Pure red cell aplasia (PRCA) is a serious complication after ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT). Following HSCT, persistent anti-donor isohemagglutinins against donor ABO antigens are considered the immunological cause of PRCA. Patients with post-transplant PRCA are at risk for graft rejection and prolonged red blood cell transfusion dependency. No standard treatment exists. Recently however, the anti-CD38 monoclonal antibody daratumumab has been reported to be an effective treatment for post-transplant PRCA in patients with complete donor chimerism. Here, we describe the first case of PRCA in a patient with mixed lymphoid patient/donor chimerism that was successfully treated with daratumumab. This is also the first report of a transplant recipient with sickle cell disease who was treated with this relatively new approach. Fourteen months post-transplantation and twelve months after treatment with daratumumab, our patient has a normal complete blood count and the anti-donor isohemagglutinins remain undetectable despite mixed lymphoid chimerism. Mixed chimerism is a common manifestation in adult patients with sickle cell disease transplanted with non-myeloablative conditioning and a matched sibling donor. The application of non-myeloablative HSCT for patients with sickle cell disease is steadily increasing. Therefore, the incidence of PRCA in this setting might also increase. As the risk of graft rejection due to PRCA can be especially high in patients with mixed chimerism, clinicians should be aware that daratumumab can be an effective treatment in the setting of mixed chimerism. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only established curative treatment option for sickle cell disease (SCD). In adults with SCD, myeloablative conditioning is associated with significant toxicity, primarily because of cumulative organ damage. Newer non-myeloablative conditioning regimens, however, have rendered allogeneic HSCT a viable treatment option for adult SCD patients , 2. ThesPure red cell aplasia (PRCA) after ABO-mismatched HSCT is a serious complication that is associated with delayed engraftment , 4. FurtMixed chimerism following HSCT with a major AB0-mismatched donor in patients with SCD might be associated with an even higher risk of PRCA, as a significant proportion of the adaptive immunity in these patients is still recipient-derived. For this reason, the first studies evaluating non-myeloablative conditioning regimens  in matched sibling donor transplantations in SCD patients excluded patients with AB0-mismatched donors (1). The use of an AB0-mismatched donor was later shown to be feasible, but the exact risk of PRCA and its implications for graft failure in transplanted SCD patients with mixed chimerism is not known.(2) Although pre-transplant rituximab has been used as a strategy to prevent PRCA, it remains unclear whether it significantly decreases its incidence .Recently, several cases of post-transplantation PRCA have been described that were successfully treated with the anti-CD38 monoclonal antibody daratumumab , 8. All 9/L, 21.7% of lymphocytes). In the 12 months follow-up period after initiation of daratumumab to date, no transfusions or other immunosuppressive therapies have been necessary, and anti-B isohemagglutinins remain undetectable.In February 2022, a 27-year old male with SCD was transplanted with an ABO-mismatched HLA-identical sibling donor . He received alemtuzumab 1 mg/kg total dose and total body irradiation (3 Gy) as conditioning, followed by peripheral blood stem cell infusion. Graft versus host-disease (GvHD) prophylaxis consisted of sirolimus. The conditioning regimen was preceded by a 3 month long preconditioning phase with azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day. In the months before HSCT, the patient developed a serious delayed hemolytic transfusion reaction (DHTR). In the past, the patient was diagnosed with anti-Jk(b) antibodies, which had disappeared at the time of the DHTR. However, new anti-Wr(a) antibodies and nonspecific cold auto-antibodies were detected at the time of DHTR. The patient was successfully treated with prednisolone and immunoglobulins. Subsequently, 3 weeks before a planned pre-transplant RBC exchange transfusion, he was treated with rituximab (375 mg/m2) to reduce the risk of another episode of DHTR. Blood group genotyping of the matched sibling donor was performed, which was positive for Jk(b) and negative for Wr(a). No antibodies to the donor’s RBC antigens were present before the transplantation. After transplantation, rapid engraftment of leukocytes and platelets occurred. However, the patient remained anemic with profound reticulopenia, for which he needed regular RBC transfusions, receiving a total of seven RBC units before resolution of PRCA. Physical examination revealed no abnormalities. Donor myeloid chimerism was >95%, ruling out primary rejection of the allograft. A PCR for parvovirus B19 DNA was negative. Post-allogeneic HSCT isohemagglutinin titers remained present . No other RBC antibodies were detected at the time of the PRCA. Pure red cell aplasia was diagnosed and treatment with 4 weekly doses of daratumumab  was started on day +60 post-transplantation. Daratumumab was tolerated fairly well by the patient, besides an episode of fever grade 2 (CTCAE v.5) and headache grade 1 (CTCAE v.5), which occurred after the second dose. After 4 doses of daratumumab, prompt increases of hemoglobin and reticulocyte counts Figure 1Pure red cell aplasia after HSCT using ABO-mismatched donors is a well-known complication, but no standard treatment for post-transplant PRCA has yet been established. In case series evaluating the natural cause of PRCA after HSCT, the time to spontaneous RBC engraftment was reported to be at least several months but does not occur in all cases , 10. EarSince the first case report in 2018, 11 cases of successful use of daratumumab as a treatment for PRCA after HSCT have been published , 8. MostAfter non-myeloablative conditioning regimens in patients with SCD resulting in mixed chimerism and generally very low donor T-cell chimerism in the early post-transplant period, tapering sirolimus is not a safe option due to the increased risk of graft rejection , 13. OurCurrently, the longest documented response after daratumumab treatment is 2.5 years . Longer In conclusion, we report the first case of PRCA in the setting of mixed chimerism after non-myeloablative HSCT for SCD that was successfully treated with daratumumab. Further study of daratumumab for PRCA is warranted to optimize this approach and to determine its optimal dosing and duration.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ED and EN wrote the manuscript. BB critically reviewed the manuscript. All authors contributed to the article and approved the submitted version.


Hepatorenal syndrome type 1 (HRS-1) is an often fatal, but potentially reversible, kidney failure in patients with decompensated cirrhosis.Treatment with terlipressin in patients with HRS-1 is associated with a reduction in the need for RRT.i.e., OT-0401, REVERSE, and CONFIRM). However, these RCTs were not designed to evaluate the effect of terlipressin on the requirement of RRT. In this study, the effect of terlipressin on RRT requirements in the pooled phase III patient population was assessed.Hepatorenal syndrome type 1 (HRS-1)—also known as hepatorenal syndrome-AKI (HRS-AKI)—is a rapidly progressing and usually fatal, but potentially reversible, kidney failure occurring in patients with decompensated cirrhosis. A large proportion of patients with HRS-1 require renal replacement therapy (RRT). Terlipressin demonstrated efficacy in reversing HRS and improving renal function in patients with HRS-1 in three phase III, randomized, clinical trials .For this retrospective analysis, data from patients who participated in the OT-0401, REVERSE, and CONFIRM studies were integrated in the largest-to-date randomized database (P = 0.040) and day 60  in the pooled population and also postliver transplantation (LT) at day 60  and day 90 . More patients were alive and RRT-free by day 90 in the overall population  and among patients who received an LT . Random assignment to receive terlipressin was an independent positive predictor of avoidance of RRT (P = 0.042); while higher baseline serum creatinine (sCr) level and Child-Pugh scores were negatively associated with RRT avoidance .The need for RRT was significantly decreased in patients in the terlipressin group versus the placebo group by day 30 (28.1% versus 35.9%, respectively; Terlipressin decreased the requirement of RRT compared with placebo among patients with HRS-1, including those receiving LT. A lower sCr level at the beginning of therapy was associated with avoidance of RRT. The effect of terlipressin on RRT requirements in patients undergoing LT is of particular interest because peri-LT RRT is associated with poor outcomes post-transplant.14 Using data from the largest-to-date, pooled patient population from the three phase III studies  facilitated evaluation of the effect of terlipressin therapy on RRT and assessment of baseline predictors of avoidance of RRT.In three randomized, placebo-controlled, phase III studies  or placebo was administered through intravenous bolus injection for up to 14 days. If, after day 3, sCr levels had decreased—but by <30%—then the terlipressin dose could be increased to 2 mg every 6 hours. Concomitant albumin was strongly recommended . Figure Data from patients who participated in the OT-0401,i.e., intermittent hemodialysis and continuous RRT, including continuous hemofiltration, continuous hemodialysis, continuous hemodiafiltration, peritoneal dialysis, and other dialysis techniques). Outcomes were evaluated in the intent-to-treat (ITT) population, and in those who received an LT, up to 90 days from the first treatment dose. Patients who received simultaneous kidney and liver transplants were excluded from the post-LT outcomes analysis.RRT was defined as any procedure to replace nonendocrine kidney function ; partial response (PR)—defined here as a >30% reduction in sCr but not achieving HRS reversal; and no response (NR)—defined as a ≤30% reduction in sCr from baseline to the end of treatment.The need for RRT was evaluated with respect to response to terlipressin therapy. Complete response (CR) was defined as HRS reversal .N=608), 352 and 256 patients were randomly assigned to receive terlipressin and placebo, respectively. Baseline patient characteristics were similar between treatment groups and reflected the presence of advanced liver disease : Mean (SD) Model for End-stage Liver Disease (MELD) scores were 33.0 (SD 6.4) and 33.1 (SD 5.9) in the terlipressin and placebo groups, respectively; over 65% of the patients in both groups had Child-Pugh-Turcotte class C (scores between 10−15). Acute-on-chronic liver failure grade 2−3 occurred in 53.4% of patients in the terlipressin group and in 55.1% of patients in the placebo group  was observed in 117/352 (33.2%) patients in the terlipressin group and in 42/256 (16.4%) patients in the placebo group (P < 0.001). In the combined treatment population, the need for RRT up to day 90 was significantly reduced in patients who experienced a CR (n=159) compared with NR  versus NR .A CR (P = 0.040) and day 60 ; by day 90, the incidence of RRT was 31.5% in the terlipressin group versus 38.3% in the placebo group  and among those patients who received an LT ; Figure P = 0.276); Figure More patients who were randomly assigned to the terlipressin group (versus placebo) were alive and RRT-free by day 90 in the entire pooled ITT population  were included in this analysis.Predictors of RRT avoidance were evaluated in the pooled ITT population but excluded those patients who died before receiving RRT to avoid the competing effect of death on the resultant data; 412 patients   and higher scores for liver disease severity  were negative predictors of RRT avoidance in the combined treatment group  were included in the multivariable analysis with stepwise selection. Of note, the sCr value is included as a component in the MELD score calculation, along with bilirubin and international normalized ratio16; however, the latter two variables were not significant in the univariable analysis. Therefore, only baseline sCr values  were included in the multivariable analysis (as a continuous variable). The results confirmed that assignment to the terlipressin group was independently associated with avoidance of RRT (P = 0.042), while higher baseline sCr levels and Child-Pugh scores were associated with the need for RRT .5 Consequently, patients with HRS-1 commonly require admission to the intensive care unit and administration of continuous RRT.5 Peri-LT RRT is a negative prognostic factor for LT outcomes. For example, in a retrospective cohort study of patients with decompensated cirrhosis and HRS-1 (N=62), the duration of pretransplant dialysis was the only predictor of HRS nonreversal, with each additional day of pretransplant dialysis corresponding to a 6% increase in the risk of nonreversal.22 RRT post-LT in patients with HRS-1 is a profound risk factor for chronic RRT dependency and death in LT recipients. A large retrospective study (N=743) showed that post-transplant dialysis within 90 days after an LT was the strongest risk factor for progression to the need for chronic dialysis (relative risk=30.5), and only 37% of patients who needed RRT post-LT survived for 5 years after the first transplant.23 Conversely, patients who achieved HRS reversal with vasopressor therapy alone  experienced good post-transplant outcomes, similar to those patients without HRS-1 who received a transplant.24 Collectively, surviving without the need for RRT is associated with reduced morbidity, better quality of life, and improved outcomes in patients with HRS-1, including LT recipients.Patients who were randomly assigned to terlipressin in the OT-0401, REVERSE, and CONFIRM phase III studies had a statistically significant improvement compared with placebo in kidney function, defined as a decrease in sCr or by achieving HRS reversal .1113 Moreover, this study provides new evidence indicating that terlipressin treatment, compared with placebo, reduces RRT requirements overall and, importantly, post-LT  was not different among those who ultimately avoided RRT compared with those who needed RRT at a later time point during the study period. As expected, there were significantly more patients who achieved a CR among those who did not need RRT compared with those who did need it (P < 0.001). These results support the data presented in Table Among those who achieved a CR , the median time to a CR  were associated with a greater need for RRT by day 90 in the overall population. As expected, a higher baseline sCr was also a negative predictor of RRT avoidance in both the terlipressin and placebo groups, when treatment groups were analyzed separately. In addition, a higher MELD score was a negative predictor of RRT avoidance in the terlipressin group, while higher baseline MAP—likely indicating a less-severe hemodynamic derangement from HRS-1—was positively associated with RRT avoidance in the placebo group.Baseline factors associated with improved kidney function (defined by a reduction in sCr level) were previously evaluated. A lower baseline MELD score and lower sCr level were associated with HRS reversal in the OT-0401 and REVERSE studies; in addition, in REVERSE, baseline serum bilirubin was also identified as a significant factor associated with improved kidney function.25 As recently shown by Curry et al.,26 more patients with a sCr level of <5 mg/dl stay alive and RRT-free through day 30 compared with the sCr ≥5 mg/dl subgroup . Therefore, early initiation of treatment with terlipressin, while sCr levels are relatively low, may reduce the need for RRT in patients with AKI because of HRS-1.The multivariable analysis confirmed the significance of baseline sCr level and Child-Pugh score as independent factors associated with the need for RRT. These findings were not unexpected, as more advanced liver disease—characterized by a higher Child-Pugh score and higher sCr level—is associated with a more severe AKI and, consequently, a greater risk of the need for RRT.. Owing to the post hoc nature of the analysis, not all data were available from all three studies , which precluded RRT-free survival analyses and competing risk and hierarchical analyses in the pooled population. In addition, the duration of follow-up did not extend beyond 90 days, which prevented evaluation of longer-term outcomes. Finally, the studies were designed before the adoption of the current HRS-AKI diagnostic criteria proposed by the International Club of Ascites in 2015, which defined HRS-AKI as a doubling in sCr in 14 days, rather than a fixed threshold of sCr, allowing for an earlier detection and treatment of HRS-1.15 Consequently, we could not evaluate the effect of terlipressin on RRT when implemented as an early treatment for HRS-1.This study has several limitations1113 Extensive evidence in the literature demonstrates that AKI-RRT is associated with more ominous acute and long-term outcomes compared with AKI without the need for RRT.27 Therefore, any medication that reduces the need for RRT should be considered favorable for patients with cirrhosis and HRS-1.Despite the limitations, our findings expand on the knowledge regarding the therapeutic benefit of terlipressin in patients with HRS-1 presented in the primary analyses of the OT-0401, REVERSE, and CONFIRM studies.post hoc analysis affirm that pharmacological intervention with terlipressin plus albumin may reduce the need for RRT in patients with HRS-1, including among those who receive an LT. Association of a lower sCr value at the beginning of therapy with avoidance of RRT may support an earlier start for HRS-1 treatment initiation .The results from this


Mobile interventions enable personalized behavioral support that could improve smoking cessation (SC) in smokers ready to quit. Scalable interventions, including unmotivated smokers, are needed. We evaluated the effect of personalized behavioral support through mobile interventions plus nicotine replacement therapy sampling (NRT-S) on SC in Hong Kong community smokers.A total of 664 adult daily cigarette smokers  were proactively recruited from smoking hotspots and individually randomized (1:1) to the intervention and control groups . Both groups received brief advice and active referral to SC services. The intervention group received 1-week NRT-S at baseline and 12-week personalized behavioral support through SC advisor-delivered Instant Messaging (IM) and a fully automated chatbot. The control group received regular text messages regarding general health at a similar frequency. Primary outcomes were carbon monoxide-validated smoking abstinence at 6 and 12 months post-treatment initiation. Secondary outcomes included self-reported 7-day point-prevalence and 24-week continuous abstinence, quit attempts, smoking reduction, and SC service use at 6 and 12 months.By intention-to-treat, the intervention group did not significantly increase validated abstinence at 6 months  and 12 months , as were self-reported 7-day point-prevalence abstinence, smoking reduction, and SC service use at 6 and 12 months. More participants in the intervention than control group made a quit attempt by 6 months . Intervention engagement rates were low, but engagement in IM alone or combined with chatbot showed higher abstinence at 6 months .Personalized behavioral support through mobile interventions plus NRT-S did not significantly improve abstinence in community smokers compared to text only messaging. The suboptimal intervention engagement needs to be addressed in future studies.ClinicalTrials.gov NCT04001972. Longer term effect of mobile SC interventions is uncertain as few RCTs (15%) had a follow-up beyond 6 months2. Most trials targeted smokers willing to make a quit attempt in the next 30 days5. The population-level effect of mobile interventions remains unknown as many who do not want to quit or plan to quit were not included. Over two thirds (68.8% in 2019) of current smokers had never made a quit attempt in Hong Kong, where the smoking prevalence has been one of the lowest worldwide (10.2% in 2019)6. Mobile interventions in the community smokers with longer follow-up length are needed.Mobile interventions enable highly accessible, lowcost, and personalized behavioral support for smoking cessation (SC). A Cochrane review of 13 randomized controlled trials (RCTs) showed that text messaging interventions through Short Message Service (SMS) were more effective than minimal SC support in increasing quitting  at 6 months or longer 7. Our pragmatic RCT further showed that IM intervention was effective for SC in community smokers8. However, the intervention engagement rate was low (17%), which might be due to the unavailability of human SC advisors outside office hours8. SC support could be sustained using chatbots , online computer programs that can simulate human conversations. Evidence on chatbots for SC is emerging but remains scarce and limited. A formative study showed that a chatbot increased motivation to quit immediately after usage in a volunteer sample of young smokers9. An RCT focusing on smokers motivated to quit identified that adding a chatbot to an SC app more than doubled intervention engagement with the app , but the effect on SC was unclear because of a low retention rate at 1 month (10.7%)10. A pragmatic RCT in primary care settings showed that a chatbot was marginally more effective than usual care  despite of potential non-response bias due to a low retention rate (45.2%)11.Instant Messaging  is a popular and inexpensive alternative to SMS. Our qualitative interviews on community smokers (76% had no quit plan in the next 6 months) showed that the provision of more personalized behavioral support from human SC advisors was the most valued utility of IM for SC12 of proactively reaching community smokers who were largely unmotivated to quit and reasonably representative of the general smoking population regarding their sociodemographic and smoking characteristics8. Our 2015 RCT in the proactively recruited community smokers showed that brief advice using the AWARD model  was effective for SC13. Our 2017 RCT further developed the IM intervention combined with the AWARD model and supported the effectiveness for SC8. Nicotine replacement therapy sampling (NRT-S) has been used in unmotivated smokers and was found to be effective for increasing quit attempts and full-course NRT use14. A recent RCT in unmotivated smokers showed that mobile intervention plus NRT-S led to higher abstinence at 6 months than NRT-S alone15. Our pilot RCT showed that the IM intervention plus NRT-S was feasible with positive effects on quitting, smoking reduction, quit attempts, and NRT-S use in community smokers16. The present RCT developed a chatbot in addition to the established AWARD model, IM intervention, and NRT-S. We aimed to evaluate the long-term (6 and 12 months) effect of personalized behavioral support through IM and chatbot plus nicotine replacement therapy sampling (NRT-S) on SC in Hong Kong community smokers.The interventions in the present RCT were developed based on established evidence of our prior studies and RCTs. We have developed and tested an approach17. We followed the Consolidated Standards of Reporting Trials of Electronic (CONSORT)-EHEALTH extension (Supplementary file)18. The trial protocol is available in the Supplementary file. All participants provided written informed consent.This was a two-arm, parallel, assessor-blinded randomized controlled trial that was fairly pragmatic according to PRECIS-2 (Pragmatic Explanatory Continuum Indicator Summary) tool16. Smoking at least once cigarette daily has also been widely used for defining daily smokers in large-scale studies worldwide20. Exclusion criteria included smokers who had psychiatric/psychological diseases or were on regular psychotropic medications; were using SC medication, NRT, other SC services; or had contraindication for NRT use, including severe angina, arrhythmia, myocardial infarction, pregnancy (or intended to become pregnant within 6 months) or breastfeeding, which were screened using dichotomous questions (yes/no).Participants were proactively recruited from smoking hotspots, outdoor places where smokers gather and smoke , throughout Hong Kong from 19 August 2019 to 8 May 2020. Note that the recruitment was temporally suspended from 22 January 2020 to 9 April 2020 due to the COVID-19 pandemic . We recruited Hong Kong residents aged ≥18 years who were able to read and communicate in Chinese; currently smoked at least one cigarette daily, validated by an exhaled carbon monoxide level of ≥4 parts per million (ppm); and owned a smartphone and were willing to install an IM app . The inclusion criteria of smoking at least one cigarette daily was consistently used in our prior trials for recruiting community smokers who were largely representative of daily cigarette smokers in the general population in Hong KongAn experienced research assistant and trained SC advisors proactively approached smokers using a ‘foot-in-the-door’ approach. Smokers were asked about smoking behaviors, assessed for exhaled carbon monoxide level, and invited to participate in the study. Those showing interest were assessed for eligibility, and written informed consent was sought. Eligible participants completed a brief self-administered baseline questionnaire to provide data on sociodemographic and smoking characteristics and quality of life. To avoid intervention contamination, 1 smoker was randomly approached when there were more smokers at the same hotspot. Smoking-related outcomes were measured in follow-up questionnaires through telephone interviews conducted by the experienced research assistant or trained SC advisors at 3, 6, and 12 months after randomization (intervention initiation), and quality of life was additionally assessed at 12 months.The randomization sequence with a 1:1 allocation ratio and permuted block of 4, 8, or 12 was generated by a non-investigator. Sequentially numbered, opaque, sealed envelopes (SNOSE) were prepared by an investigator not involved in participant enrolment for allocation concealment. Once a smoker signed the consent form, one SNOSE was opened according to the serial number to determine the group allocation. Masking of participants, the research assistant, and SC advisors was not possible due to the nature of behavioral interventions. Statistical analysts were blinded from the group allocation.13. Participants were asked about smoking behaviors (Ask) and invited for an exhaled carbon monoxide test. The results were used to warn about the harms of continued smoking together with a leaflet  containing shocking pictures of smoking-induced diseases (Warn). Participants were advised to quit promptly using NRT or SC services (Advise) and offered a referral to a free SC service (Refer). Contacts of the participants were sent to the SC service providers of their choice for further treatment . The above advice was repeated at each follow-up (Do-it-again).Both groups received brief advice using the AWARD model  at baseline21. The dose of the NRT-S was assigned based on the time to the first cigarette of the day22. Participants who had their first cigarettes >30 minutes after waking up and had not previously used NRT received 2 mg nicotine gum or 14 mg nicotine patch, while those who smoked ≤30 minutes were given 21 mg nicotine patch (4 mg NRT gum is not available in Hong Kong). The research assistant and trained SC advisors briefly instructed the participants on the usage of NRT and gave an instruction card  containing information on NRT use and potential side effects.The intervention group additionally received 1-week free NRT-S  in the original packing (7 NRT patches or 84 pieces of gum). Our previous trial found no difference in quit rates between 1-week or 2-week NRT-S23, covering information such as knowledge and skills of quitting, benefits of quitting, strategies to manage urges to smoke for self-efficacy, and SC services, for example, ‘Please identify the important things in your life, which may be related to personal or family health, interpersonal relationships, finances, or others. The important thing can be the driving force for quitting smoking!’. The schedule of messages was adjusted to the participant’s baseline readiness to quit  according to the Transtheoretical Model (TTM)24. All participants received a message once a week to initiate an IM conversation. The frequency increased to once daily for the week of the targeted quit date and twice weekly for the week before and after the week of the quit date. The schedule could be adjusted as requested by smokers during IM conversations.As an extension of the AWARD model at baseline, the intervention group received 12-week personalized behavioral support delivered through SC advisor-delivered IM and a fully automated chatbot. Regular IM messages were guided by the Social Cognitive Theory (SCT)SC advisors interacted in real-time with smokers through IM, providing behavioral support to avoid or handle high-risk situations of smoking (e.g. cigarette invitation from friends), instructions the use of NRT-S and breaking the habitual smoking by time-contingent messages (e.g. first cigarette in the morning). Proactive IM messages such as asking about the recent progress of SC were used to initiate the conversation, for example, ‘During this period of time, I have heard lots of good news one after another. Some people said that they had completely quit smoking, and some had reduced smoking. How about your progress? You can share it with me’. SC advisors delivered SCT- and TTM-guided advice and actively referred the smokers if they expressed the need for SC services.8. The themes of the questions were quitting methods, craving management, self-efficacy to quit, novel tobacco products, and others, and an input textbox was available for participants to text their queries. Responses to the questions were drafted based on our previous experience in SC counselling and had been further refined according to comments from experienced SC counsellors and service users in Tung Wah Group of Hospitals Integrated Centre on Smoking Cessation, one of the main SC service providers in Hong Kong. Then, a prototype was built using IBM Watson and pilot-tested on 5 smokers recruited from smoking hotspots. The final version of the chatbot was incorporated with Application Programming Interface with a backend server support and continuous data collection. The chatbot was designed as web-based considering that unmotivated smokers were found to be unlikely to download apps for SC25. Each participant in the intervention group received a unique link to access the chatbot for tracking individual’s engagement. SC advisors proactively sent a total of 6 reminders of chatbot URL through IM every two weeks during the 12-week personalized behavioral support. The contents of the Chatbot (Supplementary file Table 1) were unchanged during the trial, being accessed only by participants in the intervention group and was not open to the public. The interventions had been archived in a local server. We conducted post hoc qualitative interviews with chatbot users after the completion of the trial and reported results elsewhere26.A rule-based chatbot called ‘Quit Buddy’ had been developed by a multidisciplinary research team comprising experts in public health/ community medicine, computer engineering and experienced SC advisors. See Supplementary file for the structure, schematic of the system, contents, and screenshots of the chatbot. The chatbot was developed for supplementing human SC advisors to answer common queries related to SC, which were identified from the IM dialogues between over 200 smokers and SC advisors in our previous trial27.The control group received the same AWARD model as the intervention group at baseline, an established standard care model for Hong Kong community smokers. They additionally received regular SMS messages on healthy lifestyles and reminders to participate in the follow-up surveys for quitting, with a similar frequency to the regular IM sent to the intervention group. Our previous RCT isolating the effect of regular SMS messages on general health resulted in no improvement in quitting28. Participants who reported having quit tobacco use for 7 days or longer at follow-up at 6 and 12 months were invited for breath carbon monoxide tests. Those who agreed to the tests were given HK$300 (approximately US$38) in cash for their time and travelling expenses.Data were collected in person at baseline and through telephone interviews at 3, 6, and 12 months after randomization (intervention initiation). The primary outcomes were carbon monoxide-validated (<4 ppm) smoking abstinence at 6 and 12 months after intervention initiation29.Secondary outcomes included self-reported 7-day point prevalence and 24-week continuous abstinence; quit attempts; smoking reduction, defined as the self-reported reduction in the number of cigarettes per day by at least 50% of the baseline amount; and SC service use, defined as having attended at least one treatment session delivered by a SC service provider, at 6 and 12 months. Quality of life was assessed at baseline and at 12 months using the validated Chinese EQ-5D-5L questionnaire, with responses transformed using the standard Hong Kong value set form ranging from -0.864, the worst to 1, the best13. Given an assumed effect size of 1.8 derived from a meta-analysis of mHealth SC RCTs (RR=1.83)30, power of 80% and an allocation ratio of 1:1, the required sample size for detecting a significant difference in biochemically validated abstinence rates between the intervention group and control group at two-sided type I error of 0.05 is 664 (each group 332).The sample size was estimated based on our previous trial, which found that the group receiving brief advice and active referral had a 6-month biochemically validated abstinence rate of 9.0% by intention-to-treat analysis8. Fifty imputed datasets were generated, and results were pooled according to Rubin’s rule31.All analyses were performed according to a prespecified statistical analysis plan. Primary analyses were by intention-to-treat, assuming participants with missing outcomes to have had no change in smoking behaviors from baseline. Logistic regression was used to compare the SC outcomes between groups. Planned sensitivity analyses were conducted for primary analyses. First, complete case analyses were conducted by excluding participants lost to follow-up. Second, multiple imputation by chained equations assuming data were missing at random was conducted. The imputation models included the outcomes, group allocation, and sociodemographic and baseline smoking-related characteristics that were associated with abstinence or missingness, including sex, age, education level, monthly household income, daily cigarette consumption, time to the first cigarette after waking, previous quit attempt, and readiness to quita priori subgroup analyses by baseline characteristics, including sex, age group, education level, nicotine dependence level, any previous quit attempt, and readiness to quit in 30 days. Multiplicative interaction terms of baseline characteristics × group allocation were included in logistic regression models to calculate the p values for interaction, although the study was not powered to examine interaction. In the intervention group, we examined the associations of intervention engagement, defined by IM/chatbot use (verified by WhatsApp conversation log8 and chatbot backend), self-reported use of NRT-S at 3 months, or both, with validated abstinence outcomes, adjusting for established predictors of SC outcomes, including sex, age, nicotine dependence, previous quit attempt, and readiness to quit32. All analyses were conducted in Stata/MP version 15.1. A 2-tailed p<0.05 indicated statistical significance.We conducted In the intervention group, 33.1% (110/332) had used mHealth technologies  and 25.6% (85/332) had used NRT-S by 3 months. Participants had only minor problems in their health status at baseline  and 12 months . No differences were found between the 2 groups.This pragmatic RCT found that behavioral support through IM and chatbot combined with NRT-S compared with SMS on general health did not significantly improve validated abstinence (primary outcome), self-reported 7-day point-prevalence abstinence, smoking reduction, and use of SC services at 6 and 12 months, in proactively recruited community smokers in Hong Kong. However, engagement with the combined intervention of behavioral support through IM, chatbot, and NRT-S was low in the intervention group.1 and meta-analyses2. One explanation was the inclusion of many participants who were not motivated to quit . The validated abstinence at 6 months of the intervention group (3.9%) was lower than those of previous RCTs in smokers with high motivation to quit (6.0–11.1%)5. Note that a direct comparison might not be feasible due to the differences in study settings and populations. Besides, the control group in our group received brief advice and active referral, which has been proven highly effective in increasing quitting in our previous RCT13. Through an active referral, the control group was given the same access to conventional, evidence-based smoking cessation treatment  as the intervention group. The addition of mobile interventions and NRT-S might provide small additional benefits on quitting, as evidenced by the smaller than expected effect size.Our findings were discrepant with the individual and additive effects of mHealth text messaging interventions for SC in the Cochrane review33. Similarly, we found low intervention engagement . Engagement in IM only was associated with a higher abstinence rate, and engagement in both IM and chatbot further increased the abstinence rate at 6 months, suggesting the suboptimal intervention engagement might lead to an underestimation of the intervention effects. Our trial included over 85% of participants were employed, and long working hours, particularly in Hong Kong, might be one of the barriers of IM interactions. Our previous qualitative study showed that ‘too busy’ was one of the most common reasons for not engaging in IM interventions34. Future trials on mHealth SC support may balance the busy schedule of participants by extending IM-based service hours. Our qualitative interviews showed that participants in this RCT perceived the chatbot as too robotic and unable to proactively initiate conversation, hence discontinuing the chatbot usage26, despite that a total of 6 reminders were proactively sent by SC advisors. Future SC chatbots could incorporate artificial intelligence techniques such as natural language processing and machine learning to better simulate human-to-human interaction. The use of an URL to enter the web-based chatbot might also reduce its convenience and accessibility, which are known barriers of engagement in mHealth interventions33. Some SC chatbots have been embedded in popular IM apps to improve the accessibility.Engagement has been a major challenge for mHealth interventions, particularly for those not ready for behavior change8 and in workplaces 35. Though empirical evidence on the effectiveness of chatbot for SC is limited, a qualitative study showed that chatbot could be used for seeking distraction from cravings and maintaining motivation to quit36. Our qualitative findings further indicated that the chatbot could provide more credible information on quitting than other online information sources, and the information acted as quitting reminders for participants26. The increase in quit attempts might also be explained by the addition of 1-week NRT-S at baseline, which is known to promote quit attempts for unmotivated smokers14. We noted that participants with no previous quit attempts and no readiness to quit in the next 30 days showed stronger intervention effects on validated abstinence at 6 and 12 months, although the interaction effects were non-significant, possibly due to the small sample size. The combination of IM, chatbot, and NRT-S focused on enhancing psychological support and self-efficacy, which might be particularly effective in participants who did not have a motivator to quit. Our findings imply that smokers not having committed to quitting yet might be receptive to mHealth plus NRT-S to make quit attempts or quit smoking.An interesting result was that significantly more quit attempts were shown in the intervention group than the control group at 6 months . The quit attempt rates, particularly of the intervention group, and effect size were larger than those observed in our previous IM-based interventions in the community 14. Future RCTs comparing the effects of the interactive chatbot with one-way text messaging are warranted for advancing mHealth strategies for SC. Second, at 6 and 12 months, 32.8% and 26.8% of participants were lost to follow-up, respectively, and 61.7% and 50.0% of self-reported abstinence were not biochemically verified, comparable with our previous low-contact mobile SC RCT8. Nevertheless, our sensitivity analyses using multiple imputations and by complete case yielded similar results by intention-to-treat, reducing concerns about non-response bias. Third, the effects of interventions on SC might be influenced by unmeasured factors, such as the duration participants had been smoking and digital health literacy. Fourth, participants were mainly male and were mostly with a low to moderate level of nicotine dependence, without past quit attempts, and not ready to quit in the short-term. The generalizability of our results is uncertain to other populations with different sociodemographic and smoking characteristics. Fifth, this trial may be less applicable to other interventions that do not refer to SC services or in other settings with limited SC services. Sixth, future user-centered research may explore the usability, easiness of use, and aesthetic design of the chatbot.Strengths of this trial include an evidence-based, proactive approach to reach community smokers, a randomized study design, long-term follow-up at 6 and 12 months, and biochemical verification of abstinence. Our trial has several limitations. First, the combined interventions restricted us to disentangle the effects of each intervention component . IM and NRT-S have been found effective independently in previous SC trialsMobile interventions plus NRT-S showed small non-significant increases in abstinence in community smokers. Improving intervention engagement is needed to maximize the effectiveness of such interventions.Click here for additional data file.


Intensive care units (ICUs) had to rapidly adapt infection prevention and control (IPC) practices during the coronavirus disease 2019 (COVID-19) pandemic.To determine ICU nurses’ COVID-19 IPC-related knowledge, attitudes, practices, and perceptions.A mixed-methods study was conducted at the Groote Schuur Hospital ICU, Cape Town, South Africa (20 April 2021 and 30 May 2021). Participants completed anonymous, self-administered, knowledge, attitudes and practices (KAP) questionnaires. Individual interviews were conducted regarding nurses’ lived experiences and perceptions of COVID-19 IPC in critical care.n = 99; 85.3%). Nurses’ overall COVID-19 IPC knowledge scores were moderately good (78%); professional nurses had greater knowledge of COVID-19 transmission (p < 0.001). Intensive care unit nurses’ attitude scores towards COVID-19 IPC were low (55%), influenced by limited IPC training, insufficient time to implement IPC and shortages of personal protective equipment (PPE). Respondents’ scores for self-reported COVID-19 IPC practices were moderate (65%); highest compliance rates were for hand hygiene after touching patient surroundings (68%). Only 47% ICU nurses underwent N95 respirator fit-testing despite working in a COVID-19 ICU.In total, 116 ICU nurses participated (93.5% response rate) including 57 professional nurses (49%), 34 enrolled nurses (29%) and 25 enrolled nursing assistants (22%); young females (31–49 years) predominating (Regular COVID-19 IPC training is needed to equip ICU nurses with the knowledge and skills to prevent healthcare-associated COVID-19 transmission. Enhanced IPC training and consistent PPE availability may support more favourable attitudes and better IPC practices. Comprehensive IPC and occupational health support should be offered to ensure ICU nurses’ wellbeing during pandemics.Enhanced IPC training and consistent PPE availability may support better attitudes and IPC practices. The pandemic resulted in surges in ICU bed demand, higher patient-to-nurse ratios and increased staff absenteeism because of COVID-19 infection-related sick leave. Furthermore, ICU nurses were particularly at risk of developing mental health problems, including depression, anxiety and burnout during the pandemic.5 These guidelines are intended to provide direction for healthcare workers (HCWs) to ensure both occupational and patient safety in the care of patients with infectious diseases. Specific recommendations in the ICU setting include the use of the closed endotracheal tube and patient suctioning, bed spacing of 3 m and dedicated patient care equipment.4South African healthcare facilities follow the national Infection Prevention and Control (IPC) strategic framework published in March 2020 including those specifically developed for COVID-19 IPC in April 2020, which outline the recommended IPC measures for different clinical areas, clinical activities and staff.6 Acknowledging the key role of ICU nurses in attaining COVID-19 IPC compliance, several studies from low-and middle-income countries (LMICs) surveyed HCWs’ knowledge, attitudes and practices (KAP) during the COVID-19 pandemic.9 Studies from Uganda, Ethiopia and Nepal concluded that HCWs in LMIC settings had adequate knowledge and a positive attitude to IPC during the COVID-19 pandemic, but to our knowledge at the time of our study, none had included interviews with ICU nurses.11 Intensive care unit nurses are highly qualified, skilled and experienced in caring for acutely ill patients and represent a cadre of healthcare workers with high exposure to COVID-19 and high risk for suffering adverse work-related mental health effects during the pandemic.12 We aimed to describe ICU nurses’ KAP and lived experiences of COVID-19 IPC at a tertiary hospital, dedicated COVID-19 ICU in Cape Town, South Africa.Intensive care unit nurses’ understanding, acceptance and implementation of national and local COVID-19 IPC practice guidelines are key to ensuring safe ICU working environments, as they carry the primary responsibility for IPC policy implementation and practices.13 Groote Schuur Hospital has 10 ICUs (with six beds each and one isolation unit with seven beds), of which seven were designated for COVID-19 patients  since 05 April 2020. The seven COVID-19 ICUs were staffed by 120 permanent nurses and four sessional nurses. Every nurse was responsible for implementing IPC in the ICU. The nursing categories consisted of professional nurses (PN), enrolled nurses (EN) and enrolled nursing assistants (ENA).14 Professional nurses are senior nurses with a 4-year nursing degree who supervise EN and ENA, perform skilled nursing procedures, administration of patient medication as well as administrative duties. Each PN was responsible for the care of two ventilated patients, executing doctors’ orders and administering intravenous infusion medication. Enrolled nurses have a 2-year nursing diploma programme and cared for non-ventilated COVID-19 patients and administered oral medications only. Enrolled nursing assistants have a 1-year diploma and provide supportive duties for the PN and ENA, personal hygiene care for patients and assisted with environmental cleaning in the ICU.This study was conducted in the COVID-19 dedicated ICUs at Groote Schuur Hospital (GSH), Cape Town, South Africa. Groote Schuur Hospital is a 991-bed academic hospital situated in the City of Cape Town Metropolitan health district, which was the epicentre of COVID-19 infection in the Western Cape province during the first, second and third infection waves.Groote Schuur Hospital has an on-site Unit for IPC employing three IPC nurse specialists and one nursing clinical facilitator. Prior to the COVID-19 pandemic, the ICU clinical facilitator conducted in-service training every two weeks for ICU nurses. From the onset of the COVID-19 pandemic, a single face-to-face COVID-19 IPC in-service training session was held for each ICU, and nurses were encouraged to watch a COVID-19 IPC video on the hospital computers. The limited training time for COVID-19 IPC resulted from the huge pressure of COVID-19 patient admissions to the ICU, which precluded ICU nurses from attending more in-service training sessions.All patients admitted to the COVID-19 ICUs had nasopharyngeal swabs taken to confirm the presence of SARS-CoV-2 using reverse transcription polymerase chain reaction (RT-PCR) tests. The Occupational Health Service at GSH monitored HCWs’ COVID-19 infection rates at the facility from April 2020 onwards.11 The questionnaire and interviews were used to explore ICU nurses’ knowledge, attitudes and practices related to COVID-19 IPC. Quantitative data were collected using a self-administered anonymous, 33-item questionnaire to assess participants’ KAP regarding COVID-19 IPC, as well as participants’ demographics . We developed a semi-structured interview questionnaire comprising six open-ended questions to further explore and provide insights into the three quantitative constructs covered in the quantitative assessment  visited all seven COVID-19 dedicated ICUs five times during the study period (including day and night shifts) to explain the purpose of the study and to invite all the nurses working in the COVID-19 ICU to participate. Nurses completed the questionnaires manually, in English, providing written informed consent, and the questionnaires were collected after each 12-h shift by the study PI.15 The sample included all the nursing categories  working in COVID-19 ICUs with varying years of work experience, gender , and education level (diploma and degree). The participants included staff from the day and night shifts. The purpose of the study was explained to each participant. Interviews were conducted in English in a private room. The data were transcribed, analysed, coded and triangulated with the quantitative data.Purposive sampling was used to select participants to interview for the qualitative arm of this study.10 The instrument was adapted and modified to assess the ICU nurses’ KAP of COVID-19 IPC. The closed-ended questionnaire consisted of four parts: participant demographics (10 questions), knowledge (9 questions), attitudes (15 questions) and practices (8 questions). Scoring criteria were set, giving a score of ‘1’ for a correct answer and a score of ‘0’ for an incorrect answer. Knowledge questions assessed nurses’ understanding of COVID-19 IPC measures, attitude questions sought to determine the ICU nurses’ attitudes level towards COVID-19 IPC measures, while practice questions collected nurses’ self-reported practices regarding prevention of COVID-19 infection . The categorical data were summarised using the frequency and percentages. The proportions for KAP were compared by nursing job category (EN vs ENA vs PN). The chi-square or Fisher’s exact test was used for comparing categorical data. The Spearman’s rho correlation test was used to find the relationship between knowledge, attitude and practices, following the conversion of individual items in the questionnaire to overall percentages of the correct answers (scoring 1 for correct and 0 for incorrect responses). The statistically significant level was set in all tests at p < 0.05.Quantitative data from the manually completed questionnaires were entered into a RedCAP database by the PI and analyses were performed using Stata16 Emerging themes developed from respondents’ lived experiences while working with COVID-19 IPC precautions in the ICU, and direct participants’ quotes that best reflected these emerging themes were selected.Qualitative data were obtained by posing six pre-specified open-ended questions to participants. Participants’ responses were audio-recorded and transcribed verbatim, and a six-step thematic analysis approach was employed: familiarisation with data, generating initial codes, searching for themes, reviewing themes, defining, naming themes and producing a report.17 Themes that represented the knowledge, attitudes and practices of ICU nurses regarding COVID-19 IPC were identified, and conclusions were drawn in conjunction with the quantitative data.The interconnected themes from the qualitative data were integrated and aligned with the results of the quantitative data.Ethics approval was obtained from the Human Health Research Ethics Committee of the University of Cape Town (774/2020). All participants provided written informed consent.n = 99; 85.3%; 59.5% aged 31–49 years) , EN  and ENA . Almost half of the respondents had substantial (> 10 years) ICU nursing experience . Approximately one-quarter of all nurses had one or more underlying medical conditions that placed them at increased risk for severe COVID-19 disease . Fifty-two nurses (44.8%) reported previously having undergone one or more COVID-19 RT-PCR tests, and 21 (18.1%) were previously diagnosed with COVID-19 infection at the time of the study.Of 124 eligible COVID-19 ICU nurses, 116 nurses participated in the study (response rate of 93.5%). Respondents were predominantly young females (9 years) . Respondp < 0.001, Respondents’ overall knowledge scores pertaining to COVID-19 transmission mechanisms and prevention measures in the ICU were moderate to good (78%). Professional nurses had significantly higher scores than other nursing categories regarding the role of aerosol transmission of the SARS-CoV-2 virus (p < 0.005) believed that the high workload during the COVID-19 pandemic resulted in decreased time to adhere to standard IPC practices in the ICU. Professional nurses were more likely to agree with the statement that there was adequate availability of PPE in the ICU, compared to EN and ENA .Intensive care unit nurses’ attitudinal scores with regard to COVID-19 IPC were marginally positive (55%), . Half ofp = 0.039 . The highest reported compliance was for the performance of hand hygiene after touching the patient’s surroundings (68%), as well as the performance of hand hygiene before and after touching COVID-19-infected patients (67%). Less than half of respondents (47%), especially ENAs (40%),  = 0.039 , had undr = 0.484, p = 0.047) between higher knowledge scores and desired practices. There was also a significant positive correlation between positive attitudes and desired practices . However, the knowledge and attitudes scores were not significantly correlated . Thus, knowledge appears not to influence attitudes but does influence practices. Attitudes appear to influence practices.n = 7, 64%), aged 31–49 years (60%), including five PNs, three ENs and three ENAs. Half (50%) of the participants had over 10 years of experience in ICU nursing. Three interconnected themes comprising coping mechanisms and interventions to limit the occupational risk of COVID-19 infection emerged: inadequate IPC training during the COVID-19 pandemic, limited adherence to COVID-19 IPC practices, and emergence of coping methods, resilience and teamwork among ICU nurses during the COVID-19 pandemic.In the qualitative arm of the study, 11 participants were recruited and were predominantly females ‘I need a continuous update on new evidence regarding COVID-19 IPC … on how to conduct infection prevention controls in the ICU environment and most importantly how to prevent ourselves from contracting this disease’. Respondents understood that the COVID-19 IPC guidelines were intended to combat virus transmission to HCWs and patients. Respondents commonly described how they applied COVID-19 IPC precautions to protect themselves from infection but had limited time to implement these IPC measures despite their intent to comply. The increased workload because of increased responsibilities, the volume of patients and the complexity of caring for COVID-19 patients were further factors that negatively influenced their compliance:to] comply with COVID-19 IPC all the time, but it is difficult and sometimes you forget because we found ourselves looking after more than three intensive patients, ventilated on inotropic support, and besides that, you have guided our colleague from other departments, who have no ICU experience’. ‘We tried [‘The workload is too much, and we have minimal time to follow the COVID-19 IPC due to the severe illness of our patients, but we try all the time, but COVID patients are complicated’. ‘It is very strenuous working with COVID patients because patients are critically ill all the time. It is impossible to adhere to the IPC protocol for the latter because we are trying to save lives. We acknowledge the importance of the COVID-19 IPC, we have limited time’. During the pandemic, ICU nurses had to balance the need to protect themselves and their families, while doing their best to ensure optimal patient outcomes under difficult circumstances at work and in their personal lives. Nurses expressed the strongest emotions regarding their care of patients with COVID-19 pneumonia or acute respiratory distress syndrome (ARDS) and expressed that they felt the weight of the responsibility of caring for these patients:‘COVID-19 patients are very infectious. I feel vulnerable to contracting COVID-19 infection and spreading to my family. It also feels like everything is weighing heavy on us during this COVID-19 pandemic’. Respondents appeared to have changed their behaviours within the workplace and home and adopted a range of coping strategies such as leaving their work clothes in the garage, not hugging their families, praying, exercising and other self-care measures:‘When working in the COVID ICU, we changed our clothes before and after the shift. We put on PPE, aprons and N95 masks. After the shift, we changed back to nursing uniforms. When arriving home, I leave my working clothes, shoes, and bag in the garage, take a full shower, and do hand hygiene. We are trying to protect my children and the rest of my family from COVID-19 infection’. The high workload during the pandemic and the low patient survival rate diminished the morale of ICU nurses, and at times they became pessimistic about the care they provided to COVID-19 patients. The respondents were overwhelmed by the shortage of PPE and constantly changing IPC protocols and procedures. This negatively impacted their attitudes to and compliance with IPC measures. Yet, the ICU nurses shared sentiments like ‘we will survive’ and ‘we are determined to serve our patients.’ Intensive care unit nurses displayed resilience and coping mechanisms with the high workload of COVID-19 patients. Despite all the uncertainty, they remain committed to their frontline duties, returning to work each day to provide nursing care during the public health pandemic and displaying a high level of altruism and dedication, often at the expense of their own health:‘It’s very stressful to work with COVID patients and the first precaution is to counsel yourself and be calm within, because if by any chance you are stressing, then you will miss out on a lot of things. So, as long as you are calm, I think that’s the first thing to protect yourself because you know what to do. Try by all means to adhere to IPC protocols’. ‘Yoh, it was so draining, draining … You feel exhausted. You feel like you must go off sick. Then you think if you go off sick, who is going to look after the patients. You must force yourself to go to work. Although you get exhausted and tired, you must force yourself because you pledged’. Intensive care unit nurses also highlighted the importance of teamwork in caring for COVID-19 patients:‘The workload has increased significantly in the ICU since COVID19 came. We need each other, teamwork was the key to navigating away through COVID-19 waves. COVID-19 patients are very heavy and you will need help from your colleague, that is why teamwork is very crucial’. ‘Generally, ICU work needs teamwork among nurses. COVID-19 patients are difficult to nurse because of their infectious status. Teamwork is required throughout the day. We are helping each other in these difficult circumstances’. 19 Knowledge scores were generally lowest among nurses with the least training . Despite minimal COVID-19-specific training opportunities, ICU nurses’ Knowledge scores were moderate, possibly helped by staff members’ existing knowledge of IPC transmission precautions and extensive media coverage of COVID-19 preventive measures.A mixed-methods design was used to assess the COVID-19 IPC KAP of ICU nurses working at an academic hospital in a middle-income setting. Most respondents had moderate-to-good knowledge levels related to COVID-19 IPC, similar to recent reports from Nigeria and South Africa.Qualitative responses, however, did not support this interpretation. The respondents commonly identified the lack of regular IPC training during the COVID-19 pandemic as a major setback. They expressed their concerns more broadly about a ‘new’ and ‘highly’ ‘infectious disease’, which in their opinion required IPC training for adequate patient management and safety. Furthermore, guidance and regular in-service training for COVID-19 IPC are needed to correct some misconceptions and empower all nursing categories with accurate scientific information.17 The attitude of ICU nurses may affect their practice of COVID-19 infection prevention and control measures. In this study, we assessed the acceptance and experience of the COVID-19 IPC by ICU nurses. Most respondents demonstrated a marginally positive attitude towards COVID-19 IPC adherence and practice in the ICU. Our qualitative data suggest that attitudes are influenced by fear of infection, high workload and perceived negative impacts of COVID-19 on HCWs’ health and that of their families. Similar findings were observed in Uganda and Nigeria.18 The marginally positive attitude could possibly be attributed to the limited training in IPC, insufficient time to implement IPC protocols and PPE shortages. Respondents also reflected on the ICU environment and the complexity of patient management brought on by COVID-19 ARDS patients, as well as that introduced by new or frequently updated IPC measures.Knowledge levels on the key concepts of COVID-19 IPC measures, such as hand hygiene, routes of infection transmission and environmental cleaning were good. Most respondents correctly understood that alcohol hand rub is an adequate measure to limit the direct and indirect contact spread of COVID-19 infection, with many describing hand hygiene as a ‘key’ mitigation measure. This is reassuring because a good knowledge of COVID-19 transmission patterns and prevention measures will improve ICU nurses’ practices and thereby limit occupational risk. However, the respondents expressed concern about their working environment, especially the rapid changes in protocols and the severity of illness among their patients. These results are in keeping with the sentiments expressed in previous reports of COVID-19 IPC in ICUs.20Half of the respondents believed they had received inadequate training in procedures for safely donning and doffing PPE for COVID-19. Most respondents, however, felt that the high workload during the COVID-19 pandemic resulted in decreased time to adhere to standard IPC practices in the ICU. Respondents expressed similar concerns about the inconsistent availability of PPE and fears of contracting COVID-19 themselves. The availability of PPE in ICUs in protecting staff from COVID-19 infection and an adequate supply of PPE may therefore improve ICU nurses’ attitudes to work. The major demand caused limited availability of PPE, but the situation was corrected over time and may no longer be a major problem within this hospital.7 Less than half of respondents had performed N95 respirator fit testing despite their high-risk work environment. Similar results were reported in a recent study from Nigeria.21 During the COVID-19 pandemic, qualitative fit testing was discontinued in Western Cape facilities (owing to the risk of cross-infection), and this may have contributed to the low numbers of staff who had been fit-tested.We found a positive relationship between positive attitudes and practices suggesting that attitude influences the respondents’ COVID-19 IPC practice. The self-reported compliance of ICU nurses with recommended COVID-19 IPC practice was moderate. Similar findings were reported from China regarding moderate to good compliance with COVID-19 IPC.Most respondents did not adhere to transmission-based precaution signs in the COVID-19 ICU. Factors for this low adherence did not emerge during the qualitative inquiry. The practice of effective preventative measures such as handwashing and donning of appropriate personal protective equipment (PPE) will ensure the safety of HCWs by reducing healthcare-associated COVID-19 transmission.22Qualitative data suggest that respondents were willing to adapt to rapid changes in COVID-19 IPC guidelines despite some having indicated that this added to their workload, which in turn had likely adversely affected their compliance with COVID-19 IPC recommendations. There was generally a positive attitude among the respondents towards COVID-19 IPC, and the respondents expressed a desire for more regular in-service training on new evidence-based COVID-19 IPC precautions. The infrastructure and shortage of nursing staff are long-standing issues, and the COVID-19 pandemic has compounded them. Their resolution requires interventions at an institutional level.We found low attitudes and some non-compliant IPC practices in these ICU nurses with regard to the management of COVID-19. In planning for future pandemics, the provision of an uninterrupted supply of PPE, ongoing IPC training opportunities and timeous and clear communication of relevant information may assist in encouraging IPC compliance and more positive attitudes. Given the risk of staff burnout during health crises, employee wellness and support should remain a priority for healthcare employers and managers.23 Future studies should evaluate COVID-19 vaccine uptake among ICU nurses, given their reported low uptake of the annual influenza vaccine.The study’s major limitation is using self-reported rather than directly observed COVID-19 IPC practices. Reporting bias may have been introduced by the subjective nature of the survey. This was also a single-centre study, which limits generalisability of the findings. This study was performed before the COVID-19 vaccination was readily available in South Africa, which may have increased ICU nurses’ adherence to IPC measures, in an effort to reduce their personal infection risk. The Johnson & Johnson COVID-19 vaccine initially rolled out to South African healthcare workers in February 2021, providing 72% protection against severe disease and death from COVID-19.This study has several strengths. To the authors’ knowledge, this is the first mixed-methods assessment study performed in a resource-limited setting. The qualitative data gives meaning and explanation to the quantitative results. Data for this study were collected immediately after the second peak of the COVID-19 pandemic, the timing of which allowed for study participants to share fresh experiences with explicit examples. One of the strengths of this study is that there is unlikely to be selection bias, as the survey studied ICU nursing staff, and the majority responded.Despite very limited specific training, ICU nurses’ COVID-19 IPC knowledge was moderately good, whereas nurses’ attitude scores towards COVID-19 IPC were low (55%). Nurses attitudes to COVID-19 IPC were influenced by limited IPC training, insufficient time to implement IPC precautions, and shortages of PPE. Inadequate training in IPC, difficulty in implementing COVID-19 IPC guidance and development of resilience in ICU nurses emerged as major themes in the qualitative study. This study highlighted the need for enhanced support in IPC and occupational health and safety to preserve the well-being of ICU nurses during the COVID-19 and future pandemics


Oral corticosteroids (OCS) are commonly used for the acute management of severe asthma exacerbations or as maintenance therapy; however, chronic use is associated with significant toxicities, e.g., osteoporosis. In the REal worlD Effectiveness and Safety (REDES) study of mepolizumab in a multicentric Spanish cohort of asthma patients, mepolizumab effectively reduced clinically severe asthma exacerbations and decreased OCS dependence. This post-hoc analysis further evaluates mepolizumab’s de-escalation effect on OCS dose. Patients enrolled in REDES who had OCS consumption data available for 12 months pre- and post-mepolizumab treatment were included in this analysis. Primary outcomes were to determine the change in the proportion of patients eligible for anti-osteoporotic treatment due to the changes in OCS consumption before and after 1 year of mepolizumab treatment. All analyses are descriptive. Approximately one-third  of patients in REDES were on maintenance OCS at the time of mepolizumab treatment initiation. In REDES, mean cumulative OCS exposure decreased by 54.3% after 1 year of treatment. The proportion of patients on high-dose OCS (≥7.5 mg/day) fell from 57.1% at baseline to 28.9% after 12 months of mepolizumab treatment. Thus, 53.6% of OCS-dependent asthma patients treated with mepolizumab would cease to be candidates for anti-osteoporotic treatment according to guidelines thresholds. Corticosteroids (CS) have potent anti-inflammatory and immunosuppressant properties and are consequently used in a variety of indications in medicine. In asthma, they are widely used in an inhaled form. The oral  forms are principally used in the acute management of severe asthma exacerbations, or as alternative maintenance therapies when preferred treatments do not provide adequate disease control . HoweverAlthough an in-depth discussion of interventions to prevent systemic CS-related toxicities is beyond the scope of this article, the adverse skeletal effects of these agents deserve special mention because of the high prevalence of bone disorders in patients with severe asthma . Bone-reThere is a need for increased clinician awareness and foresight regarding downstream toxicities caused by the management of asthma via CS. Effective disease management, avoidance of systemic CS-related osteoporotic fractures, and thus improvements in patient quality of life rely on early initiation of equally effective, OCS-sparing treatments, e.g., biologics.Mepolizumab is a humanized monoclonal antibody marketed for T2 eosinophilic asthma, with a high affinity for interleukin-5 (IL-5), a key factor regulating the eosinophil pathway  . MepolizHere, we present a post-hoc analysis of the REDES study, which aimed to evaluate whether mepolizumab treatment de-escalated OCS dose, allowing for a subsequent discontinuation of anti-osteoporotic treatments in patients with severe eosinophilic asthma.Details of the REDES study design have been described previously . BrieflyThe REDES study was performed in line with the guiding principles of the Declaration of Helsinki and order SAS/3470/2009. Approval was granted by the ethics committee of Hospital La Princesa, Madrid, Spain. Informed consent for the aggregation, anonymization and publication of health data was obtained from all participants included in the study. Separate ethics approval was not required for this analysis.This post-hoc analysis of the REDES study evaluates the difference in the proportion of patients who would be candidates for anti-osteoporotic treatment , before and after 1 year of treatment with mepolizumab.To determine patient eligibility for initiation of anti-osteoporotic treatment (anti-resorptives or bone forming agents), this analysis uses the OCS thresholds provided by the Spanish Society of Rheumatology , which rThe aim of this post-hoc analysis was to determine the change in the proportion of patients eligible for anti-osteoporotic treatment , and interquartile range (IQR) values, while categorical variables were described using the number and percentage within categories. As all post-hoc analyses were descriptive, no statistical comparisons were performed.In the REDES study, almost one-third of patients  were on maintenance OCS at the time of initiating mepolizumab treatment; mean (SD) OCS dose was 12.14 (9.97) mg/day. Importantly, the number of patients on high-dose OCS (≥7.5 mg/day) fell from 56/98 (57.1%) at baseline to 26/90 (28.9%) after 12 months of mepolizumab treatment . Thus, 3At 12 months, nine patients (2.8%) reported 13 adverse events while on treatment with mepolizumab, none of which were severe. The complete list of adverse events, which were generally mild and temporary, has been previously published .As OCS or parenteral CS therapies are likely to remain as a tool used for the management of acute severe asthma exacerbations for the foreseeable future, it is important to consider the impact of episodic CS courses on the risk of CS-related toxicities. Episodic systemic CS courses increase CS exposure beyond that of maintenance oral/inhaled CS. The risk of osteoporosis diagnosis and fracture has been shown to increase per 1-g increase in systemic CS exposure in patients with asthma . In recoCompared to CS, asthma biologics such as mepolizumab have shown a more favorable safety profile, which, together with the efficacy of biologics, has helped position CS as a last resort choice after biologics. In the clinical studies of mepolizumab, the most commonly reported adverse drug reactions were headache, injection site reactions, and back pain, up to 4.8 years after treatment initiation .Although chronic use of prednisolone-equivalent OCS doses as low as 2.5 mg/day are enough to increase the risk of fractures , this riThe minimization or avoidance of chronic OCS use in asthma treatment is pertinent in reducing osteoporosis and fracture risk and lessening patient exposure to other pharmacologic interventions. In this respect, the data derived from the REDES study support the benefits mepolizumab may offer in decreasing the indication of anti-osteoporotic treatment.Despite asthma guidelines recommending mepolizumab and other biologics over OCS as maintenance therapies for severe asthma , it is iThis post-hoc analysis shows that mepolizumab allows the reduction of OCS in CS-dependent asthma patients, lowering their fracture risk and therefore allowing them to discontinue anti-osteoporotic treatment, avoiding or reducing potential long-term drug-related complications, such as atypical femoral fractures or osteonecrosis of the jaw.The REDES study and, therefore, this post-hoc analysis have some limitations. The most important limitation is that our calculation of the proportion of patients who were candidates for anti-osteoporotic treatment discontinuation is only an estimation. Another limitation is that although participating centers had dedicated asthma units for data collection, the retrospective nature of the study may have resulted in incomplete data collection and/or data may have been subject to time-varying confounders. An example of this is the lack of reliable data on cumulative OCS dose that included all OCS courses patients had received during the study, meaning we had to limit our analysis to those patients receiving a maintenance daily OCS dose.Mepolizumab has shown a de-escalation effect in OCS maintenance dose, as well as a reduction in cumulative CS exposure, in a high proportion of severe asthma patients. However, its potential effect on anti-osteoporotic treatment had not been reported. Our study quantifies for the first time that 53.6% of CS-dependent severe asthma patients, would cease to be candidates for anti-osteoporotic treatment after 12 months of mepolizumab therapy.


Sepsis survivors are at elevated risk for cardiovascular disease during long-term follow-up. Whether diabetes influences cardiovascular risk after sepsis survival remains unknown. We sought to describe the association of diabetes with long-term cardiovascular outcomes in adult sepsis survivors.Population-based cohort study in the province of Ontario, Canada (2008–2017). Adult survivors of a first sepsis-associated hospitalization, without pre-existing cardiovascular disease, were included. Main exposure was pre-existing diabetes (any type). The primary outcome was the composite of myocardial infarction, stroke, and cardiovascular death. Patients were followed up to 5 years from discharge date until outcome occurrence or end of study period (March 2018). We used propensity score matching  to adjust for measured confounding at baseline. Cause-specific Cox proportional hazards models with robust standard errors were used to estimate hazard ratios (HR) alongside 95% confidence intervals (CI). A main secondary analysis evaluated the modification of the association between sepsis and cardiovascular disease by pre-existing diabetes.78,638 patients with pre-existing diabetes who had a sepsis-associated hospitalization were matched to patients hospitalized for sepsis but without diabetes. Mean age of patients was 71 years, and 55% were female. Median duration from diabetes diagnosis was 9.8 years; mean HbA1c was 7.1%. Adult sepsis survivors with pre-existing diabetes experienced a higher hazard of major cardiovascular disease —including myocardial infarction  and stroke —during long-term follow-up compared to sepsis survivors without diabetes. Pre-existing diabetes modified the association between sepsis and cardiovascular disease .Sepsis survivors with pre-existing diabetes experience a higher long-term hazard of major cardiovascular events when compared to sepsis survivors without diabetes. Compared to patients without sepsis, the absolute risk increase of cardiovascular events after sepsis is higher in patients with diabetes .The online version contains supplementary material available at 10.1186/s13054-023-04586-4. Sepsis is conceptualized as a life-threatening acute organ dysfunction in response to infection and represents a leading cause of morbidity and mortality worldwide –5. AcuteSocial determinants of health and baseline burden of disease such as nutrition, lifestyle choices, and comorbid conditions may all interact with the risk of both short- and long-term outcomes following sepsis , 18–23. We sought to describe the association of pre-existing diabetes with long-term cardiovascular outcomes in adult sepsis survivors using population-based data from the province of Ontario. We hypothesized that pre-existing diabetes would be associated with a higher risk of cardiovascular disease in sepsis survivors.We created the study cohort using population-based provincial health administrative databases contained at ICES, an independent, non-profit research institute whose legal status under Ontario’s health information privacy law allows it to collect and analyze healthcare and demographic data, without consent, for health system evaluation and improvement. These datasets were linked using unique encoded identifiers. Our study was developed in accordance with the amended Declaration of Helsinki, and this report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) . The useOur cohort included adults (age 18 years or older) in the province of Ontario, Canada, who survived a first sepsis-related hospitalization between April 2008 and April 2017. The study dates were chosen to optimize data completeness, and to allow a minimum follow-up of one year for all patients (to March 2018). Sepsis was identified using a previously validated algorithm , 36. To Our exposure of interest was pre-existing diabetes at the time of sepsis hospitalization, defined using a previously validated algorithm . This alPatients’ demographic, clinical, and hospital level characteristics were summarized using proportions for categorical variables and mean and standard deviation (SD) or median and interquartile range (IQR) for continuous variables, as appropriate. Baseline characteristics of patients with or without diabetes were compared using standardized mean differences (SMD) . SMD greWe used propensity score matching to control for measured confounding . SpecifiTo further explore the impact of diabetes on long-term cardiovascular disease after sepsis, our main secondary analysis explored the modification of the association between sepsis and subsequent cardiovascular events by pre-existing diabetes. Specifically, we explored whether the previously identified effect of sepsis on cardiovascular disease during long-term follow-up varied across subgroups of patients with and without diabetes . For thiE-value for the point estimate and lower bound of the 95% confidence intervals for our main analysis on the primary outcome of interest [We also conducted several sensitivity analyses to assess the robustness of our main findings. First, we report the interest . Second,interest . Third, interest . Fourth,interest . Fifth, interest . Furtherinterest , 49. Sixinterest . FinallyAll analyses were performed using SAS Enterprise Guide version 7.1  and STATA v.14.2 . A p-value of 0.05 was used as threshold for statistical significance and all tests were two-sided.Overall, 78,638 sepsis survivors with pre-existing diabetes were matched to sepsis survivors without diabetes during the study period  of cardiovascular disease ranged from 7.2% in patients without sepsis and no pre-existing diabetes to 12.2% among patients who survived a sepsis episode and had prevalent diabetes Table . On the The main effect estimates were similar across several sensitivity analyses, namely while 1) using Fine and Gray models .Pre-existing diabetes represents a classic cardiovascular risk factor in the general population, whereas mounting evidence from observational studies show the increased risk of cardiovascular disease in sepsis survivors , 51–53. A strength of our study is the matching of patients with and without diabetes and exploring several cardiovascular outcomes of interest, while also considering characteristics of the sepsis hospitalization. Our study highlights how diabetes appears to increase the risk of experiencing future cardiovascular outcomes after sepsis but does not increase the risk of other outcomes including recurrent sepsis or all-cause mortality. Furthermore, the presence of additive effect measure modification by diabetes of the association between sepsis and cardiovascular outcomes suggests that, in addition to being considered as independent risk factors, the combination of both carries potentially the highest risk during long-term follow-up. This is in alignment with previous findings showing a differential effect of sepsis on cardiovascular disease introduced by both age and sex . Such grOur study has several limitations. First, sepsis was identified using an administrative algorithm, and some degree of misclassification is expected . This miIn conclusion, sepsis survivors with pre-existing diabetes face a higher long-term hazard of experiencing major cardiovascular outcomes when compared to sepsis survivors without diabetes. Pre-existing diabetes further intensifies the effect of sepsis on major cardiovascular events during long-term follow-up. Future studies should evaluate which subgroups (if any) of patients with diabetes remain at highest risk, and whether improvements in metabolic control and specific prescription patterns can mitigate the cardiovascular risk after sepsis in patients with diabetes.Additional file 1. Supplementary appendix.