To examine attitudes towards physician-assisted suicide (PAS) among physicians in Sweden and compare these with the results from a similar cross-sectional study performed in 2007.A random selection of 250 physicians from each of six specialties  and all 127 palliative care physicians in Sweden were invited to participate in this study.A postal questionnaire commissioned by the Swedish Medical Society in collaboration with Karolinska Institute in Stockholm.The total response rate was 59.2%. Slightly fewer than half [47.1% (95% CI 43.7–50.5)] of the respondents from the six specialties accepted PAS, which is significantly more than accepted PAS in the 2007 study [34.9% (95% CI 31.5–38.3)]. Thirty-three percent of respondents were prepared to prescribe the needed drugs. When asked what would happen to the respondent’s own trust in healthcare, a majority [67.1% (95% CI 63.9–70.3)] stated that legalizing PAS would either not influence their own trust in healthcare, or that their trust would increase. This number is an increase compared to the 2007 survey, when just over half [51.9% (95% CI 48.0–55.2)] indicated that their own trust would either not be influenced, or would increase.The study reveals a shift towards a more accepting attitude concerning PAS among physicians in Sweden. Only a minority of the respondents stated that they were against PAS, and a considerable proportion reported being prepared to prescribe the needed drugs for patient self-administration if PAS were legalized. In recent years, there has been a lively public debate about physician-assisted suicide (PAS) both internationally and in Sweden –11. CaliA study we performed in 2007 (published in 2008) revealed that approximately 34% of Swedish physicians were in favour of PAS, given certain conditions . This nuAn important part of the public discussion in Sweden is whether PAS is a decision for citizens to make for themselves, or whether it is a decision that physicians must make, both professionally  and on a case-by-case basis . It is important to point out that in Sweden there is no legal room for a physician to conscientiously object to PAS or any other procedure . RegardlThe current study is a follow-up to the study we conducted 2007, with the aim of examining trends and comparing current attitudes towards PAS among physicians in Sweden . The reaA randomized selection of 250 physicians from each of six specialties  were asked to participate . Furthermore, all registered palliative care physicians in Sweden (n = 127) were invited to participate. Palliative care started as a specialty in Sweden in 2015, so this group was not included in the 2007 study.Random samples of the seven specialties and postal addresses were requested from a commercial database, IQVIA in Stockholm. Some letters were returned to sender due to unknown addressee (n = 50), and these questionnaires were omitted for the purpose of calculating the response rate. Table The postal questionnaire was commissioned by the Swedish Medical Society in collaboration with Karolinska Institute in Stockholm and was distributed in the autumn of 2020. The first questionnaire was followed by a reminder letter mailed ten days later. Another ten days later, if no response had been received, the questionnaire was posted again. Finally, after yet another ten days, a short version of the questionnaire (including only two key questions and background variables) was sent to those who had still not responded.Yes, No and Undecided, in order to be identical to the earlier survey from 2007. Space was left for free comments after each item, but in the present paper we focus on the primary, quantitative results. The cover letter with its invitation to participate and information for the participants about the study and the applied terminology used are also provided  they personally thought most persuasive.The questionnaire also included questions about what physicians thought would happen to patients’ trust in healthcare if PAS were legalized in Sweden, and whether the respondent’s own trust in healthcare would be affected. If a respondent thought that their own trust in healthcare would decrease, that response was interpreted as a negative attitude about PAS, and if trust in healthcare would increase, that response was interpreted as a positive attitude. Finally, respondents were asked about their age, sex and clinical specialty, and were encouraged to write general comments.Overall, the questionnaire was similar to the one used in the previous study in 2007, which we wished to match as closely as possible so that the two studies could be easily and usefully compared. Revisions include changes to the main question about attitude, i.e., a few clarifying words were added to the fifth question about decision-making competence, and unbearable suffering was excluded as a necessary condition. In addition, questions about readiness to prescribe drugs for PAS and/or having the possibility to be offered PAS were added, while a few questions about ethical arguments were removed .p-value < 0.05. All methods were performed in accordance with the relevant guidelines and regulations.The responses were registered and analysed using the EPI-info 6.04 software program . When caThe study was approved by the Swedish Ethical Review Authority, Dnr: 2020–01,842, and no separate informed consent document was required.The sample population comprises 1 577 possible respondent physicians. Of these, 934 responded, and 819 answered the long version of the questionnaire and 115 answered the short version, for an overall response rate of 59.2% (95% CI 56.0–62.4). Background variables are presented in Table The sex distribution of the respondents was the same as the overall distribution within these specialties .Undecided about PAS. In the 2007 study, 34.9% (95% CI 31.5–38.3) of respondents in those six specialties said they would accept PAS, 39.7% (95% CI 36.2–43.2) would not accept PAS, and 25.4% (95% CI 22.3–28.5) were Undecided. Thus, compared to 2007 study, attitudes in 2020 were significantly more accepting towards PAS.Combining the six specialties, 47.1% (95% CI 43.5–50.7) of respondents would accept PAS, 33.2% (95% CI 29.8–36.6) would not accept PAS, and 19.7% (95% CI 16.8–22.6) were Among palliativists, 26.3% (95% CI 16.4–36.2) would accept PAS, 55.3% (95% CI 44.1–66.5) would not accept PAS, and 18.4% (95% CI 9.7–27.1) were undecided.Respondents from all specialties seem to have changed their general attitudes towards acceptance of PAS Fig. . OncologRegarding age groups, among the compared six specialties and the principal attitude, younger physicians (< 46 years) were significant more accepting towards PAS [53.9% (95% CI 48.1–59.7)] than middle aged physicians (46–60 years) [40.2% (95% CI 36.2–46.2)]  probably would not actively fight against PAS legalization. The corresponding result from the 2007 survey was 39.5% (95% CI 35.7–43.5). As contrast to these results, a majority of palliativists [65.3% (95% CI 54.3–76.3)] stated that their own trust in healthcare would decrease if PAS were legalized.Among those who stated that their own trust in healthcare would not be influenced (n = 456), 59.9% in principle accepted PAS, 15.8% were against PAS, and 24.3% were undecided.The questionnaire also included questions about whether or not the respondents would like to be offered PAS for themselves, and whether or not they would consider prescribing the drugs for self-administration to an eligible patient who requested it. As can be seen from Table No regarding the principle attitude and 19.3% (95% CI 16.6–22.0) answered Undecided. Regarding having PAS for oneself, 34.8% (95% CI 31.5–38.1) answered No and 22.6% (95% CI 19.7–25.5) were Undecided; regarding considering prescribing drugs to an eligible patient, 47.4% (95% CI 44.0–50.8) answered No and 19.1% (95% CI 16.4–21.8) were Undecided.In total, 35.3% (95% CI 32.0–38.6) answered Yes) was 47.1% (95% CI 43.5–50.7), 33.2% responded No, and 19.7% were Undecided. The answers followed a similar trend in to the question about whether or not they would like to have the option for PAS for themselves; 43.8% (95% CI 40.4–48.2) answered Yes, 32.7% (95% CI 29.3–36.1) answered No and 23.5% were Undecided. When asked if they would prescribe drugs for PAS, 34.3% (95% CI 30.9–37.7) answered Yes, 45.6% (95% CI 42.0–49.2) answered No, and 20.1% were Undecided.If we exclude the palliativists and focus on the specialties that were included in the 2007 study, the proportion who were accepting of PAS in principle  and the response option Yes or No to PAS (excluding the response option Undecided). The Risk Ratio (RR) regarding the principal attitude towards PAS was 16.7 (95% CI 10.2–27.2); for having the option for PAS for oneself, RR was 20.2 (95% CI 11.3–35.9); finally, for prescribing the drugs, RR was 253.6 (95% CI 35.9–1793.7).We have examined the association between the question “What would happen to [the respondent’s] own trust in healthcare if PAS was legalized?” in terms of the two collapsed response options In the questionnaires, the respondents were asked to prioritize a number of fixed and optional arguments for or against PAS. Fixed arguments in favour of PAS focused on autonomy and whether respect for a patient’s autonomy should overrule the non-maleficence principle. Fixed arguments against PAS were that the non-maleficence principle should overrule concerns about autonomy, and that a patient in such a situation did not know their own best interests. The results are presented in Table Younger physicians (< 46 years) tended to prioritize autonomy arguments [52.9% (95% CI 47.0–58.8)] more than middle-aged respondents (46–60 years old), who prioritized autonomy arguments to a lesser extent [41.1%  responded in a way similar to the youngest group [52.2% (95% CI 44.9–59.5)]. The younger physicians tended, to a lesser extent, to favour the non-maleficence argument [36.4% (95% CI 30.8–42.0)] more than the middle aged physicians [44.8% (95% CI 38.6–51.0)] .Compared to the 2007 survey, significantly higher proportions of six clinical specialists accepted PAS, and fewer could not accept PAS or were undecided about it. This shift in attitude is in line with follow-up studies from other countries –6. ThereInterestingly, the younger (< 46 years) and the older (> 61 years) physicians both seemed to prioritize the autonomy argument, whereas the age group in the middle (between 46–60 years) prioritized the non-maleficence argument.Some other differences between the results from the 2007 survey and the 2020 study are worth noting. For instance, oncologists changed their views the most, moving from opposing to supporting PAS. This trend among Swedish oncologists is in accordance with the general trend among Swedish doctors, but seems to be against the trend in attitudes towards PAS among oncologists worldwide . A possiWhen comparing the results of a Swedish survey of PAS to similar surveys done in other countries, it is important to know that there is no tradition or legislation in Sweden that allows physicians to conscientiously object to specific issues. For instance, when abortion rights were introduced in Sweden in 1975, it meant that all gynaecologists were required to perform abortions . The facPerhaps not surprisingly, palliative care physicians were mostly against PAS, which is also in accordance with position papers in the field –21, althYes and No answers, and whether trust would increase or decrease, or not change.This study has a number of strengths. First, we believe that our random sample is truly representative of the population of the clinical specialties, because the sex distributions in each of the clinical specialities (which is known) corresponded to the distribution of our participants, which strengthens our assumption that this sample is representative . Second,Yes, No, Undecided) to questions about attitudes to PAS. This decision was made for the 2007 study, and the 2020 version used the same three possible answers in order to correspond directly to the earlier survey. However, this constraint may have created a higher degree of polarization than if there had been broader spectrum of more nuanced answers.A factor that is both a strength and a limitation is that respondents were allowed only three alternative answers (A limitation of the study is that we had a rather low response rate (59.2%) compared to the 2007 survey (75%). One reason might be that the 2020 survey was conducted during an ongoing and second peak of the Covid-19 pandemic (between the beginning of November and the end of December 2020), putting strain on the respondents in their professional capacities. There were, however, no differences in response patterns among those who responded to the first (n = 600) or second (n = 219) dispatches (the long questionnaire) or the third (n = 115) dispatch (the short questionnaire) in regards to the main issue of attitude towards PAS. It seems reasonable to assume that responses of those who did not participate would have been similar to those who did.We do not believe that the slight changes to the 2020 version of questions about reasons for being for or against PAS caused fewer physicians to respond to the long version than did in 2007. If these questions had been perceived as particularly difficult to understand or to respond to, then we might have expected more physicians to simply [wait for and] answer the short version of the questionnaire. In fact, significantly fewer physicians answered the short version of the questionnaire in 2020 than answered the short version in 2007 (p = 0.003). This difference in response rate can be taken as at least weak evidence that the long questionnaire in 2020 was not perceived as more difficult than the 2007 version.Finally, we are aware that the wording and framing of a questionnaire, as well as the introduction with preconditions in the cover letter, might influence how the participants respond, at least regarding the general public , 23. SomOn average, about 47% of respondents reported an accepting attitude towards PAS in Sweden. Thirty-three percent were prepared to prescribe the needed drugs under the condition of legal possibility.Compared to the 2007 survey, the present study indicates a significantly higher acceptance of PAS today under the stipulated conditions. Moreover, a large majority of physicians stated that their trust in healthcare would neither decrease nor be influenced at all if PAS was legalized, which also points to a trend of a more accepting attitude towards PAS.In general, compared to middle aged physicians (46–60 years), both younger physicians (< 46) and older physicians (> 61 years) seem to support PAS based on respect for a patient’s right to participate in decision-making at the end of life. If this trend persists, we might in the future see an increased willingness among Swedish physicians to participate in PAS.


Perinatal asphyxia is a condition associated with multiple organ dysfunctions inclusive of cardiovascular dysfunction. Neurologic predictors of survival have been studied, but little has been reported regarding cardiovascular signs and their role in determining outcome in asphyxia.The study aimed to determine the relationship between cardiovascular signs and outcomes in asphyxiated newborns with hypoxic ischaemic encephalopathy.This was a cross sectional study involving asphyxiated new-born babies recruited within the first 24 hours of life. Hypoxic ischaemic encephalopathy staging was done using Sarnat and Sarnat staging. All patients had a detailed cardiovascular examination on admission, after initial resuscitation (30 – 60 minutes) into admission, and were followed till final outcome: discharge or death.Eighty-five asphyxiated new-borns with HIE were studied over seven months. Abnormal cardiovascular-related signs identified in the patients included respiratory distress (64.7%), small volume pulse (57.6%), hypotension (52.9%), hypoxemia (48.2%) and shock (32.9%). Five babies died. None of the clinical signs had a significant relationship with mortality.Abnormal cardiovascular signs increased with the progression of HIE staging but had no relationship with mortality. Perinatal asphyxia is defined as progressive hypoxaemia and hypercarbia accompanied by the progressive development of metabolic acidosis.1 It occurs during the perinatal period as a result of compromised placental or pulmonary gas exchange.6Perinatal asphyxia is a common neonatal problem that contributes significantly to morbidity and mortality occurring in 1.5/1000 live births in high income countries.This was a cross sectional study in the neonatal unit of the University of Ilorin Teaching Hospital between January and July 2017. The hospital new-born unit serves as a referral centre for patients from neighbouring states. The Neonatal Intensive Care Unit (NICU) monthly admission range between 100 to 150 babies. Perinatal asphyxia among term babies accounts for 10 to 15% of the total admissions. The NICU has facilities for oxygen delivery, ventilatory support (continuous positive airway pressure), non-invasive monitoring, radiant warmers, incubators, phototherapy units and a functioning side laboratory.A sample size of 85 was calculated using the Kish Leslie formula and prevalence of cardiovascular signs in asphyxiated babies as 73.3%.Inclusion criteria were term AGA neonates with at least stage I HIE, with or without 5th minute Apgar score ≤ 6 admitted within 24 hours of life. The diagnosis of HIE was based on Sarnat and Sarnat staging and the highest stage was assigned.th and the 95th percentile were recorded as normal, values < 5th percentile as hypotension and above the 95th percentile as hypertension.All the babies had their anthropometric parameters measured and were classified based on gestational age using the Lubchenco chart.Data obtained was entered into a computer and analyzed using Statistical Package for Social Sciences (SPSS) software version 20.0 for Windows . Frequency and mean of categorical and continuous variables were generated respectively. The Chi-square test was used to document relationship between categorical variables. Other statistical tests were used as appropriate. A p value of less than 0.05 was considered statistically significant.Eighty five asphyxiated neonates (AGA) with hypoxic-ischaemic encephalopathy were recruited for seven months. Twenty-three (27.0%) had HIE stage I, 52 (61.2%) had HIE stage II and 10 (11.8%) had HIE stage III. The median (IQR) age at admission was 1.5 (0.5 to 6.0) hours. The study participants comprised 51 (60.0%) males. The mean ± SD gestational age was 39.5 ± 1.4 9 weeks), birth weight 3.0 ± 0.3 (kg), occipitofrontal circumference 34.7 ± 1.4 (cm), and length 49.0 ± 3.2 (cm).The common abnormal cardiovascular findings were respiratory distress in 55 (64.7%), small volume pulse in 49 (57.6%), hypotension in 45 (52.9%), low oxygen saturation (hypoxemia) in 41 (48.2%), reduced peripheral perfusion in 39 (45.9%) and shock in 28 (32.9%). The least common were cardiac murmur [8 (9.4%)], heart failure [5 (5.9%)] and hypertension [1 (1.2%)] as shown in There was an increasing proportion of abnormal cardiovascular signs from HIE I through HIE II and HIE III. Global chi square demonstrated a significant difference in peripheral perfusion, oxygen saturation, pulse volume, pulse rhythm, presence of shock and heart failure, (each p < 0.05), across the three categories . FurtherThe significant cardiovascular signs in the earlier univariate analyses were subjected to multivariate logistic regression analysis with HIE categories using HIE I as reference category against HIE II and III combined. Pulse volume was the only significant cardiovascular parameter with an independent relationship (four times likelihood) among subjects with HIE II and III compared with HIE I. Five of the 85 patients with HIE died, giving a case fatality of 5.9%. The case fatality was highest with stage III disease (40.0%) and lowest with stage I (0.0%). Hypoxic ischaemic encephalopathy stage III constituted the highest proportion of 4 (80.0%) of the total mortality. There was a significant difference between stages of HIE and mortality, (p < 0.001), Regression analysis of significant cardiovascular signs with mortalityOxygen homeostasis is critical for survival and function of all cells in the body including the myocardium. Hypoxia is characterized by inadequate oxygen delivery to the myocardium.2Myocardial hypoxia/ischaemia following perinatal asphyxia may manifest by changes in the heart rate, poor peripheral perfusion, and rise in systemic and central venous pressure. As the myocardium fails, central venous pressure rises further, systemic pressure decreases, and the heart rate drops further.18The mean systolic blood pressure (SBP) of 58.47 mmHg herein reported is close to 66.00 mmHg reported by Hall et al.20Hypotension was recorded in 52.9% while hypertension was documented in 1.2% of the subjects. Hypotension, being the commonest blood pressure abnormality in the current study may be related to the age at examination (up to six hours). Abnormal blood pressure in asphyxia has been linked to initial non-cerebral vasoconstriction, myocardial ischaemia and eventual heart failure.2Respiratory distress was seen in 64.7% of asphyxiated neonates with HIE. This is within the range of 47.5% to 66.7% reported by other workers.21Shock was present in 32.9% of the patients which was slightly lower than 45.0% to 48.3% reported by some authors in neonates with moderate to severe asphyxia.23Cardiac failure was present in 5.9% of the patients. This is comparable to 7.5% reported among asphyxiated neonates in India.2Systolic murmurs were present in 9.4% of the patients This is close to 10.0% reported by other workers.26Reduced peripheral perfusion was reported in about half of the patients, which is similar to 43.4% documented in an earlier study.None of the clinical signs was a significant predictor of mortality. It is difficult to compare our findings on the relationship between cardiovascular signs and stages of HIE because other studies did not subject these parameters to statistical tests.The significant cardiovascular signs of clinical interest in HIE were poor peripheral perfusion, hypoxemia, small pulse volume, shock and heart failure. Pulse volume was the only parameter with independent relationship with HIE severity. None of the prarameters had any relationship with mortality. Identification of these signs may be a pointer to myocardial related ischaemic injury in asphyxiated neonates.A large scale study among term asphyxiated babies with documentation of blood gases to assess the severity of metabolic acidosis is recommended. Electrocardiography and echocardiography might enhance our understanding of the cardiovascular status among the asphyxiated babies.


To determine the course and outcomes of cataract surgery in one-eyed patients.  This retrospective cohort study was conducted at the University Hospital of Nice, France. All one-eyed patients who underwent cataract surgery in their functional eye between January 2014 and December 2018 were included. A one-eyed patient was defined as having a visual acuity (VA) ≤20/200 in the other eye. Data were collected from the medical records and included the sociodemographic factors, the past medical history, data from the preoperative and postoperative clinical examinations, the surgical course, and the visual outcomes. p < 0.001).  One hundred one-eyed patients with a mean age of 74.01 years were included (48 men/52 women). The mean preoperative VA was 20/100 (+0.74 logMAR). The VA ranged between 20/200 and 20/40 in 75 (75%) patients, was >20/40 in 8 (8%), and was <20/200 in 17 (17%) patients. Fifty-eight (58%) patients were operated on an outpatient basis. General or locoregional anesthesia was used in 29 (29%) and 9 (9%) patients, respectively. All cataract surgery procedures were performed by phacoemulsification. Five (5%) patients experienced intraoperative complications. Seventy-three (73%) one-eyed patients achieved a final VA ≥20/40. The mean final VA was 20/50 (+0.37 logMAR) ( A low rate of intraoperative complications was observed in one-eyed patients during cataract surgery. In most cases, a good visual recovery was achieved after cataract surgery, even in patients who experienced a surgical complication. Cataract is one of the leading causes of blindness worldwide . CataracA one-eyed patient has only one functional eye, the other being severely visually impaired for various reasons: the ocular loss can be functional and/or anatomical. When one-eyed patients have a cataract in their seeing eye, ophthalmologists face several challenges : would iThis study aimed to determine the course and outcomes of cataract surgery in one-eyed patients, considering the operating conditions, the course of the surgical procedure, the postoperative visual outcomes, and the incidence and evolution of the intra- and postoperative complications.A retrospective observational cohort study was conducted in the Ophthalmology Department of Nice Pasteur 2 University Hospital Center between January 2014 and December 2018. This study was conducted in accordance with the principles of the Declaration of Helsinki. The study was approved by the French National Society of Ophthalmology (IRB Number: 00008855).All one-eyed patients who underwent cataract surgery in their functional eye between January 2014 and December 2018 were included. Patients were considered “one-eyed” when the Best-Corrected Visual Acuity of the visually impaired eye was ≤20/200 regardless of the etiology .Data were retrospectively collected from the patient charts. Clinical data included the general characteristics of the studied population, the past ophthalmologic and general history, the clinical features of the visually impaired eye, data from the preoperative clinical examination, the surgical procedure, and the postoperative follow-up.All patients underwent cataract surgery using the ultrasonic phacoemulsification technique .Data from postoperative examinations performed one day (D1), one week (D7), and one month (M1) after surgery were collected. Data of the last ophthalmological examination were also recorded. Early and late postoperative complications were recorded . The occurrence of posterior capsule opacification (PCO) was also recorded.p < 0.05 was considered statistically significant. All VA were converted into a logMAR unit for the statistical analysis. The Kaplan–Meier method was used to assess the time to onset and probability of occurrence of postoperative complications and PCO. Due to the small number of events, no multivariate analysis was performed.Quantitative variables were compared using the nonparametric Kruskal–Wallis test. A value of n = 94), only 6 patients lived in a nursing home.One hundred one-eyed patients from Nice Pasteur 2 University Hospital were included in the study (100 cataract surgeries). Patient demographics and clinical characteristics are shown in High blood pressure, diabetes, and cognitive disorders were found in 56 (56%), 25 (25%), and 9 (9%) patients, respectively. Thirty-eight out of 99 patients (38.08%) were treated with anticoagulants and/or antiplatelets and 7 out of 48 male patients (14.58%) were treated for prostatic disease.The medical and surgical ophthalmologic history of the eye planned for surgery is reported in n = 24/95, 25.26%), retinal detachment , and age-related macular degeneration . Seven (7.37%) patients lost their first eye following cataract surgery, with 3 cases of expulsive choroidal hemorrhage, 1 case of pseudophakic retinal detachment, 1 case of acute postoperative endophthalmitis, and 1 case of recalcitrant Irvine Gass syndrome. Nine (9%) eyes had phthisis bulbi, 5 (5%) were eviscerated, and one (1%) was enucleated.p=0.91). The mean preoperative VA of patients with no light perception in the other eye (n = 17/100) was 20/160 (+0.93 logMAR), and the VA was about 20/100 (+0.66 logMAR) for the other patients (p=0.52).The mean preoperative VA was 20/100 (+0.74 logMAR). It ranged between 20/200 and 20/40 in 75 (75%) patients, was >20/40 in 8 (8%) patients and <20/200 in 17 (17%) patients. The mean VA of patients living at home was 20/100 (+0.73 logMAR), versus 20/160 (+0.88 logMAR) for patients living in a nursing home, without significant difference  patients and locoregional anesthesia in 9 (9%) patients. The surgeon was a senior physician  in 57 (57%) cases and a young physician  in 43 (43%) cases.Capsule staining with trypan blue dye was needed in 16 (16.16%) eyes and iris retractors in 9 (9.09%) patients. No capsular tension ring was used.All operated one-eyed patients could be implanted at the same time. Implantation was not possible in the capsular bag in 5 (5%) patients: three sulcus implants  and 2 iris-claw intraocular lenses (Artisan posterior implant for one patient with capsular rupture and for one patient with zonulolysis).p=0.024).Five (5/99 : 5.05%) patients experienced intraoperative complications: two had a capsular rupture, one had a capsular lesion without rupture, one had iris laceration, and one had zonulolysis. These 5 patients had a preoperative VA <20/40 and it was <20/200 in 2 of them. Regarding complicated surgeries, the operator was a young physician in 80% of cases. General anesthesia was used in 4 out of the 5 complicated surgeries  had lost their first eye following cataract surgery. Among the 3 patients with intraoperative capsular complication (capsule rupture or tear), none experienced pseudoexfoliation syndrome. No floppy iris was reported in the operative reports of patients treated for prostatic disease (benign prostatic hyperplasia). Complementary anterior vitrectomy was needed in only one (1.01%) patient following posterior capsular rupture. No intraoperative complication required conversion to posterior vitrectomy or subsequent surgery.n = 99/100) patients attended the D1 follow-up visit. Among the 99 patients, 81 (81.8%) patients reported ocular discomfort after cataract surgery, which was considered as a sharp ocular pain in 3/81 (3.70%) patients. The incision was not sealed (positive Seidel test) in 7.07% (7/99) of cases. All these patients were treated with a bandage contact lens. Anterior chamber inflammation was reported in 78/99 (78.8%) eyes and was graded as severe  in 6.41% (5/78 eyes with inflammation). Corneal edema was present in 86/99 (86.9%) eyes and considered as major (3+) in 8.14% . The D1 IOP was recorded in 89/99 patients. The mean IOP was 18.69 (range: 7–63) mmHg: 29.21% (26/89 eyes) had an IOP ≥21 mmHg. Among these 26 patients, 16 (61.54%) had preoperative glaucoma.Ninety-nine  attended the D7 follow-up visit and the mean VA was 20/50 (+0.44 logMAR). Among the eyes with postoperative corneal Seidel on D1, only one eye still had corneal Seidel on D7 (which was sutured on D7). The mean IOP was 14.56 (3–35) mmHg: 8.14% of patients were still hypertonic on D7. The IOP was normalized in 4 (16.67%) patients who had ocular hypertension on D1.Ninety-nine percent of patients (n = 79) attended the M1 follow-up visit. The mean VA was 20/40 (+0.31 logMAR). The mean IOP was 13.66 (6–26) mmHg. Five cases  still had ocular hypertension. Four of these patients (80%) with ocular hypertension at M1 had previously been followed and treated for glaucoma.Seventy-nine percent of operated patients  patients experienced late complications with 5 cases of Irvine–Gass syndrome (IGS), one case of rebound inflammation (postoperative treatment was not correctly taken), one case of uncontrolled ocular hypertension, and one case of phthisis bulbi. Phthisis bulbi occurred in a context of recurrent retinal detachment related to familial vitreoretinopathy in the patient who underwent cataract surgery combined with silicone oil removal. Regarding the cases of IGS, the meantime to the clinical diagnosis was 91.4 days .p=0.42).PCO was found in 42 (42%) eyes, with a mean time to onset of 248.6 days . It occurred in 31.5% (5/16) of cases, after implantation of a hydrophobic IOL, and in 44.05% (37/84) of cases after implantation of a hydrophilic IOL .p < 0.001). Seventy-three percent of one-eyed patients had a final VA ≥20/40. Eighty-seven (87%) patients had an improvement in their VA compared to the preoperative examination. For the other 13 patients, 10 (76.92%) had a preoperative ocular history limiting the final visual recovery. The mean final VA was 20/20 (+0.08 logMAR) in patients operated on early . In patients operated on later , the mean final VA was 20/250 (+1.1 logMAR). In patients with no ophthalmologic history (n = 24), the mean final VA was 20/25 (+0.13 logMAR), compared to 20/50 (+0.45 logMAR) in patients with a preoperative history (n = 76) (p=0.014). Patients who experienced an intraoperative complication (n = 5) all showed an improvement after surgery, with a postoperative VA greater than the initial VA. Patients with postoperative IGS (n = 5) had a mean final VA at 20/25 (+0.14 logMAR) and they all showed an improvement after surgery despite this complication.The final VA was 20/50 (+0.37 logMAR). The mean final VA was significantly better than the mean preoperative VA  with a preoperative VA >20/40, while most of our patients (n = 75/100) were operated on with a preoperative VA ranged between 20/200 and 20/40. Our results were similar to those of a large Swedish national study based on the Swedish National Cataract Register (NCR) including about one million cataract surgeries [p=0.52). It could be assumed that one-eyed patients might be afraid to undergo cataract surgery in their remaining eye and thus delay surgery as long as they can. Regarding the postoperative visual outcome, a better visual recovery was achieved in patients operated on early with a mean final VA of 20/20 (when the preoperative VA was >20/40) compared to patients operated on late with a mean final VA of 20/250 (when the preoperative VA was <20/200). The intraoperative complication rate was low , but these 5 patients all had a preoperative VA <20/40. In our study, over a mean follow-up period of 10.77 months, early surgery seemed to be an option to be considered in one-eyed patients as it was associated with better visual recovery and a lower risk of complications.VA loss is currently the main reason to propose cataract surgery , 4. SeveRegarding the modalities of hospitalization, 42% of patients were hospitalized in a traditional ward. An outpatient setting is often preferred, with good visual outcomes and no significantly higher rates of complications , 12. ButGeneral anesthesia and locoregional anesthesia were, respectively, used in 29% and 9% of cases. The use of general anesthesia was decided in patients with cognitive disorders (9 patients), a deforming osteoarticular disease with painful back position (1 patient), nystagmus (3 patients), associated ocular comorbidities (9 patients), and a history of complicated cataract surgery in the other eye (7 patients). Nowadays, local anesthesia is the gold standard for cataract surgery  because The intraoperative complication rate found in our study was 5.05% (5/99). Four out of the five complicated surgical procedures were performed by a fully certified but still young physician. It has previously been shown that cataract surgery performed by residents is associated with higher rates of pre-and postoperative complications and of reinterventions , 17. HarEarly postoperative adverse events, such as corneal Seidel and corneal edema, did not affect the final postoperative vision. Corneal Seidel and corneal edema were associated with dense cataract. Late postoperative complications mainly included IGS (5 patients), and despite this, the postoperative VA of all patients was improved. To note, nonsteroidal anti-inflammatory and corticosteroid drops were prescribed to all patients after cataract surgery.n = 100), the inclusion of a heterogeneous population representative of the general population. The study's limitations were its monocentric design and the limitation associated with data collection. In our study, the outcomes and complication rates were not compared to those of our 2-eyed patients who had cataract surgery during the same period. This would have provided a better picture of the difficulties encountered in our monocular population.In the literature, a few articles have investigated one-eyed patient condition. To our knowledge, no recent study has been published on cataract surgery in one-eyed patients. The main strengths of our study were the large sample size  in patients operated on early (preoperative VA >20/40), and 20/250 (+1.1 logMAR) in patients operated on later (preoperative VA <20/200), cataract surgery in one-eyed patients may not be delayed.


Staphylococcus aureus (MRSA) is one of the most common causes of nosocomial infections. One of the potential risk factors for nosocomial staphylococcal infections is colonization of the anterior nares of healthcare workers (HCWs). Our study aimed to determine the rate of nasal carriage MRSA among HCWs at Manmohan Memorial Medical College and Teaching Hospital, Kathmandu.  Methicillin-resistant S. aureus isolates were subjected to the antimicrobial susceptibility test by the modified Kirby–Bauer disc diffusion method. MRSA and iMLSB (inducible macrolide lincosamide streptogramin B) resistance was screened using the cefoxitin disc (30 μg) and D-test (clindamycin and erythromycin sensitivity pattern), respectively, following CLSI  guidelines. Risk factors for MRSA colonization were determined using the chi-square test considering the p value ˂0.05 as significant.  Two hundred and thirty-two nasal swabs were collected from HCWs of Manmohan Memorial Medical College and Teaching Hospital, Kathmandu, Nepal, within six months (February 2018–July 2018). Nasal swabs were cultured, and S. aureus were isolated, out of which 12 (35.3%) were MRSA. The overall rate of nasal carriage MRSA among HCWs was 5.2% (12/232). Colonization of MRSA was higher in males (8.7%) than in females (4.3%). MRSA colonization was found to be at peak among the doctors (11.4%). HCWs of the postoperative ward were colonized highest (18.2%). All MRSA isolates were sensitive to linezolid and tetracycline. iMLSB resistance was shown by 7(20.6%) of the isolates. MRSA strains showed higher iMLSB resistance accounting for 33.3% (4/12) in comparison to methicillin-susceptible strains with 13.6% (3/22). Smoking was found to be significantly associated with MRSA colonization (p=0.004).  A total of 34/232 (14.7%)  Rate of nasal carriage MRSA is high among HCWs and hence needs special attention to prevent HCW-associated infections that may result due to nasal colonization. Staphylococcus aureus is a major human pathogen which has potential to cause ample of clinical infections ranging from bacteraemia and infective endocarditis to osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections [Staphylococcus aureus (MRSA) is increasing worldwide, resulting in longer hospital stay, prolonged antibiotic administration, and higher costs [fections . With a er costs .S. aureus developed resistance to it. Later, methicillin was introduced in 1959, but in 1961, S. aureus isolates acquired resistance to methicillin as well [β-lactams, often associated with resistance to other classes of antibiotics [mecA gene, present on the staphylococcal cassette chromosome (SCC), codes for a low antibiotic affinity PBP (penicillin-binding protein) known as PBP2a, responsible for the resistance among MRSA strains [Penicillin was introduced in the 1940s to treat staphylococcal infections; however, in 1945, strains of  as well . MRSA stA few options are available for the treatment of MRSA-associated infections, such as macrolides, lincosamides, and streptogramin B (MLSB) with clindamycin being a good alternative, particularly for skin and soft tissue infections, and also works as an alternative in penicillin-allergic patients . HoweverS. aureus nasal carrier, a nurse, caused outbreaks in two newborn nurseries at different hospitals in association with upper respiratory tract infections in 1986. Phage typing revealed that the nurse's strain of S. aureus and the outbreak strains were identical [S. aureus nasal carriage among the general adult population shows global variation [S. aureus and MRSA among HCWs along with their current antimicrobial profile becomes necessary in the selection of appropriate treatment options for these carriers. Several studies have shown that the elimination of carriage in the anterior nares reduces the incidence of staphylococcal infections [It has been reported that HCWs have been the source of MRSA outbreaks in several cases . S. auredentical . Previoudentical . S. aureariation . The knofections .S. aureus and MRSA along with their antimicrobial profile among HCWs. Also, this study aimed to determine the associated risk factors for nasal carriage MRSA.Hence, this study was carried out to determine the rate of nasal carriage A hospital-based cross-sectional study was performed in the Department of Microbiology of Manmohan Memorial Medical College and Teaching Hospital, Kathmandu, Nepal, within six months (February 2018–July 2018) among 238 HCWs with informed written consent. However, six HCWs did not provide consent, and hence, only 232 HCWs were included in the study. All the participants in the study were interviewed with a standard questionnaire for the clinical history and demographic data.All the hospital staff who provided patient care directly were involved in the study.HCWs presented with wound and upper respiratory tract infection in the last three months were excluded from the study.Nasal swabs were collected using sterile cotton swab moistened with normal saline. The swab was introduced 1-2 cm in the nasal cavity and rotated 3 times both clockwise and anticlockwise. For each specimen, both nostrils were sampled using the same swab and immediately transported to the laboratory on peptone water. The swabs, after 4 hours of incubation at 37°C on peptone water, were inoculated on mannitol salt agar.S. aureus was isolated using mannitol salt agar. The isolates were identified by examination of colony characteristics, Gram staining, oxidase test, catalase test, slide coagulase test, tube coagulase test, and deoxyribonuclease test.S. aureus were tested with 30 μg cefoxitin on Muller Hinton Agar (MHA) for MRSA screening. The zone size was interpreted according to CLSI guidelines. An inhibition zone diameter of ≤21 mm was reported as MRSA and ≥22 mm was reported as methicillin-sensitive Staphylococcus aureus (MSSA).All isolated μg), amoxicillin (10 μg), cefepime (30 μg), cefotaxime (30 μg), cefoxitin (30 μg), chloramphenicol (30 μg), ciprofloxacin (5 μg), clindamycin (2 μg), cloxacillin (10 μg), cotrimoxazole (25 μg), erythromycin (15 μg), gentamicin (10 μg), linezolid (30 μg), ofloxacin (5 μg), teicoplanin (30 μg), and tetracycline (30 μg). The result was interpreted as per the guidelines of CLSI zone size interpretative chart in terms of “sensitive,” “resistant,” and “intermediate sensitive.”Antibiotic susceptibility testing was performed by the modified Kirby–Bauer disc diffusion method on MHA using standard methods as recommended by CLSI guidelines. The antibiotics tested were amikacin (30 μg) and E (15 μg) discs were placed 15 mm apart from the center on the MHA. Plates were analyzed after 18 hours of incubation at 37°C. If the E zone was ≤13 mm and the CD zone was ≥21 mm and both had a circular shape, the organism was negative for inducible resistance (D-test negative). If the E zone was ≤13 mm and the CD zone was ≥21 mm with a D-shaped zone around the CD, the organism was positive for inducible resistance (D-test positive).Erythromycin (E) and clindamycin (CD) sensitivity patterns were reported following CLSI guidelines. Isolates were tested for inducible resistance using the D-test. For the detection of iMLSB resistance, 0.5 McFarland equivalent suspension of organism was inoculated into MHA plate as described in the CLSI recommendation. CD . Risk factors for MRSA colonization were determined using the chi-square test considering the S. aureus, and among them, 12/34 (35.3%) HCWs were found to be MRSA carriers. Overall distribution of MRSA was found to be 5.2% (12/232)  were found to be carriers of (12/232) .The age of study participants ranged from 16 to 65 years, with a mean age of 28.71 ± 7.8 years. The age group of 25–35 years (47.8%) participated in the study was in higher frequency followed by <25 years (34.1%), 35–45 years (13.4%), and least with the age group of ≥45 years (4.7%). Females were predominantly in higher fractions (80.2%) in the present study .Distribution of MSSA was the highest in HCWs of the age group 25–35 years with 11.7% (13/111) and MRSA in the age group ≥45 years with 9.1% (1/11). MSSA and MRSA were found to be 19.6% (9/46) and 8.7% (4/46), respectively, in males being higher in comparison to females .Similarly, the prevalence of MSSA was found to be the highest among laboratory staffs with 25% (5/20), while MRSA was found to be the highest among doctors with 11.4% (5/44) .Distribution of MSSA was found to be highest in laboratory staffs with 19.2% (5/26), while MRSA was found to be the highest in postoperative ward staffs with 18.2% (2/11) .S. aureus, 12 were methicillin-resistant, whereas 22 were methicillin-sensitive. Beside penicillins and cephalosporins, MRSA strains were lowest sensitive to ofloxacin and ciprofloxacin (25% each), followed by erythromycin (33.3%) and gentamicin (50%). However, all MRSA strains were sensitive to linezolid and tetracycline, highest sensitivity followed by teicoplanin and chloramphenicol (91.7% each), amikacin and clindamycin (83.3% each), and cotrimoxazole (75%).Among 34 isolated Among MSSA, the lowest sensitivity was found for amoxicillin (36.4%), followed by erythromycin (40.9%) and ofloxacin and ciprofloxacin each being equally sensitive (63.6%). All isolated MSSA strains were found sensitive to cloxacillin, cefotaxime, cefepime, and chloramphenicol in addition to linezolid and tetracycline. MSSA also showed higher sensitivity to amikacin, clindamycin and teicoplanin (95.5% each), and gentamicin (90.9%) .Among 34 isolates, 12 (35.3%) were sensitive to both erythromycin and clindamycin and 2 (5.9%) were resistant to both erythromycin and clindamycin. Similarly, 7 (20.6%) were resistant to erythromycin and sensitive to clindamycin with the D-test being positive, whereas 13 (38.2%) were sensitive to erythromycin and resistant to clindamycin but with the D-test negative. Our study showed higher iMLSB resistance in MRSA strains with 33.3% (4/12) in comparison to MSSA strains with 13.6% (3/22). A total of 7/34 (20.6%) of the isolates showed iMLSB resistance .p=0.004). No other factors were significantly associated with MRSA colonization  [S. aureus in comparison with the study performed by Vaidya et al. in India (22%) [nditions . In our  (15.7%)  and Khat (15.7%)  and Lege (15.7%) . In contia 22%) , Chen etia (22%) , Boncomp% , Chen ia (22%) , and sevia (22%) –26.S. aureus and MRSA among HCWs may be attributed to different factors such as sampling techniques, culture methods, identification of S. aureus and MRSA basis, study population, study criteria, and hospital environment.In our study, the overall rate of nasal carriage MRSA was found to be 5.2%. Similar results were found in study performed by Vaidya et al. in India (6%) , Boncompp > 0.05). Similarly, Boncompain et al. reported higher MRSA colonization in males (7.2%) in comparison to females (5.8%) in Argentina [Our study also reported that colonization of MRSA was high in males (8.7%) than in females (4.3%) . This could be due to the traumatic and postoperative immunological suppression of the patients . As most.2%. ThisS. aureus (both MRSA and MSSA) were sensitive to linezolid and tetracycline. However, in a study performed by Karimi et al., only 58.4% of S. aureus was sensitive to tetracycline [In our study, all isolated acycline . MRSA stAmong 34 isolates, 7 (20.6%) were resistant to erythromycin and sensitive to clindamycin with the D-test being positive. D-test positive was higher (33.3%) in MRSA in comparison to MSSA (13.6%). Our study showed lower iMLSB resistance (33.3%) among MRSA strains in comparison to a study performed by Khanal et al. in Nepal (66.7%) . The difp=0.004). Cigarette smoking increases mucus production, impairs epithelial elastic properties, decreases IgA production, and affects phagocyte activities which facilitate bacterial colonization and exacerbate inflammatory responses leading to epithelial damage, further impairing host immunity and promoting bacterial colonization of the respiratory tract [Our study also aimed to determine the risk factors for MRSA colonization. The colonization of MRSA was significantly high among smokers . Also, this study only determines the carriage status but does not suggest about the ways for its decolonization.This study is based only on the phenotypic methods. It reveals only about the carriage status of S. aureus and MRSA is high among HCWs, especially among the doctors and the HCWs of the postoperative ward. iMLSB resistance is higher in MRSA than in MSSA strains. The high rate of nasal carriage MRSA among HCWs indicates the need for standard infection control precautions to be employed in the professional practice to minimize the carriage as well as the transmission rate. Our study also suggested that smoking is significantly associated with MRSA colonization.Our study revealed that the nasal carriage


SIRT, also known as radioembolization, is a new treatment for hepatocellular carcinoma. However, the precise role is still not clearly determined. Here, we describe how a new score, ALBI, used to better assess liver functions, can help to select patients for this treatment. We clearly showed that the ALBI grade was associated with toxicity and survival after this treatment.p = 0.002). Of the 207 patients with data, 77 (37.2%) had a worsening of ALBI grade after one SIRT. The baseline ALBI grade was significantly associated with OS (p = 0.001), also in the multivariable analysis. The ALBI grade after the first SIRT was significantly associated with OS (p ≤ 0.001), with median OS of 26.4 months (CI 95% 18.2–34.7) for ALBI grade 1 patients (n = 48) versus 17.3 months (CI 95% 12.9–21.8) for ALBI grade 2 patients (n = 123) and 8.1 months (CI 95% 4.1–12.1) for ALBI grade 3 patients (n = 36). Conclusions: The baseline ALBI grade is a strong predictor of REILD. The baseline ALBI score and variations of ALBI are prognostic after SIRT.Background: Selective internal radiation therapy (SIRT) is an innovative treatment of hepatocellular carcinoma (HCC). The albumin-bilirubin (ALBI) score was designed to better evaluate liver functions in HCC. Methods: We studied, retrospectively, data from patients treated with SIRT for HCC. The primary endpoint was the occurrence of radioembolization-induced liver disease (REILD). The secondary endpoint was overall survival (OS). Results: 222 patients were studied. The ALBI grade 1 patients had significantly less REILD (3.4%) after the first SIRT than ALBI grade 2 or 3 patients (16.8%,  Hepatocellular carcinoma (HCC) is the seventh commonest cancer and the fourth commonest cause of cancer-associated death worldwide in 2017 . The ChiSelective internal radiation therapy (SIRT) using Yttrium-90 microspheres was studied for the treatment of HCC, especially in patients with portal vein thrombosis . CurrentThe aim of the study was to demonstrate the value of ALBI as a predictor of toxicity following SIRT, focusing on REILD, and to study the variations of ALBI after SIRT. We also wanted to confirm the prognostic value of ALBI, and to study the variation of ALBI after SIRT as a prognostic factor.This retrospective and noninterventional cohort study included HCC patients undergoing SIRT at our center from January 2008 to January 2017. They could have previously been treated or not. They all met the following inclusion criteria: age ≥18 years old, PS ≤ 2, treatable by SIRT therapy. This study received institutional review board approval.Pretreatment planning angiography and technetium-99m macroaggregated albumin scans were performed to predict the microsphere distribution and identify potential lung or digestive shunt . In our Treatment efficacy was assessed by liver MRI or CT-scan by a radiologist using the mRECIST criteria. Biological and clinical follow-up were regularly performed and consisted of a clinical exam, an interview looking for potential adverse effects, and blood tests including complete blood counts, liver function tests, and kidney functions.Baseline assessment was made within 2 weeks before pretreatment angiography, then follow-up assessments were done between 6 weeks and 3 months after first SIRT or second SIRT and then regularly every 3 to 4 months until progression or death. The variation of ALBI score was assessed at the time of first imaging evaluation. Adverse events were graded according to NCI-CTCAE v5.0. REILD was defined according to previous publications ,23 as thThe CP score was then calculated from raw data, according to the original publication and adaptation for normalization of units used . If the p-values for toxicity comparison according to the different ALBI grades was calculated using a Chi2 test when the groups were made of at least 5 patients and the Fisher’s exact test when they were not. Logistic regression analysis was performed to assess the odd ratio of occurrence of REILD according to ALBI grade. Kaplan−Meier curves were constructed for OS, and log-rank tests were performed to compare survival distributions. Overall survival was defined as the time between first SIRT and death or last follow-up. Univariate and multivariate Cox regression analysis was performed to calculate unadjusted hazard ratios (HR) and 95% confidence intervals (CI). Variables statistically significant (p < 0.1) were entered in the multivariate model with backward selection. Statistical analysis was performed with SPSS v18. All reported p values were two-sided and considered statistically significant when <0.05.From January 2008 to January 2017, 222 HCC patients underwent SIRT at our center. The clinical characteristics of the patients included in the cohort and the treatment received are presented in p = 0.001), with a median OS of 24.0 months (95% CI 20.7–27.4) for patients with ALBI grade 1 (n = 88) versus 12.9 months (95% CI 9.5–16.4) for ALBI grade 2 (n = 130) (p = 0.001 for ALBI 1 vs. 2) versus 8.3 months (95% CI NE–18.8) for ALBI grade 3 (n = 4) (p = 0.190 for ALBI 2 vs. 3)  A.The univariable Cox-regression model analysis of variables potentially associated with OS is presented in p = 0.059 and p = 0.026 respectively) and baseline ALBI grade (p < 0.001 and p < 0.001 respectively) were found to be independent prognostic factors for survival after SIRT. In this cohort, ALBI score or grade were the stronger prognostic factors.Upon multivariable analysis including either ALBI score as a continuous variable or as a 3- point grade, only macrovascular invasion (n = 131), ALBI grade 1 patients (n = 79) had significantly better survival than ALBI grade 2 (n = 52), with median OS of 24.2 (95% CI 21.0–27.4) and 11.0 months , respectively  (p = 0.493) and C−P B7 (n = 18) (p = 0.089) patients, probably because of the small numbers in these subgroups.In patients classified as C−P score A5 (ectively B. The dip = 0.079).Toxicity follow-up was available for 218 patients. Patients with baseline ALBI grade 1 had significantly less hospitalization, grade 3/4 adverse events, ascites, hospitalization and REILD three months after first SIRT than patients with ALBI grade 2 or 3 . The oddTwo hundred and seven patients had ALBI evaluation after SIRT. The ALBI score frequently increased after SIRT, showing a worsening of liver function. It increased by a median of 0.35 points (standard deviation (SD) = 0.45) after one SIRT and 0.55 points (SD = 0.57) after two SIRT. Of the 207, 77 (37.2%) patients had a worsening of ALBI grade after 1 SIRT, and a further 20 out of 51 (39.2%) had a worsening after the second SIRT . Only 46n = 48) versus 17.3 months (CI 95% 12.9–21.8) for ALBI grade 2 patients (n = 123) and 8.1 months (CI 95% 4.1–12.1) for ALBI grade 3 patients (n = 36) . The results were significant when considering ALBI grade 1 versus 2 (p = 0.003) and for ALBI grade 2 versus 3 (p = 0.001).The ALBI grade after the first treatment was also significantly associated with OS with a median OS of 26.4 months (CI 95% 18.2–34.7) for ALBI grade 1 patients (n = 8) was 25.3 months (CI 95% 10.9–39.7) versus 18.9 months (CI 95% 11.4–26.5) for ALBI grade 2 patients (n = 33) and 7.1 months (CI 95% 5.4–8.8) for ALBI grade 3 patients (n = 10) . Comparison of ALBI grade 2 versus 3 was significant (p = 0.03), but comparison of ALBI grade 1 vs. 2 was limited by low numbers (p = 0.23).The ALBI grade after the second treatment was significantly associated with OS, but the analysis was limited by the low number of patients. The median OS for ALBI grade 1 patients (p < 0.001).In a multivariable analysis, variations of ALBI score after SIRT was also significantly associated with OS. Continuous ALBI score variation remained a significant independent prognostic factor for survival together with macrovascular invasion (HR 2.08 (95% CI 1.46–2.98), In this study, several important properties of the use of ALBI grade in the context of SIRT were shown. The baseline grade was for the first time clearly and strongly associated with toxicity, including REILD. ALBI score was confirmed as an important baseline prognostic factor. Moreover, its variations were studied for the first time, and two important messages arise: ALBI score variations are frequent after SIRT and are also an independent prognostic factor for OS.This study demonstrated that severe toxicities were far less frequently seen in patients with ALBI grade 1 patients. Adverse events grade 3 or more were six times less frequently seen in this population. Specifically, the occurrence of REILD was much lower in ALBI grade 1 patients (3.4%) vs. grade 2 or 3 (16.8%), which could clearly help to assess risk/benefit ratio for treatment. Moreover, there was a strong trend for a prediction of death during the first 3 months. Conversely C−P classification was not able to predict for death following treatment, with all patients dying of liver dysfunction within 3 months classified as C−P A, all but one of these patients were classified as ALBI grade 2. This relationship between ALBI and toxicity could help with patient selection for treatment. Specifically, the very high rates of severe toxicity of ALBI grade 3 patients should lead to contraindicate the treatment in them. However, it should also guide clinicians for the follow-up after treatment, patients with ALBI grade 2 probably needing more frequent clinical and liver function follow-up assessments after SIRT than patients with ALBI grade 1. The first randomized studies to compare SIRT with sorafenib in advanced HCC, the SARAH, SORAMIC and SIRVENIB trials were negative ,13,24, bMoreover, ALBI score and grade frequently increased after SIRT. Faced with the multiplication of systemic therapeutic possibilities, it is essential to monitor the evolution of liver function and to keep a good hepatic function to offer as many therapeutic lines as possible to the patient, possibly switching earlier to systemic treatment when liver function tends to deteriorate under locoregional therapies . The comOur data confirmed that ALBI grade at baseline is better than C−P score for the discrimination of the prognosis of HCC patients treated with SIRT ,17. The Our study has some limitations. First, the size of our cohort was not big enough to find a significant difference of median survival among C−P score A6 or C−P score B, contrary to Antkowiak et al. . SecondlBaseline ALBI could be a useful tool for the selection of patients for SIRT. ALBI can predict the risk of occurrence of toxicity. Moreover, its variations also have important prognostic information, and deterioration of ALBI score is frequent after SIRT. In view of the multiplication of systemic treatments, it is important not to deteriorate the liver functions of patients with local treatment, and deterioration of ALBI score might be an important parameter to consider in this context. Hence, it would be interesting to retrospectively study the ALBI score and its variations in previous phase III trials. In addition, they should be taken into account for the next studies to come.


The purpose of this phase II study was to evaluate the feasibility of hypofractionated radiotherapy (HFRT) with a dose of 36.5 Gy in 10 fractions in postmastectomy patients.From March 2014 to December 2015, 85 patients with locally advanced breast cancer were eligible to participate in this study with a schedule of 36.5 Gy in 10 fractions. Intensity-modulated radiation therapy (IMRT) was delivered to the chest wall with or without the supraclavicular region. The primary endpoint was radiation-related toxicities. The secondary endpoints were locoregional failure-free survival (LRFFS), disease-free survival (DFS) and overall survival (OS). And the outcomes were compared with our retrospective study of 72 patients with 42.5 Gy in 16 fractions.The median follow-up was 69.0 (range 66.5-71.5) months in the 36.5 Gy group and 93.0 (range 91.9-94.1) months in the 42.5 Gy group, respectively. Radiation-related toxicities were mainly grade 1, although a few patients had grade 2 plexopathy (1.2%) and acute skin toxicity (1.2%) in the 36.5 Gy group, and grade 2 acute skin toxicity (5.6%) and lymphedema (4.2%) in the 42.5 Gy group. There were no significant differences between the groups in acute and late toxicities. For all the patients, the 5-year LRFFS, DFS and OS were 97.7 and 100.0%, 93.1 and 90.3%, 98.8 and 97.2%, respectively, without significant differences between the groups.Postmastectomy HFRT with a schedule of 36.5 Gy in 10 fractions was feasible, with mild toxicities and excellent 5-year clinical outcome.ChiCTR-ONRC-14004391.Trial registration number: Date of registration: 9/3/2014. According to the latest estimates on the global burden of cancer released by the International Agency for Research on Cancer (IARC) in Dec 2020, female breast cancer is the most commonly occurring cancer worldwide , posing a serious threat to women’s health .For breast cancer patients, conventionally fractionated radiotherapy (CFRT) typically delivers 50Gy in 25 fractions of 2Gy over 5 weeks. In recent years, hypofractionated radiotherapy (HFRT) as an alternative to CFRT has been widely carried out in patients treated with breast-conserving surgery . WhereasBeginning in Mar 2014, we launched a monocentric phase II study with a novel schedule of 36.5Gy in 10 fractions, which is one of the shortest courses of postmastectomy HFRT designed to date. We retrospectively analysed the data of our previous study on HFRT with 42.5Gy in 16 fractions as the historical control to confirm the feasibility of the hypofractionation regimen with 10 fractions.This study is a prospective phase II trial (registration number ChiCTR-ONRC-14004391), with 85 patients recruited in a single centre  from March 2014 to December 2015. Another retrospective study on HFRT with the schedule of 42.5Gy in 16 fractions was conducted from April 2010 to September 2013, with 72 patients enrolled. The inclusion criteria of patients were as follows: Female patients with invasive breast cancer were eligible if they were aged 18-70 years, had a KPS of 70% or higher, had undergone mastectomy and axillary lymph node dissection with negative margins, had no reconstruction of the breast, had at least one pathologically positive axillary lymph node or a primary tumour with stage pT3-4 disease if they had undergone primary surgery , and had a timespan of less than 8 months between radiotherapy and mastectomy. Patients with positive hormone receptors were treated with hormonotherapy, and those with positive HER2 gene expression were treated with trastuzumab. The characteristics of the patients are shown in Table All the patients were treated in a supine position and immobilised on a breast board. Computed tomography–based treatment planning was mandatory. The clinical target volume (CTV) included the ipsilateral chest wall for patients with pT3-4 tumours or one to three pathologically positive axillary lymph nodes, and included the chest wall and supraclavicular fossa  for patients with four or more metastatic nodes or with pathologically positive nodes if they had received neoadjuvant chemotherapy. The planning target volume (PTV) was the CTV with an expansion of 5 mm while remaining 3 mm under the skin surface. Patients received step-and-shoot IMRT using 6-MV photon beams. The chest wall was irradiated with the 2- or 4-beam tangential IMRT technique, while 6-beam integrated IMRT plans were created to irradiate not only the chest wall but also the supraclavicular fossa. Radiotherapy was delivered five days per week, one fraction per day, without tissue-equivalent bolus application or mastectomy scar boost. Dose homogeneity within the treatment volume was required to be within 90 to 110% of the prescribed dose, and V105%-V107% < 5%, V107%-V110% < 2%.For patients in the 36.5Gy group, the dose-volume constraints for organs at risk (OARs) were as follows: ipsilateral lung V16 < 20%, contralateral lung V5 < 8%; the mean dose of heart <5Gy for women with tumours in the left breast, and < 2.3Gy for those with tumours in the right breast. For patients in the 42.5Gy group, the dose-volume constraints were as follows: ipsilateral lung V20 < 20%, contralateral lung V5 < 10%; the mean dose of heart <5.5Gy for left breast cancer patients, and < 2.4Gy for right breast cancer patients. The dose to the contralateral breast should be as low as possible.Patients underwent weekly physical examination during treatment and up to 2 weeks after radiotherapy, and then were followed up every three months for two years, every six months from 3 to 5 years, and yearly thereafter. Acute and late toxicities were evaluated according to the established Common Terminology Criteria for Adverse Events, version 4.0.The Mann–Whitney U test was used for the analysis of acute and late toxicities. Locoregional failure-free survival (LRFFS), disease-free survival (DFS) and overall survival (OS) were assessed by the Kaplan-Meier test. All data analyses were performed using the SPSS 24.0  statistical data package, and p < 0.05 was considered significant.The incidences of acute and late toxicities in the two groups are shown in Table At the time of last follow-up, one patient  in the 36.5Gy group developed regional recurrence (in the nonirradiated supraclavicular fossa), while no locoregional recurrence was detected in the 42.5Gy group. The 5-year LRFFS rates were 97.7 and 100.0% in the 36.5Gy and 42.5Gy groups, respectively. Four of 85 patients (4.7%) in the 36.5Gy group and 10 of 72 (13.9%) in the 42.5Gy group developed distant metastases, with 5-year DFS rates of 93.1 and 90.3%, respectively  of the HFRT schedule for breast cancer was about 70Gy, corresponding to an equivalent dose in 2Gy fractions (EQD2) of 49Gy, using linear quadratic formalism and an α/β ratio of 4Gy, an α value of 0.3, a T 14 days . CompareData from our study indicated that the delivery of this postmastectomy HFRT regimen was feasible, with a very low incidence of grade 2 or more acute and late toxicities and good 5-year locoregional control. In the current study, acute and late toxicities were mainly grade 1. Compared with the study of Wang et al , in whicResults of radiation-related toxicities and clinical outcomes in the current study are consistent with a few published studies , 15–18. It is well known that the ipsilateral chest wall and regional lymphatic drainage areas are considered the primary target volume for postmastectomy radiotherapy. However, CTV delineation of the chest wall is controversial, especially in the definition of the ventral border. The RTOG guidelines define the chest wall as containing the skin and subcutaneous tissue ; howeverIn postmastectomy radiotherapy, irregular target volumes associated with the chest wall and regional nodes may increase the complexity of treatment planning, even when using a 3D conformal technique. IMRT has been increasingly used in breast cancer radiotherapy in recent years due to its excellent dose distribution . SeveralIt is obvious that HFRT with fewer fractions and a shorter course is inherently more cost- and medical resource-effective for both patients and society. A rough calculation indicates that HFRT with a 2-week schedule instead of the 5-week CFRT might allow up to 60% more breast cancer patients to be treated with existing equipment, consequently results in an improvement in cancer-related survival, which has particular significance in countries with inadequate medical resources.In conclusion, this study demonstrated a low incidence of radiation-related toxicities and satisfactory locoregional control for the schedule of postmastectomy HFRT with 36.5Gy in 10 fractions. Based on this study, we have designed a phase III trial , in which we expect to confirm the noninferiority of the HFRT with 36.5Gy in 10 fractions to the CFRT with 50Gy in 25 fractions.


Moreover, patients with impaired kidney function tended to have a delayed subretinal fluid absorption. Therefore, careful investigation of preoperative systemic conditions, especially kidney function, should be considered before TRD surgery in diabetic patients.(1) Background: We analyzed the duration of persistent subretinal fluid (PSF) and the contributing factors of PSF after pars plana vitrectomy in patients who had a macula with diabetic tractional retinal detachment (TRD). (2) Methods: Forty eyes of 40 patients who had pars plana vitrectomy due to a macula with diabetic TRD, between 2014 and 2020, were retrospectively reviewed. The duration of PSF, as well as relevant ocular and systemic factors, was analyzed. (3) Results: The mean duration of PSF was 4.4 ± 4.7 months. The prevalence of PSF was 75.0% at 1 month, 50.0% at 3 months, 30.0% at 6 months and 10.0% at 12 months after surgery. Blood urea nitrogen, creatinine, and estimated glomerular filtration rate (eGFR) were significantly associated with the duration of PSF in the univariate analysis. In the multivariate analysis, only eGFR was significantly associated with the duration of PSF ( The prognosis of proliferative diabetic retinopathy (PDR) is greatly improved in the era of panretinal photocoagulation and anti-vascular endothelial growth factor (VEGF) intravitreal injection ,2. HowevPars plana vitrectomy for TRD may still be one of the most complex vitreoretinal procedures. The goals of this surgery are to remove vitreous hemorrhage, reduce the anterior-to-posterior vitreous traction on the retina, and to relieve epiretinal tangential traction on which proliferative tissue grows. However, iatrogenic retinal breaks are the most major surgical complication, and intraocular tamponade is used to repair retinal breaks.Persistent subretinal fluid (PSF) was detected via optical coherence tomography (OCT) after the repair of rhegmatogenous retinal detachment ,4,5, andThis study reports the prevalence of PSF and analyzes ocular and systemic factors contributing to the duration of PSF after pars plana vitrectomy in patients with PDR accompanying a macula with TRD.Medical records were reviewed after receiving approval from the Institutional Review Board of Kyungpook National University Hospital (IRB No. 2021-02-009), and the requirement for informed consent was waived because of the retrospective nature of the study. The research was conducted in accordance with the tenets of the Declaration of Helsinki.We included PDR patients who had pars plana vitrectomy in macula with diabetic TRD from January 2014 to December 2020. The study included only the patient’s eye that had PDR involving macula with TRD and showed subretinal fluid (SRF) on preoperative OCT. If the patient who had a macula with TRD in both eyes, the eye with poorer visual acuity was used. All patients showed successful anatomical results after vitrectomy and completed at least a 6-month follow-up period with OCT examinations. Patients were excluded according to the following criteria: (1) diabetic TRD without a macula; (2) diabetic TRD without SRF on the preoperative macular OCT scan; (3) the presence of vitreous haze or hemorrhage that is unsuitable for OCT imaging.Ophthalmic examinations were performed, including the best-corrected visual acuity (BCVA) using a Snellen chart, intraocular pressure (IOP) measurement, slit lamp examination, fundus examination, and OCT examination. All examinations were repeated at baseline and at 1, 2, 4 weeks and every month after vitrectomy. BCVA was converted to the logMAR (logarithm of the minimum angle of resolution) for statistical analyses. The detachment of the macula was confirmed by a preoperative OCT scan. The volume scan of the 6 × 6 mm area was performed using the spectral-domain OCT . The presence of SRF was defined on the OCT image as a hyporeflective space between the photoreceptor layer and the retinal pigment epithelium (RPE). PSF is defined as SRF present within any area on 6 × 6 mm OCT scans that persists after vitrectomy. Subretinal fluid height (SRFH) was manually measured after vitrectomy by one examiner (YKK) using the built-in ruler in the software of OCT scan. SRFH was measured by determining the vertical distance from the outer interface of the neuroepithelial layer to the inner surface of the RPE in the subfoveal area  Figure .Preoperative laboratory testing, including serum glycosylated hemoglobin (HbA1c), blood urea nitrogen (BUN), and creatinine was conducted. The estimated glomerular filtration rate (eGFR) was calculated using the equation recommended by the Chronic Kidney Disease Epidemiology Collaboration .A microinvasive pars plana vitrectomy was conducted using 23- or 25-gauge instrument. Phacoemulsification of the cataract with intraocular lens implantation was conducted prior to vitrectomy in phacovitrectomy cases. Vitrectomy was performed using the Constellation surgical system . It included removal of the posterior vitreous and shaving of the peripheral vitreous body; removal of the posterior hyaloid, neovascular, and fibrous epiretinal membranes from the retinal surface with triamcinolone acetonide (TA); and endolaser photocoagulation. If epiretinal membranes with a risk of postoperative re-proliferation were presented, internal limiting membrane (ILM) peeling was conducted after staining with indocyanine green (ICG) dye using membrane forceps. The internal drainage of SRF was conducted if a preexisting or iatrogenic retinal break was found during surgery. For silicone oil (SO) tamponade, if necessary, 5700 centistokes SO  was injected into the posterior surface of the pupil after fluid–air exchange. Secondary SO removal surgery was conducted among the SO-filled eyes after confirmation of SRF absorption on OCT scans.p-value < 0.05 was considered significant for all statistical tests.Statistical analyses were performed using the Statistical Package for the Social Science software version 20 . Repeated-measures analysis of variance, corrected by the Bonferroni method, was performed to compare the mean BCVA for the follow-up periods. The Pearson correlation coefficient was used to calculate the mean BCVA at the final visit and the duration of PSF. Ocular and systemic factors associated with PSF duration were analyzed using univariate and multivariate linear regression analysis. Kaplan–Meier analysis was used to show the survival time of PSF; One hundred patients were initially included; however, 60 patients were excluded according to the exclusion criteria. Thus, 40 patients (40 eyes) were enrolled in this study. The demographic and clinical characteristics of the enrolled patients are presented in 2. Thirty-four eyes had received panretinal photocoagulation, whereas 14 eyes received anti-VEGF treatment before surgery. Thirty-three eyes received an intravitreal bevacizumab injection one day before vitrectomy, and thirty-two eyes received phacovitrectomy. During pars plana vitrectomy, ILM peeling was performed in nine eyes. Moreover, thirty-three eyes had a preexisting or iatrogenic retinal break during vitrectomy, and SO tamponade was conducted after fluid–air exchange. Among the 33 eyes, intraoperative SRF drainage was conducted from a retinotomy site in 23 eyes by active aspiration. SO-filled eyes underwent secondary SO removal surgery at 9.6 ± 5.3 months  after primary surgery.Among the 40 patients, 23 were male and 17 were female. The mean age of all patients was 49.9 ± 12.0 years, the mean interval between diagnosis and surgery was 31.1 ± 32.8 days, and the mean duration of follow-up was 27.3 ± 18.2 months. The duration of diabetes mellitus was 9.2 ± 6.7 years. Fifteen patients had hypertension, and 10 patients had chronic kidney disease following hemodialysis. The preoperative laboratory results revealed that HbA1c was 9.3 ± 2.3, BUN was 24.7 ± 11.2 mg/dL, creatinine was 1.4 ± 0.9 mg/dL, and eGFR was 65.7 ± 29.2 mL/min/1.73mThe mean duration of PSF was 4.4 ± 4.7 months . The prevalence of PSF after surgery was 75.0% at 1 month, 50.0% at 3 months, 30.0% at 6 months, and 10.0% at 12 months. The mean SRFH was 106.7 ± 120.7 μm at 1 month, 57.3 ± 91.5 μm at 3 months, 32.3 ± 63.8 μm at 6 months and 5.3 ± 16.4 μm at 12 months after surgery. p = 1.0), 1.355 ± 0.454 after 3 months (p = 1.0), 1.116 ± 0.530 after 6 months (p = 0.372), 0.939 ± 0.532 after 12 months (p = 0.001), and 0.894 ± 0.695 at the final visit (p = 0.003). The mean BCVA significantly improved 12 months after surgery. The mean BCVA at the final visit had no significant correlation with the duration of PSF .The changes of mean BCVA were logMAR 1.401 ± 0.653 at baseline, 1.552 ± 0.489 after 1 month  = 0.029 to 0.286, p = 0.018), creatinine , and eGFR  were significantly associated with the duration of PSF in the univariate analysis. However, in the multivariate analysis, only eGFR was significantly associated with the duration of PSF . There were no significant associations between the duration of PSF and surgical factors, such as internal SRF drainage  or intraocular SO tamponade .Univariate and multivariate linear regression analyses of associations between clinical factors and PSF duration are presented in The surgical repair of TRD in patients with PDR is technically challenging. Iatrogenic retinal breaks are most likely to occur because of the friable nature of the ischemic retina and intraocular bleeding commonly occurs during the peeling of fibrovascular membrane . TheoretHowever, there is controversy over intraoperative procedures such as internal drainage or intraocular tamponade during pars plana vitrectomy in TRD. Meredith et al.  proposedKarimov et al.  reportedJung et al.  reportedInstead, we found that a lower eGFR level was a significant risk factor for long-standing PSF. The absorption of SRF depends on passive diffusion and the active pumping by RPE . HoweverGiven the similar pathophysiological features in diabetic retinopathy and nephropathy, studies found associations between the kidney function with diabetic retinopathy and diabetic macular edema. Man et al.  suggesteThis study has some limitations. It is a retrospective study with a small sample size and lack of a control group. Serum albumin was measured in only small number of patients. Therefore, further studies involving a greater number of cases will be necessary. Nevertheless, this study is significant for analyzing the risk factors of PSF in diabetic TRD patients after surgery.In conclusion, we showed that OCT detects PSF after successful diabetic TRD surgery. In addition, patients with impaired kidney function due to diabetic nephropathy tend to have a delayed SRF absorption. Therefore, the investigation of preoperative systemic conditions in PDR patients should be considered before TRD surgery. Additionally, it is important to explain to patients with impaired kidney function that PSF could be long-lasting after having a macula that requires diabetic TRD surgery.


The COVID-19 pandemic has led to increased usage of hand sanitizer products by the public to prevent the spread of COVID-19 and decrease the likelihood of acquiring the disease. The increase in demand has also led to an increase in the number of manufacturers. This work describes the FDA’s Center for Drug Evaluation and Research (CDER) laboratories efforts to develop tests to assess the quality of hand sanitizer products containing ethanol or isopropanol as the primary active ingredient. The products were evaluated for the active ingredient content and determination of the 12 impurities listed in the FDA Hand Sanitizer Temporary Guidance, followed by a spike recovery assay performed to verify the test results. Extensive method development was conducted including an investigation into the stability of ethanol, isopropanol, and the 12 impurities. Stability and kinetic studies confirmed the instability of acetal in acidic liquid hand sanitizer products during spike recovery assay testing. The headspace GC-MS method was validated according to ICH Q2 (R1) guidelines and the spike recovery assay was validated using three concentrations of standards for the drug product. During method application, six liquid hand sanitizer products were tested and all were determined to have ethanol or isopropanol above 70% v/v. Two liquid hand sanitizer products were determined to contain acetaldehyde as an impurity above the FDA recommended safety levels.The online version contains supplementary material available at 10.1186/s41120-021-00049-8. Responding to the Coronavirus Disease 19 (COVID-19) pandemic, the World Health Organization (WHO) and the Center for Disease Control (CDC) have placed a heightened importance on hand hygiene. The WHO and CDC have advised the use of alcohol-based hand sanitizers to help prevent viral infection when soap and running water were not available WHO . These rThe FDA has continued to regulate hand sanitizer products to ensure to product quality and protect the public from unsafe products from poor manufacturing practices FDA . The FDAAnalytical methods using infrared (IR) and Raman spectroscopy have been developed for determining ethanol and isopropanol content in hand sanitizer products  ICH  for specThis research describes the development of a headspace GC-MS method for ethanol, isopropanol, and 12 impurities in liquid hand sanitizer products. A unique challenge in the spike recovery of impurities was addressed and the cause of the variability in analytical results was determined to be hand sanitizer products with acidic pH. The headspace GC-MS method was validated according to ICH Q2 (R1) ICH  specificEthanol , acetaldehyde , acetal , acetone-d6 , cyclohexane , dimethyl sulfoxide , and acetic acid  were purchased from Sigma Aldrich. Certified reference standards of isopropanol (Lot: R048P0), methanol (Lot: R084K0), benzene (Lot: R101F0), acetone (Lot: I0M548), 1-propanol (Lot: R04060), ethyl acetate (Lot: R09350), 2-butanol (Lot: R09520), Isobutanol , 1-butanol (Lot: R048N0), 3-methyl-1-butanol (Lot: F0E242), and amyl alcohol  were purchased from the United States Pharmacopoeia . Water , ammonium hydroxide , and ammonium acetate  were purchased from Fisher Scientific. Dimethyl sulfoxide  was purchased from EMD Millipore. Orion buffer standards with pHs of 1.68, 4.01, 7, and 10.01 were purchased from Thermo Scientific. The liquid hand sanitizer products were received through the sampling assignment program issued by the Office of Quality Surveillance, a suboffice in the Center of Drug Evaluation and Research’s (CDER) Office of Pharmaceutical Quality.An Agilent GC 7890A coupled with a headspace sampler 7697A and an MSD 5977B was used for the analysis. A J&W DB-Select 624 UI GC column  was used for analysis. As part of method development, a J&W DB-Wax UI GC Column  was also tested. An Agilent ultra-inert split liner  was used in the inlet. Headspace GC vials  with Teflon/silicon septa screw caps (5188-2753) were purchased from Agilent. Rainin E4XLS electronic repeater pipettes were used for preparation of standards and samples. A vortex mixer and Mettler Toledo analytical balance were used for preparation of standards and samples. Chemglass amber vials and Pyrex glass bottles were used for storage of standards and samples.Headspace extraction of the 2 mL samples was performed at 125 °C for 10 min. One milliliter of headspace volume was then injected into the GC column over a period of 1 min using a split ratio of 100:1. The GC oven temperature started at 40 °C for 2 min, then increased at 20 °C/min to 160 °C, then increased at 60 °C/min to 240 °C, and held at 240 °C for 4 min. The GC run time was 13.33 min, post run time was 2 min at 240 °C, and the GC cycle time was 20 min. Mass detection by selected ion monitoring (SIM) was used for identification of product peaks. Retention times, quantifier ions, and qualifier ions for all compounds are listed in Table An Oakton series 11 pH meter was used for the pH measurements. The pH meter was calibrated using a 3-point calibration that covered the pH range of 1.68–7 or 4–10. After each measurement, the pH electrode was rinsed with deionized water.Each pH kinetic study was performed on a separate day. The compounds  were prepared as a concentrated stock solution. Three minutes prior to the 0 h timepoint, 100 μL of the concentrated analyte was added to 9.9 mL of buffer solution and the vial was vortexed for 30 s. Three minutes before each timepoint, a 200-μL aliquot was added to a GC vial containing 1.8 mL DMSO. The GC cycle time was 20 min so timepoints of 0, 1.66, 3.33, and 6 h were selected to accommodate the analysis of the five buffer solutions. Negative controls  were prepared by taking a 200-μL aliquot of the buffer only and adding to a GC vial containing 1.8 mL DMSO.Buffers for kinetic study. A stock solution of 0.2 M ammonium acetate buffer was prepared using 1.54 g of ammonium acetate per 100 mL water. The 0.2 M ammonium acetate buffer had a pH of 6.6. For the ammonium acetate buffers at pH 3 and pH 5, concentrated acetic acid was added dropwise until the desired pH was reached. For the ammonium acetate buffer at pH 8.5, concentrated ammonium hydroxide was added dropwise until the desired pH was reached. In addition to the four ammonium acetate buffers, water was included as a control.Acetal solution for kinetic study. One hundred twenty-seven microliters of acetal and 9.87 mL of DMSO were combined.Acetaldehyde solution for kinetic study. One hundred twenty-seven microliters of acetaldehyde and 9.87 mL of DMSO were combined.Ethanol solution for kinetic study. Pure ethanol was used.The analytical method was validated according to ICH Q2 (R1) ICH  for specIndividual stock of benzene (428 μg/mL). Four hundred twenty microliters of a 10.2 mg/mL benzene reference standard was added to a 20 mL vial containing 9.58 mL of DMSO.Individual stock of acetaldehyde (4985 μg/mL). One hundred twenty-seven microliters of an acetaldehyde standard was added to a 20-mL vial containing 19.873 mL of DMSO.Individual stock of acetal (10554 μg/mL). One hundred twenty-seven microliters of an acetal standard was added to a 20-mL vial containing 9.873 mL of DMSO.Individual stock of acetone-d6 . Three hundred eighty microliters of an acetone-d6 standard was added to a 20-mL vial containing 9.62 mL of DMSO.Individual stock of cyclohexane (10049 μg/mL). One hundred twenty-nine microliters of a cyclohexane standard was added to a 20-mL vial containing 9.871 mL of DMSO.Mixture A (ethanol and isopropanol). Two milliliters of ethanol and 2 mL of isopropanol were added to a 100 mL bottle containing 36 mL of DMSO.Mixture B . 3.61 mL of a 14.8 mg/mL methanol reference standard, 400 μL of individual stock of benzene, 400 μL of individual stock of acetal, and 852 μL of individual stock of acetaldehyde were added to a 100-mL bottle containing 34.74 mL of DMSO.Mixture C . Two hundred thirty-seven microliters of acetone, 53 μL of 1-propanol, 104 μL of ethyl acetate, 328 μL of 2-butanol, 1.15 mL of isobutanol, 52 μL of 1-butanol, 215 μL of 3-methyl-1-butanol, and 215 μL of amyl alcohol were added to a 20-mL vial containing 17.6 mL of DMSO.System suitability mixture. Two milliliters of mixture A and 2 mL of mixture B were added to a 20-mL vial containing 16 mL of DMSO. The vial was capped and vortexed for 20 s.Internal standard mixture. One milliliters of individual stock acetone-d6 and 1 mL of individual stock of cyclohexane were added to 250 mL bottle containing 98 mL of DMSO. The bottle was capped and mixed for 30 s.The system suitability standard containing ethanol, isopropanol, methanol, benzene, acetal, and acetaldehyde was injected six times at the start of each day of sample analysis. The retention time, peak area, USP tailing factor, and resolution were recorded for each peak. The repeatability of retention time (< 2% relative standard deviation (RSD)), peak area (< 2%RSD), USP tailing factor , and resolution (> 2) based on six replicate injections was calculated.Calibration curves (CC) for ethanol, isopropanol, benzene, acetaldehyde, acetal, and methanol were prepared using seven concentration levels. Linearity was determined by calculating the regression line by the method of least squares with a weighting factor of 1/x. Linearity was expressed as the correlation coefficient (r2) and required to be ≥ 0.99.Preparation of calibration standards . Seven vials were appropriately labeled CC1-CC7. Thirty-eight milliliters of DMSO was added to CC1, 18 mL of DMSO was added to CC2, 8 mL of DMSO was added to CC3, 4.66 mL of DMSO was added to CC4, 3 mL of DMSO was added to CC5, 1.33 mL of DMSO was added to CC6, and 0.5 mL of DMSO was added to CC7. To each CC vial was then added 1 mL of mixture A and 1 mL of mixture B. Each vial was capped and vortexed for 20 s.n = 3, at each QC level) were prepared using the mixture A and mixture B stock solutions in DMSO. All QC control standards were prepared in triplicate by adding 1.6 mL of DMSO, 0.2 mL QC control standard, and 0.2 mL of internal standard to the headspace GC vial.Quality control (QC) standards (Lower limit of quantitation (LLOQ) QC. One hundred fourteen milliliters of DMSO, 3 mL of mixture A, and 3 mL of mixture B were combined and vortexed for 30 s. The LLOQ QC concentration for each impurity was 25% of the allowable limit for hand sanitizer products.Low QC. Thirty-four milliliters of DMSO, 3 mL of mixture A, and 3 mL of mixture B were combined and vortexed for 30 s. The Low QC concentration for each impurity was 75% of the allowable limit for hand sanitizer products.Mid QC. Fourteen milliliters of DMSO, 3 mL of mixture A, and 3 mL of mixture B were combined and vortexed for 30 s. The Mid QC concentration for each impurity was 150% of the allowable limit for hand sanitizer products.High QC. Four milliliters of DMSO, 3 mL of mixture A, and 3 mL of mixture B were combined and vortexed for 30 s. The high QC concentration for each impurity was 300% of the allowable limit for hand sanitizer products.Spike mixture at 50% of the allowable impurity limit. Ninety milliliters of DMSO, 5 mL of mixture A, and 5 mL of mixture B were combined and vortexed for 30 s.Spike mixture at 100% of the allowable impurity limit. Thirty-five milliliters of DMSO, 5 mL of mixture A, 5 mL of mixture B, and 5 mL of mixture C were combined and vortexed for 30 s.Spike mixture at 200% of the allowable impurity limit. Fifteen milliliters of DMSO, 5 mL of mixture A, and 5 mL of mixture B were combined and vortexed for 30 s.The pH of all hand sanitizer products was measured using an Oakton series 11 pH meter. The density (g/mL) of each hand sanitizer product was determined by adding 2 mL of product to a vial and recording the weight (g).Preparation of a product for content assay. Thirty-one milliliters of DMSO and 1 mL of hand sanitizer product were combined and vortexed for 30 s. 0.5 mL of the solution was then added to a vial containing 24.5 mL of DMSO and vortexed for 30 s. To a 20-mL headspace GC vial, 1.6 mL of the hand sanitizer sample in DMSO was added with 0.2 mL of internal standard mixture and 0.2 mL of spike mixture. Negative control samples used 0.2 mL DMSO instead of 0.2 mL spike mixture.Preparation of a product for impurity analysis. Hand sanitizer volumes were adjusted so that the final concentration of hand sanitizer product in the GC vial was 21.25 mg/mL.A hand sanitizer product with a density of 0.85 g/mL was prepared by combining 1 mL of hand sanitizer product and 31 mL of DMSO in a vial and vortexed for 30 s. To a 20-mL headspace GC vial, 1.6 mL of the hand sanitizer sample in DMSO was added with 0.2 mL of internal standard mixture and 0.2 mL of spike mixture. Negative control samples used 0.2 mL DMSO instead of 0.2 mL spike mixture.n = 9 samples. The QC samples were injected in triplicate before the hand sanitizer samples, in the middle of the batch sequence, and after all hand sanitizer samples were injected. The spike recovery assay was conducted using the spike mixture at 100% of the allowable impurity limit.The method was applied to test six liquid hand sanitizer products. The products were tested for active ingredient content and impurity concentration. The system suitability test and calibration curve were prepared as described in the method validation section. Quality control standards at LLOQ QC and high QC concentrations were used to monitor instrument performance during the testing day. Each QC concentration was prepared as The analytical method was designed to quantitate ethanol, isopropanol, methanol, benzene, acetaldehyde, and acetal levels in hand sanitizer products, while also qualitatively determining whether the remaining eight impurities were above or below the allowable impurity limit Table . InjectiThe diluent selection was examined to best accommodate the mixture of alcohols and organics that needed to be evaluated. A mixture of water and DMSO was explored initially but an instability of response was observed using the headspace injection method  ICH  for specThe system suitability test measured the performance of the analytical system and must adhere to the criteria stated in USP general chapter <621> chromatography USP  for reteSpecificity of the method was determined by observing that no interfering peaks were present in the GC chromatograms of blanks and standards. Compounds were chromatographically separated, identified by retention time, and selectively resolved using MS selective ion monitoring detection with unique quantifier and qualifier ions  solution of ethanol in water and a 70% (v/v) solution of isopropanol in water were prepared. The dilution integrity test was conducted by diluting the 70% solutions according to the content assay protocol and comparing the determined concentration to the nominal concentration. The ethanol solution displayed accuracy of 108% with a %RSD of 1.9%  and as a collective group (n = 9). The accuracy among all compounds ranged from 90 to 110% and the precision ranged from 0.3 to 5.7%RSD . The table reports the % acetal remaining over 6 h in the various buffers tested. Acetal displayed instability in pH 5 and pH 3. Supplementary information Table 5. Acetaldehyde Kinetics Study . The table reports the % acetaldehyde remaining over 6 h in the various buffers tested. Acetaldehyde displayed stability in all buffers tested. Supplementary information Table 6. Ethanol Kinetics Study (% Ethanol remaining). The table reports the % ethanol remaining over 6 h in various buffers tested. Ethanol displayed stability in all buffers tested. Supplementary information Table 7. Spike Recovery after pH Neutralization of Acidic Liquid Hand Sanitizer Product. The recovery of acetaldehyde and acetal is improved after the pH of Product K is adjusted to pH 6 using ammonium hydroxide. Supplementary information Table 8. Intraday (n=3) and interday (n=9) accuracy of quality control standards. Supplementary information Table 9. Intraday (n=3) and interday (n=9) precision of quality control standards. Supplementary information Table 10. Signal-to-Noise at LLOQ. Supplementary information Table 11. Robustness Results. Supplementary information Table 12. Stock solution stability, 96 h. Supplementary information Table 13. Autosampler stability in DMSO, 72 h. Supplementary information Table 14. Autosampler Stability in Hand Sanitizer Products, QC LLOQ (25% of NMT Limit), 72 h. Supplementary information Table 15. Autosampler Stability in Hand Sanitizer Products, Spiking Solution (100% of NMT Limit), 72 h. Supplementary information Table 16. Autosampler Stability in Hand Sanitizer Products, QC High (300% of NMT Limit), 72 h. Supplementary information Table 17. Dilution Integrity. Supplementary information Table 18. Check QC standards to monitor instrument performance at QC LLOQ and QC High for accuracy and precision during product testing. Supplementary information Table 19. Spike Recovery Results During Method Application.


Optimal dose of methylprednisolone in patients with moderate or severe COVID-19 is unclear. In our hospital, the use of 250-500 mg/day of methylprednisolone was frequent in the first wave of the pandemic. Lower dose were recommended in our protocol since September 2020. The aim was to evaluate the impact of methylprednisolone dose in the outcome of patients with moderate or severe COVID-19.This is a retrospective and observational study. Inclusion criteria: SARS-CoV-2 infection diagnosed by PCR, admission to our hospital between March 2020 and February 2021, SatO2 < 94% or SatO2/FiO2 < 447. Two treatment groups were compared: patients treated with 0.5-1.5 mg/kg/day (group 1) and patients treated with more than 1.5 mg/kg/day (group 2). The primary outcome analyzed was orotracheal intubation (OTI) or death from any cause at 28 days after admission. Differences in demographic, clinical and laboratory characteristics between treatment groups were analyzed. Variables with P < 0.1 were included in a binary logistic regression model, calculating a propensity score for assigning each patient to group 1 treatment. Bivariate analysis was performed to identify variables associated with worst outcome. Finally, Cox regression was performed including treatment group, propensity score as covariate and all the variables with P< 0.05 in the bivariate analysis.285 patients were included, 197 in group 1 and 88 in group 2. The median age was 73 years, 52,3% were male. Mortality or OTI at 28 days was 24,9%. There was a higher proportion of patients in group 1 with COPD , dyspnea , sepsis . Patients in group 2 had more impaired consciousness . The median of lymphocytes count was lower in group 1 . There were no differences in the primary outcome between treatment groups . The use of high dose of methylprednisolone compared with intermediate dose is not associated with a better outcome in patients with moderate or severe COVID-19.All Authors: No reported disclosures