undergo D3 radical resection and be removed together with No.203 and No.213 lymph nodes. We hope that our research could provide a certain basis for the implementation of lymph node dissection for colon cancer patients in different periods.


To assess influenza vaccine uptake during the 2020/2021 flu season and compare it with that of the 2019/2020 flu season among respondents to the second phase of the web-based EPICOVID-19 survey, we performed an observational web-based nationwide online survey (January–February 2021) in which respondents to the first survey (April–June 2020) were contacted and asked to complete a second questionnaire. Factors associated with vaccine uptake in the 2020/2021 flu season were assessed by applying a multivariable multinomial logistic regression model. Out of the 198,822 respondents to the first survey, 41,473 (20.9%) agreed to fill out the follow-up questionnaire; of these, 8339 (20.1%) were vaccinated only during the 2020/2021 season, 8828 (21.3%) were vaccinated during both seasons and 22,710 (54.8%) were vaccinated in neither season. Educational level (medium (aOR 1.33 95%CI 1.13–1.56) and high (aOR 1.69 95%CI 1.44–1.97) vs. low) and socio-economic deprivation according to SES scoring (1 point aOR 0.83 (95%CI 0.78–0.89), 2 aOR 0.68 (95%CI 0.60–0.77) points or ≥3 points aOR 0.42 (95%CI 0.28–0.45) vs. 0 points) were found to be associated with flu vaccine uptake. Our study shows that social determinants seemed to affect flu vaccination uptake and identifies specific categories of the population to target during future influenza vaccination campaigns. Influenza vaccination is a major public health intervention that is able to reduce the influenza burden both at the individual and population levels ,2,3,4. TA vaccination coverage that was much lower than the 75% coverage of target groups recommended by the World Health Organization has been registered in Italy across several flu seasons . In partThe 2020/2021 flu season was faced with unprecedented challenges due to the potential collision of the SARS-CoV-2 pandemic and seasonal flu epidemic . AlthougWhile the determinants of the higher vaccination rates during the 2020/2021 flu season are yet to be clearly understood, clinicians and public health officials are seeking to uncover what categories of the population are not being reached or are being left behind by information campaigns to educate patients about the benefit of the flu vaccine during the COVID-19 pandemic period. Therefore, the aim of our study was to assess and compare influenza vaccine uptake during the 2019/2020 and 2020/2021 flu seasons in a self-selected sample of respondents to the web-based EPICOVID-19 survey and to identify the factors associated with getting an influenza vaccination.https://epicovid19.itb.cnr.it/ accessed on 26 October 2021). The inclusion criteria were age ≥18 years, access to a mobile phone, computer or tablet with internet connectivity and the provision of online consent to participate in the study. Participants who consented to be contacted by providing their personal e-mail address during the first phase  received an email invitation containing a personalised link to complete the second questionnaire (from 15 January to 28 February 2021). After excluding the individuals who did not receive the invitation to participate, who did not respond , who did not provide consent (n = 653) and those with incongruences in the email contacts or who answered more than once using the same email address (n = 26), we were left with 41,473 individuals who agreed to participate in the second phase of the study.The study design and methodology are described in detail elsewhere . BrieflyFor the purpose of the study, the participants were categorized according to the influenza vaccine uptake during the 2019/2020 and 2020/2021 flu seasons and classified as: vaccinated in neither one of the seasons, vaccinated in both seasons, vaccinated in the 2019/2020 season only or vaccinated in 2020/2021 season only.The following variables were also considered: biological sex ; age ; education (categorized as low (primary school or less), medium (middle or high school) or high (university degree or post-graduate)); employment and work category at risk of infection ; smoking habit ; and alcohol consumption .A set of proxy variables (dichotomized) were decided upon and assessed as a measure of the participant’s socio-economic status (SES). These were employment vs. unemployment, ownership vs. non-ownership of home, ownership vs. non-ownership of a car and a congruous number of people living in the house vs. house-crowding  . The totp-values of statistical significance were set at 0.05. All of the statistical analyses were carried out using SPSS .The sample characteristics are expressed as mean and standard deviation (SD) for continuous variables and as count and percentages for the categorical variables. Comparison of the participants’ characteristics according to influenza vaccine uptake was performed with a chi-squared test. Flu vaccine rates were calculated for each age class and for every Italian region. The factors associated with vaccine uptake in the 2019/2020 and 2020/2021 flu seasons were assessed by applying a multivariable multinomial logistic regression model considering those who were not vaccinated during neither flu season as the reference category. A set of a priori arbitrary chosen variables which have been considered to be potentially related to influenza vaccination uptake were entered and adjusted for in the final multivariable multinomial model . Adjusted odds ratios (aOR) and 95% confidence intervals (CIs) were estimated for each independent variable. We further performed a sensitivity analysis stratifying by age group (participants aged <65 years and aged ≥65 years). Two-tail The Ethics Committee of the Istituto Nazionale per le Malattie Infettive  IRCCS Lazzaro Spallanzani approved the protocol for the first phase of the EPICOVID-19 study  and later the protocol for the second phase . The participants were requested to give their informed consent when they first accessed the online platform. Participation was voluntary and no compensation was given to respondents. The planning, conduct, and reporting of the study were in line with the Declaration of Helsinki, as revised in 2013. The data were handled and stored in accordance with the European Union General Data Protection Regulation (EU GDPR) 2016/679; data transfer included encryption/decryption and password protection.Out of the 198,822 respondents to the first survey, 41,473 (20.9%) accepted to respond to the follow-up questionnaire; of these, 8,828 (21.3%) said they had been vaccinated during both the 2019/2020 and the 2020/2021 flu seasons, while 1596 (3.8%) were vaccinated only during the 2019/2020 season, 8339 (20.1%) were vaccinated only during the 2020/2021 season and 22,710  said they had been vaccinated in neither year.The characteristics of the study population according to vaccine uptake in the 2019/2020 and 2020/2021 flu seasons are reported in The mean age of respondents was 50.7 (SD ± 13.5) years, 25,146 (60.6%) were females, 27,158 (65.5%) reported a high education level, 26,124 (62.3%) reported that they had a stable work position. Among respondents, 26,029 (62.8%) reported to have no comorbidities. The majority of respondents were from the Lombardia region , followed by Piemonte , Emilia-Romagna  and Lazio regions .Vaccination coverage in 2019/2020 and 2020/2021 seasons in the different Italian regions is reported in The Molise, Sicilia, Emilia-Romagna and Friuli-Venezia Giulia regions had the highest number of respondents who underwent flu vaccination during both the 2019/2020 and 2020/2021 flu seasons .Factors associated with vaccine uptake in the 2019/2020 and 2020/2021 flu seasons are reported in Age (60–64 years aOR 2.72 (95%CI 2.50–2.96) and ≥65 years aOR 4.61 (95%CI 4.07–5.23) vs. 18–59 years), education level (medium (aOR 1.33 95%CI 1.13–1.56) or high (aOR 1.69 95%CI 1.44–1.97) vs. low), number of morbidities (1 aOR 1.32 (95%CI 1.24–1.41), 2 aOR 1.51 (95%CI 1.37–1.66) or ≥3 aOR 1.83 (95%CI 1.61–2.08) vs. none), being a health care worker (vs. employment at a low risk job aOR 2.66 95%CI 2.42–2.92) results associated with higher odds of influenza vaccine uptake during the 2020/2021 flu season only. On the contrary, lower odds were observed in those with a higher deprivation according to SES score (1 point aOR 0.83 (95%CI 0.78–0.89), 2 points aOR0.68 (95%CI 0.60–0.77) or ≥3 points aOR 0.42 (95%CI 0.28–0.45) vs. 0 points), in those who drink alcohol between meals 2–3 times a week (vs. never drink aOR 0.89 (95%CI 0.82–0.98)) and in those underweight (aOR 0.84 (95%CI 0.72–0.99)).By comparing those who received influenza vaccination both in 2019/2020 and 2020/2021 with those who did not received a flu vaccine shot during neither, being male (aOR 1.25 (95%CI 1.18–1.33)), age (60–64 years aOR 2.67 (95%CI 2.44–2.93) or ≥65 years aOR 9.23 (95%CI 8.18–10.42) vs. 18–59 years), education level (high (aOR 1.71 95%CI 1.46–2.00) vs. low), number of morbidities (1 aOR 1.48 (95%CI 1.39–1.58), 2 aOR 2.12 (95%CI 1.93–2.33) or ≥3 aOR 2.94 (95%CI 2.60–3.33) vs. none), being a health care worker (vs. work not at risk aOR 4.49 95%CI 4.08–4.94) were found to be associated with higher odds of being vaccinated. On the contrary, lower odds were observed in smokers (aOR 0.63 (95%CI 0.58–0.68)), in those who drink alcohol between meals (≤1 a week aOR 0.87 (95%CI 0.81–0.94), 2–3 times a week aOR 0.78 (95%CI 0.71–0.85) or ≥4 times a week aOR 0.88 (95%CI 0.80–0.96) vs. never drink), in those underweight (aOR 0.83 (95%CI 0.70–0.99)) and in those with a higher deprivation assessed by SES score (1 point aOR 0.79 (95%CI 0.74–0.85), 2 points aOR0.59 (95%CI 0.51–0.67) point or ≥3 points aOR 0.33 (95%CI 0.21–0.54) vs. 0 points).The results of the analysis comparing those who received and those who did not receive an influenza vaccine shot during the 2020/2021 flu season stratified by age group are reported in In those aged <65 years (per 1 year more) (aOR 1.03 (95%CI 1.02–1.03)), education level (medium aOR 1.42 (95%CI 1.18–1.72) or high aOR1.87 (95%CI 1.55–2.25) vs. low), being health care staff (aOR 2.91 (95%CI 2.64–3.20)), being retired (aOR 1.95 (95%CI 1.71–2.22)) and number of morbidities (1 aOR 1.34 (95%CI 1.25–1.43) or 2 aOR 1.51 (95%CI 1.36–1.68) vs. ≥3 aOR 1.86 (95%CI 1.61–2.14)) and being overweight (aOR 1.09 (95%CI 1.02–1.16)) were associated with higher odds of being vaccinated during the 2020/2021 flu season. On the contrary, a previous COVID-19 diagnosis (aOR 0.81 (95%CI 0.74–0.89)), being an active smoker (aOR 0.86 (95%CI 0.80–0.93)), drinking alcohol between meals (aOR 0.91 (95%CI 0.83–1.00)) and a higher deprivation according to SES score (1 point aOR 0.91 (95%CI 0.85–0.97), 2 points aOR 0.75 (95%CI 0.66–0.86) or ≥3 points aOR 0.42 (95%CI 0.27–0.67) vs. 0 points) were associated with lower odds of influenza vaccine uptake.In those aged ≥65 years, a higher education level (vs. low aOR 1.51 (95%CI 1.08–2.10)) was associated with higher probability of receiving an influenza vaccination during the 2020/2021 flu season. On the contrary, a higher deprivation according to SES score (1 point aOR 0.70 (95%CI 0.58–0.86) vs. 0 points) and being underweight (aOR 0.48 (95%CI 0.27–0.85)) were associated with lower odds of influenza vaccine uptake.This study used the data obtained with a two-phase web-based online survey regarding the COVID-19 pandemic carried out in Italy to analyse and compare the differences in influenza vaccination rates during the 2019/2020 and 2020/2021 flu seasons, a time that corresponds to the ongoing COVID-19 pandemic ,15,16,17p < 0.0001, respectively) [Although not comparable to the data provided by the Italian Ministry of Health on flu vaccination coverage in the general population, the increased proportion of flu coverage observed in our study is in line with the data regarding the 2020/2021 flu season in Italy . In factctively) .Our estimates of influenza vaccine uptake were quite comparable to those reported in another survey conducted in two metropolitan cities in Italy during the second SARS-CoV-2 wave, in which 47.3% of respondents were prone to receive the influenza vaccine in the 2020/2021 flu season . In anotp = 0.001, and 2.74, p < 0.001, respectively). On the contrary, data from Ireland, Italy and Spain showed that education above primary level was associated with lower chances of flu vaccination uptake [Although the determinants of flu vaccine uptake have been extensively explored during several flu seasons ,33,34, wn uptake . The invn uptake  and, on n uptake ,40. Althn uptake  have notn uptake . The finn uptake ,43. In lIt is well established that obese patients are more likely to receive flu and pneumococcal vaccinations  and a hiThe inverse association observed between being an active smoker and influenza vaccine uptake should be carefully interpreted considering that no definitive evidence is available regarding this topic, with some studies showing a negative impact of smoking on influenza vaccine uptake and other studies a promoting effect . It coulThe positive association between an increased burden of morbidities and influenza vaccine uptake, especially for those aged <65 years, is not unexpected and is in line with the vaccination campaign during the COVID-19 pandemic period focusing on protecting more vulnerable populations.Finally, the finding of lower odds of getting an influenza vaccine uptake among those who were diagnosed with COVID-19 during the study period was quite surprising and was confirmed in the analysis to be restricted to those aged <65 years. If, on the one hand, there is some epidemiological evidence of an inverse association between influenza vaccination and SARS-CoV-2 infection ,15,16,17Our study has several limitations. First, subjects younger than 18 years were excluded from the survey and consequently the overall data from our study are not comparable to those reported by the Italian Ministry of Health for the general population. Second, the web-based characteristics of the study could have introduced selection biases toward a high proportion of respondents with a higher education level, higher health literacy and higher socioeconomic status, which could partially explain the higher proportion of respondents aged ≥65 years vaccinated for flu in our survey when compared with the Italian general population. In addition, we were not able to assess the direct impact of economic status on flu vaccination uptake, although we used as a proxy in the model education level, working position and the SES. Third, it cannot be excluded that bias toward a better attitude regarding health status and prevention could have been amplified by selecting responders willing to participate in the second point of the survey. Fourth, less than half of respondents to the first online EPICOVID-19 survey were available and allowed to fill out the second questionnaire, thus determining a suboptimal response rate .The main strengths of the study are: (1) that it presents two clear pictures of a large number of Italians and their influenza vaccination behavior during two flu seasons corresponding to the ongoing COVID-19 pandemic; and (2) the consistency of the multivariable multinomial logistic regression model applied to those receiving the influenza vaccine in 2020/2021 for the first time and those who reported receiving the vaccine during both the 2019/2020 and 2020/2021 seasons.In conclusion, a significantly higher proportion of respondents to the online EPICOVID-19 survey received a flu shot during the 2020/2021 flu season with respect to the 2019/2020 season. The respondents’ educational level and socioeconomic status appeared to be major determinants of flu vaccine uptake during the pandemic period. Although, due to the many changes in the characteristics of pandemic waves, it is not possible to directly transfer the results of the present study to the current situation (fourth wave), some signs that emerged between the second and first waves may be of interest for the present and the future. In particular, the most disadvantaged groups in the population appeared, again, to be left behind and less likely to be reached by the 2020/2021 Italian flu vaccination campaign. Health authorities and policymakers should take these findings into consideration during future influenza vaccine campaigns.


BackgroundBenefits of long-term oxygen therapy (LTOT) have been observed in hypoxemic respiratory patients. Reports have shown the lack of observance among healthcare professionals of LTOT. Thus, this study aimed to determine the demographic characteristics and observance of the medical indication of LTOT according to the international guidelines.MethodologyA cross-sectional study was conducted on patients who attended the Medical Unit in Aguascalientes, Mexico to re-evaluate the need for LTOT. Data are presented as mean ± standard deviation. Statistical analyses were performed using the chi-square test or unpaired t-tests. P-values of <0.05 were considered statistically significant.Results2 level in room air was 7.9 ± 2.3 kPa. Hemoglobin and hematocrit levels were 14.9 ± 4.1 g/dL and 44.7 ± 8.4%, respectively. The mean levels of PaO2 were higher in female patients . The most common diagnosis was chronic obstructive pulmonary disorder (60.5%). Moreover, the specialty that most indicated the use of LTOT was pulmonology (57.8%); however, 36.8% of patients who used LTOT did not have any criteria according to international guidelines.From 813 outpatients attended to re-evaluate whether they met the medical criteria to use LTOT, 93 outpatients were excluded, and the remaining 714 outpatients were enrolled. The mean age of the patients was 70.0 ± 15.1 years, with a female gender predominance (59.1 %). The mean PaOConclusionsAlthough a significant percentage of patients do not use LTOT correctly, the most important finding is that the medical indication of LTOT by physicians is not always correct, leading to an excessive prescription of oxygen. Hypoxemia is a state in which oxygen is not available in sufficient quantity in the blood to maintain adequate homeostasis in different organs, leading to a poor prognosis with high mortality; therefore, it must be treated with oxygen therapy . Long-te2) is <7.3 kPa (≤55 mmHg), arterial oxygen saturation (SaO2) is ≤88%, PaO2 is in the range of 7.3-7.9 kPa (56-59 mmHg), or if SaO2 is 89%. Moreover, LTOT should be administered in the presence of signs of cor pulmonale and at a hematocrit level of >55% [2 of <7.9 kPa (<60 mmHg) and decreased SaO2 during exercise or sleep [2 of <88% during sleep or a lowering of PaO2 to 1.3 kPa (10 mmHg) or more, a fall in SaO2 of more than 5% with signs or symptoms suggestive of hypoxemia during exercise, lowering of PaO2 to 7.3 kPa (55 mmHg), or lowering of SaO2 to 88% [2 to at least >8.0 kPa (56-59 mmHg) and/or SaO2 to 90% to preserve vital organ functions by ensuring adequate delivery of oxygen [Two randomized controlled trials, namely, the Nocturnal Oxygen Therapy Trial (NOTT) and the British Medical Research Council (MRC) trial, conducted in the late 1970s demonstrated that LTOT should be used for patients with chronic obstructive pulmonary disorder (COPD) if their resting awake oxygen tension in arterial blood  . The cri2 was ≤7.3 kPa (≤55 mmHg) or when PaO2 was 56-59 mmHg or SaO2 was ≥89%-90%, combined with radiological or electrocardiographic signs of pulmonary hypertension and/or secondary polycythemia (hematocrit exceeding 55%).The prescription of LTOT was defined as appropriate if at-rest PaOThe patient selection criteria for the survey included patients who were prescribed LTOT, those suffering from chronic non-malignant lung diseases, and those referred to the Outpatient Clinical Medical Unit of Therapy for routine follow-up at least twice per year. Additionally, patients with adequate clinical records  were considered eligible.This study was approved by the Research Ethics Committee of Clinical Medical Unit of Therapy of the IMSS Aguascalientes, Mexico, and all participating patients provided written informed consent.The results are presented as the arithmetic mean ± standard deviation (SD) or median (interquartile range) and frequencies and percentages for qualitative variables. Comparison between groups was performed using an unpaired t-test for quantitative variables with normal distribution, Mann-Whitney U-rank test for quantitative variables without normal distribution, and the chi-square test was used to compare proportions. Results were considered statistically significant at a p-value of <0.05. The analyses were performed using Stata statistical software package, version 10.0 .Over eight months, 813 patients at the Outpatient Clinical Medical Unit of Therapy underwent a routine follow-up to re-evaluate whether they met the medical criteria to use LTOT and continue with oxygen prescription. Of these, 93 outpatients were excluded from the study because they were using supplementary oxygen due to an obstructive apnea syndrome diagnosis, and the remaining 714 outpatients were enrolled in the study. Demographic and clinical characteristics of outpatients attended to in the follow-up clinic are shown in Table 2 level on room air was 7.9 ± 2.3 kPa (59.6 ± 17.7 mmHg). Hemoglobin and hematocrit levels were 14.9 ± 4.1 g/dL and 44.7 ± 8.4%, respectively.The mean age of the study participants was 70.0 ± 15.1 years , with a female gender predominance . The average time for LTOT use after therapeutic prescription by a physician was approximately 7.0 ± 8.8 years, while the average time of LTOT use was approximately 2.5 ± 3.1 years. The average daily duration of LTOT in the entire group was 11.1 ± 6.1 hours/day with an oxygen flow of 2.5 ± 0.8 L/minute. The mean PaO2 were higher in female than male patients , whereas hematocrit, although almost normal, was slightly lower .Female patients were younger than male patients (p = 0.030). Furthermore, no statistically significant differences were noted for the time since diagnosis while using LTOT, daily duration of LTOT, or oxygen flow Table . HoweverIn this survey, we found that the most common diagnosis was COPD (60.5%), followed by other diagnoses, each with a prevalence of less than 10% Table .For these patients, the medical specialty that most indicated LTOT administration was pulmonologists (57.8%), followed by internists 20.3%) and cardiologists (9.2%), although other specialties also indicated LTOT , with patients largely suffering from chronic hypoxemia. This wide range is due to the inclusion of young patients who require LTOT for different diseases such as bronchiectasis and congenital cardiovascular, renal, and other diseases. The mean age was similar to previous studies. For example, Nasilowski et al.  in PolanOur study showed that 60.5% of outpatients with an LTOT prescription were diagnosed with COPD, which is a slightly lower percentage than that reported in other studies. For example, in Denmark, Ringbaek et al.  found thFemale patients predominated in our study (59.1%) and were younger than male patients . In a seven-year prospective cohort study of 435 outpatients with COPD conducted in Brazil, Machado et al.  observed2 ≤ 55 mmHg) because this treatment was found to reduce overall mortality compared to no LTOT  [A significant number of our patients (69.2%) received the prescription for oxygen use for an average of 11 hours/day. Much of the initial research for LTOT addressed the precision of the daily duration of LTOT after therapeutic prescription. In particular, the prescription of oxygen administration for at least 15 hours/day is recommended according to current guidelines for patients with chronic hypoxemia (PaO < 0.05) .However, despite the generally recommended daily duration of oxygen usage to achieve its goals, there is a large range of mean time between different surveys. For example, Atiş et al.  found thThe most common dose of LTOT used by our outpatients was 2.5 L/minute, but doses higher than 3 L/minute were also used in 15% of cases, compared to the 10% reported by Neri et al. . AlthougWe found that the main medical specialists who recommended LTOT to patients were pulmonologists in 57.8%, internists in 20.3%, and other specialists in 12.0% of the patients. However, the proportion of patients who were appropriately prescribed according to LTOT guidelines was 63.1%. Pulmonologists often presented better adherence to the guidelines (59.2%) compared to other specialists. Similar data were reported by Verduri et al.  who repo2 as to who should receive LTOT, we observed that a significant proportion of patients received LTOT prescription for hypoxemia without meeting the criteria of LTOT guidelines. A significant number of patients (36.8%) had mean PaO2 higher than 8 kPa (9.5± 2.67 kPa) at the last visit. Our study, that evaluated the medical criteria for LTOT use previously established by LTOT guidelines showed that 36.8% of patients did not meet the proposed criteria for medical prescription of LTOT. These findings are a cause of concern because they do not correspond to evidence-based recommendations for good clinical practice.While there is a broad agreement based on resting PaO2 of >8.0 kPa [2 or SaO2), so the prescription of LTOT in patients without COPD was inappropriate. These studies demonstrate an abuse of LTOT prescription worldwide; hence, LTOT should only be administered for strict indications, in accordance with the guidelines, and only in a form suitable for individual patients.The lack of observance of LTOT criteria appears to be a frequent practice in several studies concerning LTOT. Thus, several series in different countries have reported a significant percentage of patients with LTOT who are incorrectly prescribed LTOT. Studies documenting patients with erroneous prescriptions of LTOT have been reported by Morrison et al.  in Scotl>8.0 kPa . In late>8.0 kPa  observed>8.0 kPa  in Germa>8.0 kPa , 41.9% oIt is important to consider that patients with prescription of LTOT often show poor adherence, ranging from 45% to 70% ,17,24. TOur survey results, like others, showed that LTOT is frequently prescribed without following the LTOT guidelines, regardless of the medical specialty. Patients need to be able to meet the criteria for LTOT, and they must be clinically stable and should be receiving optimal pharmacological treatment prior to commencement. LTOT is frequently prescribed in an unstable clinical situation or after a single assessment, as reported by several authors . Howard The Long-Term Oxygen Treatment Trial, a large randomized clinical trial of long-term supplemental oxygen versus no long-term supplemental oxygen in patients with COPD, demonstrated no benefit with respect to survival or first hospitalization during one to six years of follow-up . LacasseLimitationsThe limited sample of interviewed patients makes the results difficult to generalize to all local, regional, or national prescriptions. Another limitation was the lack of information concerning the measurement of blood saturation at night and during exercise. Other limitations include adherence to the time of use, used/prescribed oxygen flow, and the fact that during the follow-up the clinical condition of the patient could have changed, which may explain, at least in part, the lack of adherence to the LTOT criteria. Nonetheless, the study provides important preliminary information to design and perform more accurate and larger studies to improve the appropriate observance of LTOT guidance in clinical practice.According to our results, we can conclude that there is a significant percentage of patients who do not use LTOT correctly. Moreover, we found that the medical indication of LTOT by physicians is not always correct as they do not base their decision regarding prescribing oxygen on international criteria, which occurs in different regions of the world. The most important finding was that when LTOT is prescribed without any medical criteria, there is a clear non-necessity of LTOT in several patients. This study highlights the importance of establishing healthcare plans that encourage the proper management of LTOT.


To register all cases of urothelial cancer and renal cell carcinoma (RCC) in Norway during 1999–2018 to obtain the contemporary incidence of UTUC and UTUC incidence relative to other urothelial cancers and RCC. Further to analyse possible changes over time regarding UTUC incidence, UTUC patient characteristics, tumour characteristics and survival.3502 cases registered with ICD code C65 and C66 during 1999–2018 at the Norwegian cancer registry were entered into a database. After a selection process 3096 cases were included in the study. The crude incidences of UTUC were calculated for each year adjusting for the corresponding population data. Age-standardized rates adjusting to the European standard population (2013) were calculated. Comparisons were made with other cases of urothelial cancer and RCC. For changes over time, the material was split into 5-year periods. Regression analysis was used to calculate yearly changes and for assessing statistical significance. Survival outcomes were calculated using the Kaplan–Meier method.The overall age-standardized incidence rate was 3.88, increasing from 3.21 to 4.70 from first to last 5-year periods. The increase affected all ages except those < 60 years of age, and were observed regardless of gender or anatomical location. UTUC constituted 11.8% of all urothelial cancers, increasing from 9.9 to 12.8%. Mean patient age at diagnosis increased from 71.5 to 73.4 years. The 5-years Cancer-specific survival improved from 57.4 to 65.4%.The incidence of UTUC was higher than expected and increasing. Patient age at diagnosis was increasing.The online version contains supplementary material available at 10.1007/s00345-020-03576-3. Compared to urothelial cancer of the bladder (BC), upper tract urothelial carcinoma (UTUC) is relatively uncommon. The incidence is typically referred to be 1–2:100.000 per year or 5–10% of all urothelial carcinomas. Urothelial cancer in the kidney pelvis has been referred to constitute 7% of all renal tumours. As a source of these numbers, the yearly publication from the American Cancer Society is often quoted , 4, whilTo register all cases of UTUC together with all other cases of urothelial cancer and renal cell carcinoma (RCC) in Norway during 1999–2018 to obtain the contemporary incidence of UTUC in Norway together with UTUC incidence relative to other urothelial cancers and RCC.To look for and analyse possible changes over time regarding UTUC incidence, patient and tumour characteristics and survival outcomes.n = 14,500), BC . The database included information about patient sex, age at diagnosis, date of birth, histopathological data, clinical data , treatment and current status . The data from the NCR include nodal status and metastasis at diagnosis if present, but complete data on pathological or clinical tumour stage is not available. As a substitute, the tumours are coded as invasive (pT2 +) or non-invasive (pTa/T1). This classification is available for pure urothelial carcinomas only , biopsy  or cytology . In the remaining 127 (4.1%), the basis was a clinical report using radiological examination, endoscopic procedure or radiation therapy data as sources for the diagnosis codes. Similar inclusion and exclusion processes were performed regarding BC, urethral cancer and RCC resulting in 24,467 included cases of BC, 13,619 with RCC and 287 with urethral cancer.All patients classified with the International Classification of Diseases tenth revision  ICD-10)0n = 14,5For incidence rates, crude rates were calculated using population data in Norway corresponding to each year from 1999 to 2018. To adjust for demographic differences between the Norwegian and other populations, age-standardized rates (ASR) according to the European standard population published in 2013 were calculated [P values less than 0.05 were considered statistically significant.For the purpose of analysing changes over time, the material was split into 5-year periods . The relative proportion of UTUC cases compared to all urothelial cancer cases and pelvic urothelial tumour cases compared to RCC cases were calculated for each 5-year periods. Analyses regarding potential changes in patient age, gender distribution, location of the tumour and tumour features were performed in the same manner. For further analyses of changes over time, the estimated average percentage changes (EAPC) for incidence rates were calculated and linear regression analyses were used to calculate yearly changes and for assessing statistical significance. Survival analyses included both overall survival (OS) and cancer-specific survival (CSS) and were performed using the Kaplan–Meier method. Categorical data were analysed using the Chi-square method. Data were analysed using IBM® SPSS® Statistics v. 26. p < 0.001) resulting in an EAPC of 3%. The ASR adjusted to the European standard population was 3.88 for the whole period, increasing from 3.21 to 4.70. The increase per year was 0.10  with an EAPC of 2.5%. The ASR of UTUC in the kidney pelvis increased from 1.77 to 2.88 from first period to last, p < 0.001. For ureteral tumours the increase was from 1.44 to 1.82 during the same period, p < 0.001. The proportion of tumours in the renal pelvis compared to all UTUC increased non-significantly from 55.6 to 61.2%, p = 0.06. The ASRs adjusted to other standard populations are presented in Supplementary Table 1 and 2.The developments in crude rates and ASRs of UTUC during the study period are illustrated in Fig. p < 0.001.Analyses showed that UTUC incidence increased in all age-spans above 60 years age, see supplementary Fig. 2. There was no increase over time in new yearly UTUC cases among patients under the age of 60, but comparing first 5-year periods with the last the increase was apparent and significant for each decade from 60 to 69 years  70–79 years  and 80 + years , all Patient demographics, tumour features and developments over time are shown in Table p < 0.001. No gender-specific changes over time were observed.Mean  age of all UTUC patients during the whole period was 72.8  years. Patient mean age at diagnosis increased from 71.8 to 73.9 from the first to last 5 year periods, p = 0.07). Invasive tumours were equally frequent irrespective of gender or age. Similarly, analyses were performed regarding regional node or distant metastases, but no differences over time were observed for the entire cohort or stratified by age or gender. The proportion of cases where invasiveness was not assessable increased over time, corresponding to an increase in cases verified by biopsy only, and a decrease in radical surgery.No statistically significant stage migration over time was observed. The proportion of invasive tumours decreased non-significantly from 50.0 to 41.7% compared to non-invasive tumours . The proportion of patients with a biopsy verified diagnosis without following radical surgery increased correspondingly from 10.8 to 23.7% in the same period.During the whole study period, 75.2% of the patients were treated with radical surgery. The absolute number of patients treated with radical surgery increased by 55.5% during the study period, but since number of cases increased by 81.4%, there was a net decline in the Regarding the oldest patients (> 80 years of age) fewer patients (59.3%) were treated with radical surgery, decreasing from 64.5 to 55.6% in the study period. More of these patients were diagnosed with biopsy without following radical treatment, increasing from 18.2 to 31.2% in the study period. Among these oldest patients, it was also more common that the diagnosis was not verified with a histopathological specimen, (16.0% vs 2.8% for patients < 80 years age), stable during the study period.p < 0.001), respectively. The patients with non-invasive tumours had higher survival compared to patients with invasive UTUC . Survival deteriorated with increasing age, patients < 70 years 68.1%, 70–80 age 63.5% and > 80 years of age 46.7%, respectively, p < 0.001. No differences in survival stratified by gender or tumour location were detected.The 5, 10 and 15-years OS were 48.3%, 33.2% and 22.5%, respectively. The 5, 10 and 15-years CSS were 61.4%, 56.1% and 51.1%, respectively , respectively. This improvement over time was present for all sub-groups irrespective of age, gender, type of treatment and tumour location.Both OS and CSS improved over time, comparing the last decade with the first Supplementary file2 (DOCX 19 KB)Supplementary file3 (TIF 350 KB)Supplementary file4 (TIF 1495 KB)Below is the link to the electronic supplementary material.


The levodopa-induced dyskinesias (LIDs) in Parkinson’ disease (PD) patients during levodopa treatment can lead to significant disability. Accumulative evidence has suggested that the younger the age of onset, the more likely the development of LIDs . Till noP < 0.001). A total of 43 EOPD patients developed LIDs (15.4%) in the first 5 years of duration, and 56 patients developed LIDs after over 5 years of disease duration; and the former patients had a shorter duration at baseline than the latter ones (Table n = 144)  when genotype data of 11 candidate SNPs were added  when genotype data were added  when genotype data were added  when genotype data were added  was 0.71 (95%CI: 0.66–0.77) when only clinical variables were used, and increased to 0.86 (95%CI: 0.82–0.90) . The minor homozygous genotype of DRD3 rs6280 increased LID incidence , while the heterozygous genotype of HRAS rs12628 significantly decreased LID incidence  (Table P = 1.7e-4).Backward stepwise regression showed that for LID incidence at the first 5 years of duration, the clinical predictors included LEDD and disease duration, and the genetic predictors included 2) Table . For LIDDRD3 rs6280 GG genotype, as the strongest genetic variable, increased the risk of LIDs compared with the AA genotype in our cohort, which was consistent with the finding from a Korean cohort [In our cohort, the incidence of LIDs was 15.4% in the first 5 years of duration, and increased to 29.7% in the first 5 years of DRT. In a previous study, the incidence of LIDs has been reported to be 21.7% in Chinese LOPD patients . The DRDIn conclusion, the established clinical-genetic models and the identified independent predictors in the early stage of EOPD in Chinese patients may have good application prospects for LID prediction and DRT management.Additional file 1.Additional file 2: Table S1. Baseline characteristics of patients in the derivation cohort. Table S2. Characteristics of the selected genetic variants. Table S3. Baseline characteristics of patients with LIDs in the derivation cohort. Table S4. Baseline characteristics of patients in the validation cohort. Table S5. Comparison of different prediction models between the derivation group and the validation group. Table S6. Comparison of different prediction models between the derivation group and subgroups excluding PD-causative gene mutations. Table S7. Single-factor association with LID incidence in the multivariable non-linear models. Fig. S1. Flowchart of the study.


To identify association of neutrophil to lymphocyte ratio with disease severity and mortality.Total 720 Corona Virus RT-PCR positive patients were included in this cross-sectional study. Patients were admitted to KRL Hospital Islamabad from April 2020 to August 2020. Neutrophil to lymphocyte ratio (NLR) was recorded on admission and then serially. NLR cut-off was 3.0. WHO categories for disease severity  were used. Demographic profile, symptoms and co-morbidities were recorded.The mean age of patients was 40 ± 12.4 years with 96% being males. Majority patients (76.5%) were asymptomatic. Amongst symptoms, fever was the most common symptom. Diabetes mellitus was most common recorded co-morbidity. The mean NLR 2.5 ± 2.78. Significant association was found between NLR and disease severity as well as mortality. Difference in mean NLR amongst disease severity categories was also significantResults are compatible with worldwide studies and NLR is a cheap and easily available marker of disease severity and mortality. Coronavirus Disease 2019 (COVID-19) is a rapidly spreading disease; first cases of Corona virus emerged in China in 2019, following which it was declared a global pandemic in March 2020 by World Health Organization (WHO).2Inflammation plays a major role in development and progression of COVID-19. People infected with COVID-19 are known to have an immune system that is dysregulated and can cause abnormal immune response.Studies have been published internationally regarding the use of NLR as a short term prognostic marker in patients with COVID-19 As this is an emerging pandemic, research is rapidly ongoing in order to try to establish how the disease morbidity and mortality can be reduced. We have come across few Pakistani studiesst April 2020 to 31st August 2020 were studied. Non probability, convenience sampling was done. The sample size calculation was not applicable since there is no prevalence data of the disease as the pandemic is still emerging.We designed this as hospital-based, descriptive cross-sectional study. The study took place at KRL Hospital Islamabad. A consecutive series of patients from 1All patients admitted with confirmed COVID-19 positive test with at least one nasopharyngeal swab positive for Reverse transcription polymerase chain reaction (RT-PCR) were included in the study. Demographic profile, epidemiological characteristics including possible exposure history, signs and symptoms, comorbidities, drug histories were obtained and recorded. Laboratory investigations and radiological imaging were done as per hospital’s protocol. All X-rays and CT scans were reported by a classified radiologist. NLR was calculated as a simple ratio of absolute neutrophil count and absolute lymphocyte count. NLR cut-off used was 3.Case severity definitions were as per the interim guidance of WHO.Statistical analysis was performed using IBM SPSS 25. Continuous variables like age and NLR were reported as mean values with standard deviation. Frequency and percentages were calculated for categorical variables including disease severity categories, symptoms and comorbidities. Pearson’s Chi square test was used to calculate the statistical significance of categorical variables. Confidence interval of 95% was presumed. Tukey’s range test and ANOVA were used to check inter categorical differences in mean values. F statistic was calculated to detect between group variance of mean NLR amongst patient outcome groups i.e. those who recovered or those who died. A p value of < 0.05 was taken as statistically significant.A total of 720 patients were admitted during study duration. The mean age was 40 ± 12.4 years (Range- 19 to 87 years). Majority were males i.e. 96% with only 4% being female. Out of the total patients admitted, 76.5% (n=551) were asymptomatic while 23.5% (n=169) were symptomatic. Among the symptomatic, the most frequent symptoms were fever 88.2% (n=149), cough 51.5% (n=87), dyspnoea 36.7% (n=62), myalgia 30.8% (n=52), sore threat 16% (n=27), diarrhoea and vomiting 7.1% (n=12) headache 3% (n=5), rhinorrhea 3% (n=5) and hemoptysis 0.6% (n=1), in order of decreasing frequency.Out of total patients, 84% (n=606) had no pre-morbidity while 16% (n=114) had underlying chronic medical conditions. The reported premorbid conditions were diabetes mellitus in 8.8% (n=63), hypertension in 7.8% (n=56), ischemic heart disease in 3.1% (n=22), chronic respiratory disease in 2.5% (n=18), chronic kidney disease in 1.7% (n=12), chronic liver disease in 0.6% (n=4), chronic neuro-psychiatric condition in 0.2% (n=2) and malignancy in 0.1% (n=1).Regarding disease severity, 76.5% (n=551) were asymptomatic, 13.3% (n=96) had mild disease, 4.6% (n=33) had moderate disease and 5.6% (n=40) had severe disease. Amongst the total patients, 97.8% (N=704) recovered while 2.2% (n=16) died.The mean NLR of 720 patients was 2.5 ± 2.78 (Range- 0.14 to 31.33). The descriptive statistics of NLR across all four categories of disease severity are reported in To further explore the difference in mean NLR across various categories of disease severity, Tukey’s range test was applied. The results are reported in The mean NLR of patients who recovered from COVID-19 compared with those who died are presented in COVID-19 is a highly infectious disease which is an ongoing immense threat to global public health. It has been rapidly spreading throughout world with a second peak now evident in many countries.The mean age of patients developing COVID is variable. The mean age in our population was 40 years which is lower as compared to other Pakistani studies.Our study has shown that mean NLR value significantly increases as disease severity progresses with lowest NLR recorded in asymptomatic and mild disease. This is in line with a Cochrane Meta-analysis Review of twenty Chinese studies which established that NLR is an independent prognostic marker to differentiate severe vs non-severe COVID-19 disease.We reviewed the difference in mean NLR between disease categories as well and found that the highest difference in mean NLR is between the asymptomatic and severe patients. This was expected and in keeping with our findings of strong association between mean NLR and severe disease.We established a link between high NLR and mortality as well in our study. The sixteen patients that succumbed to the disease in our center had a mean NLR ratio of 10.5 as compared to 2.34 in those who recovered which was significantly high. This association between high NLR and mortality has been observed both nationally17Our study results are consistent with the above mentioned studies supporting the theory that NLR is a cheap, robust and easily available predictor of COVID-19 disease morbidity and mortality. It’s a simple marker giving objective evidence of patients at risk of severe disease and increased mortality.Firstly, it was conducted at a single center. Secondly predominantly male patients as being employees of the organization all males were required to be admitted if they tested positive for RT-PCR. On the other hand, female patients with mild disease opted to isolate at home and only admitted if they had moderate to severe disease requiring hospital management.In our study we highlight the importance of NLR in COVID-19 patients in predicting disease severity and mortality. In a developing country like ours where there are resource limited settings, NLR can be used as an effective marker to predict and stratify COVID-19 patients as per severity and effectively predict the outcome as well, which in turn would lead to efficient resource utilization.KT: Conceived, designed and did statistical analysis along with review of manuscript. He is also Responsible for accuracy of data collection and integrity of work.MAQ: Contributed to data collection and manuscript writing.AC: Did manuscript writing with final review of manuscript.MFS: Did data collection and entry.