Obesity and high abdominal fat mass are risk factors for developing the chronic inflammatory skin disease psoriasis. They are associated with increased incidence, prevalence and severity of the disease. A positive effect of weight loss on psoriasis activity has been shown in several studies. Obesity-related factors such as the dysregulation of glucose and lipid metabolism, the activation of adipose tissue and resultant persistent low-grade inflammation have been discussed as links of obesity and inflammatory diseases. Recently, we demonstrated a critical role of free fatty acids (FFAs) in obesity-mediated exacerbation of psoriatic skin inflammation in both mice and humans. In the present study, we translated these findings into a therapeutic intervention. An open-label study focusing on the dietary reduction of FFAs was conducted in patients with mild-to-moderate plaque psoriasis, and disease severity and serum markers of inflammation were analyzed. Here, we show that such a dietary intervention improves psoriatic disease activity independently of weight loss. Diet-related metabolic changes, such as a reduction in saturated free fatty acids (SFAs), may thus be more important than weight loss itself. Moreover, dietary intervention inhibited the overall pro-inflammatory activation status in patients, as shown by analysis of serum inflammatory parameters using the Olink platform. From our pilot study, we conclude that dietary intervention focusing on SFA reduction has the capacity to reduce disease activity and general inflammatory status in psoriasis patients. Obesity has reached epidemic proportions, affecting more than 650 million people worldwide . It is aEpidemiological studies demonstrate a substantial impact of obesity on the incidence and severity of psoriasis. For example, obesity and high abdominal fat mass double the risk for developing psoriasis ,14. ObesIn the present study, we translated these findings into a therapeutic approach. In an open-label study, we conducted a dietary intervention in patients with mild-to-moderate plaque psoriasis and analyzed disease severity and serum inflammatory markers. Indeed, a dietary intervention focused on reducing SFAs improved disease severity and decreased a wide range of serum inflammatory biomarkers detected by the Olink Proteomics Platform.https://www.dge.de/ernaehrungspraxis/vollwertige-ernaehrung/10-regeln-der-dge/en/ (accessed on 22 January 2023)) with the additional recommendation of a low SFA intake  using the human Olink target 96 inflammation panel. Analysis was performed by Olink.g for 2 min to precipitate proteins. Lipids were extracted from the supernatant by the addition of 1 mL chloroform and water according to Bligh and Dyer [Serum aliquots (60 µL) were mixed with 1 mL methanol and centrifuged at 13,000× and Dyer . After vand Dyer . Total ip < 0.05 were considered to be significant. The different degrees of significance were indicated by asterisks . Data presentation was performed using GraphPad 9.5.For statistical correlation analyses, IBM SPSS Statistics software version 27.0  was employed. The non-parametric Spearman’s rank correlation test was used to assess univariate relationships between clinical and biochemical markers. A multivariate regression analysis was performed for specific mediators adjusted for BMI, waist–hip ratio (WHR) and serum triacylglycerol concentration (TAG). Non-normally distributed variables as assessed by the Shapiro–Wilk test were logarithmically transformed prior to multivariate testing. Values of Recent data proved an essential role of elevated FFAs in the obesity-mediated amplification of skin inflammation in a mouse model of psoriasis-like inflammation as well as in patients with psoriasis . In the First, the dietary intervention in group 1 significantly reduced both TAG and BMI, demonstrating the compliance of the patients to the diet B,C. In cTo elucidate the mechanisms by which the dietary intervention reduced disease activity in patients, we analyzed the serum cytokine expression pattern by the Olink Proteomics Platform. The focus was on 92 human serum mediators of inflammation, of which 72 markers were detectable in the patients’ sera. To analyze the impact of the dietary intervention on these biomarkers, we calculated the percentage of PASI reduction and the reduction in biomarkers after 4 and 8 weeks. Correlation analysis revealed that about one-third of the mediators were dependent on disease severity, BMI or TAG .Improvement of psoriasis (determined as a decrease in the disease severity index PASI) correlated with the change in 13 biomarkers during the observation period. Univariate correlation analysis showed a positive correlation of serum CD6, CST5, IL-18, IL-18R, ENRAGE and CASP8 reduction at week 4 and IL-7, TGFb, IL-6, IL-18, CCL19, IL-10RB, IL-18R1 and INFγ reduction at week 8 . MultivaIn addition, correlation analysis revealed an association between 14 serum inflammatory markers and TAG reduction and between seven markers and BMI . MoreoveTaken together, the dietary intervention affected a wide range of inflammatory markers, depending on the disease activity, BMI or TAG.Obesity is an independent risk factor for the incidence, prevalence and severity of psoriasis. Meta-analyses revealed that a higher BMI increases the risk of psoriasis onset. Moreover, obesity reduces treatment efficacy and may predict discontinuation of biological therapy . TherefoSeveral studies have shown a positive effect of weight loss on psoriasis severity and treatment response. Diet and physical exercise may improve pre-existing psoriasis and prevent the de novo development of psoriasis . Our dieWe can exclude that study-related intensified medical care had an effect on the study outcome, since group 2, which did not receive any dietary intervention for the first three months, showed no change in TAG and BMI or PASI. Only after the crossover to the dietary intervention did metabolic parameters and disease severity improve in group 2. Thus, the dietary intervention alone is responsible for the observed effects.In parallel, serum inflammatory biomarkers are down-regulated by dietary intervention. All of the regulated mediators, both the psoriasis-dependent and BMI/TAG-dependent markers, have been described previously to be related to psoriasis. Among the down-regulated markers, there are molecules known to mediate the interaction of antigen-presenting cells (APCs) and T cells , resulting in the activation of T cells and supporting a Th1 or Th17 response ,26,27. CIn summary, this study investigated the effect of an easy-to-use dietary intervention program focused on reducing saturated FFA on disease activity in psoriasis. It shows that such a dietary intervention alone has the capacity to reduce disease activity in treated patients by an additional 25%. This is independent of weight loss, suggesting that diet-related metabolic changes such as SFA reduction may be more important than weight loss itself. We emphasize that dietary intervention should not replace an anti-psoriatic treatment but rather represents a valuable add-on approach. It also affects a range of biomarkers, both psoriasis-specific cytokines and more general pro-inflammatory signals also found in other chronic (auto)immune diseases. Thus, dietary intervention with a reduced amount of SFA may be also helpful in other inflammatory autoimmune diseases in which an association of disease activity and obesity has been described.


Roux-en-Y gastric-bypass (RYGB) induced alterations in intestinal morphology and gut-cell hormone expression profile in the bypassed biliopancreatic-limb (BPL) versus the alimentary-limbs (AL) are poorly characterised. This pilot study has therefore explored effects following RYGB in high-fat-diet (HFD) and normal-diet (ND) rats. Female Wistar rats (4-week-old) were fed HFD or ND for 23-weeks prior to RYGB or sham surgeries. Immunohistochemical analysis of excised tissue was conducted three-weeks post-surgery. After RYGB, intestinal morphology of the BPL in both HFD and ND groups was unchanged with exception of a small decrease in villi width in the ND-RYGB and crypt depth in the HFD-RYGB group. However, in the AL, villi width was decreased in ND-RYGB rats but increased in the HFD-RYGB group. In addition, crypt depth decreased after RYGB in the AL of HFD rats. GIP positive cells in either limb of both groups of rats were unchanged by RYGB. Similarly, there was little change in GLP-1 positive cells, apart from a small decrease of numbers in the villi of the BPL in HFD rats. RYGB increased GLP-2 cell numbers in the AL of ND-RYGB rats, including in both crypts and villi. This was associated with decreased numbers of cells expressing PYY in the AL of ND-RYGB rats. The BPL appears to maintain normal morphology and unchanged enteroendocrine cell populations despite being bypassed in RYGB-surgery. In contrast, in the AL, villi area is generally enhanced post-RYGB in ND rats with increased numbers of GLP-2 positive cells and decreased expression of PYY. Obesity is associated with various pathophysiological conditions such as diabetes mellitus, insulin resistance, atherosclerosis, hypertension and dyslipidemia . Roux-enThis phenomenon is further supported by two basic non-mutually exclusive theories. The first implicates loss of circulating factor(s) promoting insulin resistance resultant from the exclusion of the BPL . The secThe aim of this study was to observe the effects of RYGB surgery on intestinal morphology as well as the differential expression of four major gut hormones GIP, GLP-1, GLP-2 and PYY in the BPL compared with the AL in normal rats as well as rats with diet-induced obesity. Our pilot studies warrant detailed follow-up regarding the importance of changes in intestinal morphology and gut hormone populations in the bypassed biliopancreatic and alimentary limb following RYGB.ad libitum. Body weight and non-fasting blood glucose were monitored weekly. Only small numbers of rats were used and all animal experiments were carried out in accordance with the UK Animals (Scientific Procedures) Act 1986 and approved by the University of Ulster Animal Welfare and Ethical Review Body (AWERB).Adult female Wistar rats  were housed in the Biomedical and Behavioural Research Unit at Ulster University, Coleraine. At 4 weeks of age, rats were divided into 2 groups (n = 4), that continued on normal diet (ND) standard chow Purina 5008  or were maintained on high-fat diet . Rats were housed individually in an air-conditioned room at 22 ± 2°C with a 12 h light and 12 h dark cycle. Both standard and high-fat rodent pellet diet and drinking water were available After 23 weeks on respective diets, rats were further divided into 2 groups resulting in a total of 4 groups which were: ND-sham, ND-RYGB, HFD-sham and HFD-RYGB. Groups of rats underwent sham and RYGB surgeries, as appropriate, at 27 weeks of age. The animals were anesthetised using isoflurane. A single dose of enrofloxacin  was administered at induction of anesthesia and buprenorphine  administered at the end of surgery for postoperative pain. Lacrilube eye ointment was applied to prevent corneal dryness during anesthesia. Following supine positioning, a 2 cm upper midline laparotomy incision was made. The proximal jejunum was divided 10 cm distal to the duodenojejunal flexure to create the BPL and AL. A side-to-side jejunojejunal anastomosis was then formed using a single layer technique with interrupted 6–0 prolene sutures approximately 30 cm from the ileocecal valve. The small bowel of a rat measures about 90cm on average and as such the alimentary limb represents mid and distal jejunum in this model. The lesser curve vessels were carefully dissected, and the gastric cardia divided to create a small gastric pouch (maximum 3 ml volume). The gastric remnant was closed with interrupted 6–0 prolene sutures. An end-to-side gastrojejunal anastomosis was then formed using 6–0 prolene sutures. Warmed, sterile saline  was administered intraperitoneally before closure. The linea alba was closed with continuous 4–0 Vicryl sutures  and the skin closed with subcuticular 4–0 Vicryl sutures. The rats were placed into a clean cage with a warming pad and towel to recover from anesthesia. When fully recovered, they were returned to their home cage. For the sham operation, an upper midline laparotomy incision was made, the small bowel and stomach exposed, and the abdomen was then closed, as described above.ad libitum. Rats were housed without bedding for one day to prevent ingestion of bedding material. For 2 days post-surgery, the animals were treated with buprenorphine , as required. On day one and two post-surgery, the rats received 20 ml of oral nutritional supplement liquid diet which was then available ad libitum in the afternoon of day 2 . From days 3–6, the rats were fed wet mash and returned to Ensure if food intake was poor. On days 6–7 post surgery, all rats received standard chow (Purina 5008). Standard chow was provided to all rats as our previous investigations highlight an aversion to HFD, and preference for regular chow, post-surgery in these animals [Post-surgery, the animals were given buprenorphine . From 4 hours post-surgery, water was available  animals . For 3 w2 followed by cervical dislocation. Proximal and distal jejunum was obtained from the sham operated rats to compare with BPL and AL of RYGB rats, respectively. These intestinal tissues were fixed for 48 hours in paraformaldehyde solution  to preserve cellular architecture by cross-linking proteins. The tissues were then processed in an automated tissue processor which involved dehydrating tissues in 70% to 100% ethanol, followed by xylene immersion to remove ethanol before paraffin embedding. The tissues were then sectioned (5 μm) using a microtome  and placed on poly-l-lysine coated slides [Three weeks after surgery, animals were euthanised by lethal inhalation of COd slides .® 488 for green; To assess immunoreactive staining for GIP, GLP-1, GLP-2 and PYY, sections were dewaxed in histoclear for 30 mins before being rehydrated with decreasing concentrations of ethanol. Following this, antigen retrieval and cell permeabilization was achieved using a citrate buffer (pH 6.0) at 96°C for 20 mins followed by a cooling period. The sections were blocked with 2.5% bovine serum albumin (BSA) and then incubated with a primary antibody  for the 2 tissue. This was achieved by employing the closed polygon function in ImageJ to determine the individual area of the ileum and crypt in each image. The area of the crypt was then subtracted from the area of the ileum (crypt + villi) to calculate villi area, with only fully intact villi and crypts analysed. The total number of cells positive for each respective hormone was then divided by the ileum/crypt/villi areas.Image J software was used to assess total BPL and AL area along with their respective villi and crypt area for graphical representation. Only villi that were in the same plane as the slice were analysed. As such, villi length and crypt depth were calculated using the straight-line function. Total number of cells positive for GIP, GLP-1, GLP-2 and PYY, along with their counts in respective villi and crypts, were then counted and expressed as GIP, GLP-1, GLP-2 or PYY positive cells per mmGraphPad PRISM software was used to perform statistical analysis. A two-tailed student’s unpaired t-test with 95% confidence interval was used for comparative analysis between groups. Values are expressed as mean ± S.E.M. Difference between groups were significant if p<0.05.In the AL, RYGB in ND rats significantly (p<0.001) decreased villi width compared to their sham controls  villi width  villi cell numbers in HFD, but not ND, rats  increase in the number of GLP-2 positive cells in the crypt and villi, as well as total AL, when compared to their sham controls  decrease in the number of PYY positive cells per mm2 of total limb and crypt but not villi, when compared to their sham controls , but not different pre-surgery  increased when compared to ND rats . Non-fas-surgery . While b-surgery , with a -surgery . No sign-surgery .per se, play a key role in these changes of intestinal morphology. In the BPL, one notable observation in terms of intestinal morphology was a small but significant decrease in villi width following RYGB in ND rats, which was not apparent under conditions of previously sustained high fat feeding. Interestingly, BPL crypt depth was decreased only in HFD rats after RYGB. These changes may simply reflect re-direction of digesta away from the BPL post-surgery.In this small pilot study, RYGB was associated with relatively minor changes in intestinal morphology in rats, which were nevertheless greater in the AL than in the bypassed BPL. We observed decreased crypt depth and increased villi width in the AL of HFD-RYGB rats, with no change in villi length, in good agreement with others ,17. ThisWhilst intestinal morphology was not dramatically altered by bypass surgery, it seemed reasonable to further investigate gut hormone populations in the AL and BPL of ND- and HFD-RYGB rats. GLP-1 has long been advocated as the chief hormonal protagonist for RYGB induced metabolic benefits , originaAlso secreted from the L-cells is the intestinotrophic hormone GLP-2 which is derived from alternative processing of the proglucagon gene. This hormone is not entirely devoid of metabolic effects , but is The BPL is devoid of nutrient stimulation following RYGB, and as a result the impact of surgery on morphology and gut hormone populations within this section of the intestine has been somewhat overlooked. In our setting, only negligeable intestinal atrophy was detected in the BPL of ND-RYGB rats, and the solitary alteration of gut hormone population in this bypassed section of gut was a reduction in GLP-1 expression in the villus, but not crypts, in HFD-RYGB rats. Thus, GLP-1 positive cells are more predominant in intestinal crypts rather than villi , and incIn conclusion, our findings alongside recently published literature, suggest that early adaptation of EECs in the gut after RYGB surgery accompany the improved metabolic state. Although the pilot nature and relatively small sample size employed for the current study means it is difficult to make emphatic claims in this regard, the work does represent a firm initial standpoint for elucidation of such mechanisms. Notably, the morphology and EEC populations of the BPL are not appreciably affected by the bypass, arguing against the idea that metabolic benefits of RYGB are due to exclusion of factor derived from this intestinal region. However, despite the small number of rats studied, villi area in the AL was clearly augmented together with reciprocal changes of GLP-2 and PYY expression post-surgery. Such changes merit further exploration in terms of their direct impact to the well characterised metabolic benefits of RYGB surgery.


As disease-modifying therapies do not reverse the course of multiple sclerosis (MS), assessment of therapeutic success involves documenting patient-reported outcomes (PROs) concerning health-related quality of life, disease and treatment-related symptoms, and the impact of symptoms on function. Interpreting PRO data involves going beyond statistical significance to calculate within-patient meaningful change scores. These thresholds are needed for each PRO in order to fully interpret the PRO data. This analysis of PRO data from the PROMiS AUBAGIO study, which utilized 8 PRO instruments in teriflunomide-treated relapsing-remitting MS (RRMS) patients, was designed to estimate clinically meaningful within-individual improvement thresholds in the same manner, for 8 PRO instruments.The analytical approach followed a triangulation exercise that considered results from anchor- and distribution-based methods and graphical representations of empirical cumulative distribution functions in PRO scores in groups defined by anchor variables. Data from 8 PRO instruments  were assessed from 434 RRMS patients. For MSIS-29 v2, FSMC, MSPS, and MSNQ total scores, available anchor variables enabled both anchor- and distribution-based methods to be applied. For instruments with no appropriate anchor available, distribution-based methods were applied. A recommended value for meaningful within-individual improvement was defined by comparing mean change in PRO scores between participants showing improvement of one or two categories in the anchor variable or those showing no change. A “lower bound” estimate was calculated using distribution-based methods. An improvement greater than the lower-bound estimate was considered “clinically meaningful”.This analysis produced estimates for assessing meaningful within-individual improvements for 8 PRO instruments used in MS studies. These estimates should be useful for interpreting scores and communicating study results and should facilitate decision-making by regulatory and healthcare authorities where these 8 PROs are commonly employed.The online version contains supplementary material available at 10.1186/s41687-023-00594-8. Multiple sclerosis (MS) is a chronic immune-mediated disease affecting the central nervous system , 2. It hBoth MS-specific and generic PRO instruments are beneficial in evaluating HRQOL in people with MS and in assessing the impact of MS on function; hence, a combined approach using both generic and MS-specific PROs is often recommended . Given t®) in Routine Clinical Practice (PROMiS AUBAGIO study [TERIFL07766]) was a prospective, noninterventional study in US participants with RRMS treated with oral teriflunomide in routine clinical practice. Eight PROs were utilized in the PROMiS AUBAGIO study to evaluate the impact of RRMS on HRQOL, fatigue, functional performance, work capacity, daily activities, cognitive impairment, anxiety and depression, and satisfaction with treatment. This analysis of PROMiS AUBAGIO data was designed to estimate meaningful within-individual improvement thresholds for eight PRO instruments used in this study. It was hoped that this would enable better interpretation of improvement scores for these eight PRO instruments in past, current, and future MS studies.The Prospective, Non-Interventional Trial to Analyze Patient-Reported Outcomes in MS Patients Treated with Teriflunomide .A total of eight unique PRO instruments were administered to participants during the PROMiS AUBAGIO study; these instruments cover a variety of MS-specific symptoms, including HRQOL, fatigue, functional performance, work capacity, daily activities, cognitive impairment, anxiety and depression, and satisfaction with treatment. A summary of PRO scores and schedule of assessments is given in Table The MSIS-29 v2 is a PRO instrument developed to evaluate specific physical and psychological impact of MS from the patient’s perspective; the instrument comprises 29 items grouped into physical impact (20 items) and psychological impact (9 items) scores , 18. ParThe FSMC was developed to evaluate MS-related motor and cognitive fatigue, comprising 20 items that are grouped into a physical fatigue score 10 items), cognitive fatigue score (10 items), and combined total score (20 items) . Each di0 items, The MSPS was developed to evaluate MS-associated disability overall and in different dimensions and comprises 8 performance scales , and a total score . Each inThe MSNQ was developed to identify neuropsychological impairment in MS and includes a patient and an informant/caregiver version , 22. TheThe TSQM version-1.4) was developed as a generic instrument to evaluate patients’ satisfaction with medication and comprises 14 items grouped into side-effects score (4 items), effectiveness score (3 items), convenience score (3 items), and global satisfaction score (3 items) , 24. The.4 was deThe PDDS scale was developed to evaluate MS-associated disability overall and in different dimensions, and is a single ordinal item ranging from 0  to 8 (bedridden), with a higher score indicating more disability , 27. PDDP < 0.05) , and number of missing values. Categorical variables are described by frequency and percentages, with missing data included in calculation of percentages. Missing item responses within a PRO questionnaire were managed in the creation of PRO scores as specified by the developers of the instruments. Analyses were conducted on the FAS.Anchor-based methods are the primary approach for determining a meaningful within-individual change threshold, as recommended by the US Food and Drug Administration (FDA) , and werCorrelation between each anchor variable and the corresponding PRO score and between change in each anchor variable and change in the corresponding PRO score was estimated using Spearman’s rank-order correlation coefficients. Change in PRO scores was described in the groups defined according to the change in anchor variables over the same time period.Receiver-operating characteristic (ROC) curves were plotted to characterize the separation of groups defined according to various dichotomous categorizations of the anchor variables by the change in corresponding PRO score; from these ROC curves, change in PRO score that maximized the separation between dichotomous categorizations of the anchor variable was estimated by the smallest sum of squares of 1-sensitivity and 1-specificity .eCDF and PDF of change in MSIS-29, FSMC, MSPS, and MSNQ scores were plotted over the specified time periods according to groups defined by the potential anchors. Graphical representations of eCDFs of change in PRO scores in groups were defined by the anchor variables  thresholds  were calimprovement only, while results from the distribution-based methods are based on the score distribution hence have no direction and represent meaningful change. The reference value was established as change in PRO score of participants who showed an improvement of one or two categories in the corresponding anchor variable for PRO scores for which anchor-based methods were applied. For PRO scores in which only distribution-based methods were applied, the reference value was defined by 0.5SD at baseline.The results of the analyses were triangulated to define a reference value and a conservative value for the clinically meaningful within-individual change in MSIS-29, FSMC, MSPS, MSNQ, and a reference value for the clinically meaningful within-individual change for TSQM, PDDS, HRPQ-MS, and HADS scores. Results from the anchor-based methods represent meaningful within-individual For establishing a range of meaningful within-patient improvement, a “conservative” value was defined based on anchor-based and distribution-based methods. This value was defined to acknowledge the uncertainty of the estimate and provide a value that can be considered a “worst-case scenario”. The values obtained by the analyses were compared with the minimum detectable change nt error . The estA responder was defined as a participant with a change in score from baseline greater than the clinically meaningful within-individual improvement value. The percentage responder analysis was calculated at Month 10 for TSQM v1.4 scores, Month 11 for FSMC and HRPQ-MS v2 scores, and Month 12 for all other scores.Baseline characteristics and PRO scores in the FAS (n = 434) are summarized in Table Baseline PRO scores suggested that participants typically had moderate physical and psychological impact and symptoms, low anxiety and depression, and low satisfaction with prestudy treatment Table . ParticiCorrelations between each anchor variable and the corresponding PRO score at baseline are shown in Table Lower correlations were observed between the change in anchors and change in corresponding PRO scores from baseline to Month 12. Overall, correlations were below 0.3  instruments. Although not all of these instruments are specific to MS, determination of clinically meaningful within-individual improvement thresholds followed the principles currently recommended by the FDA  and resuPRO data are considered of central importance in the assessment of people with MS, and the use of PRO data is likely to become more widespread and clinically important with the development of on-line assessments and smartphone-based technologies that facilitate the exchange of such data between MS patients and their care providers . FurtherApplication of minimally important change represents an important tool for enhancing the interpretability of PROs; however to realize the full benefit of the value, an improved understanding is needed particularly around reporting the fundamental properties of the change . To addrOf the eight commonly used PRO instruments selected, some are validated in MS patients , 32, 35 Our study should be considered in light of certain limitations, as the determination of clinically meaningful within-individual change in PRO scores was not a prespecified objective of the PROMiS AUBAGIO study. There is, therefore, some uncertainty associated with the estimated values for meaningful within-individual improvement in all PRO scores based on both anchor- and distribution-based methods. For several PRO scores, no anchor variable assessing the same concept was available; therefore, only distribution-based methods could be applied. For example, values for meaningful change in TSQM v1.4 scores were estimated using distribution-based methods, with estimates of − 10.81 and − 9.99 for the convenience and effectiveness scales, respectively. However, given the high variability in the TSQM these values should be used with caution. The TSQM is commonly used cross-sectionally not longitudinally, although this is not unique to the current study. Although not a valid measure for assessing treatment satisfaction in people with RRMS, scale-to-sample targeting implied that treatment satisfaction may be underestimated by the TSQM; hence, further research is required to overcome this limitation . We therimprovement; as such there is no certainty that these values could also be used to characterize clinically meaningful within-individual worsening. Given MS is generally a disease of declining function, particularly over the long-term, further study is needed to clarify conclusions of clinically meaningful within-individual worsening. We also did not look at how values correlate with physician’s perspectives of clinical importance.Also of note, the anchor-based estimates were obtained using anchor variables that were not optimal, as indicated by the low correlations of changes in PRO score and anchor variables , the heterogenicity of the study population does help to ensure the calculations may be applicable to a broader range of people with RRMS. Our estimates should, therefore, be relevant to a range of future clinical studies in RRMS populations.worsening scores for all MS patient populations is an area for future research.This study has produced recommended estimates for assessing meaningful within-individual improvements based on results from PRO instruments used in MS clinical studies. These estimates will be useful for interpreting improvement scores and communicating the results of future studies evaluating the impact of RRMS on patients and will facilitate decision-making by regulatory and healthcare authorities. Additional work to estimate and confirm meaningful within-individual improvement thresholds in MS target populations, eg, primary-progressive MS (PPMS) and/or nonrelapsing secondary progressive MS (nrSPMS) patients is needed. In addition, work to estimate and confirm meaningful within-individual thresholds for Additional file 1: Fig. S1. Empirical cumulative distribution functions (eCDFs) for change in PRO scores where anchor variables were available. A MSIS-29 v2 physical impact; B MSIS-29 v2 psychological impact C FSMC Cognitive Score; D FSMC Motor Score E FSMC Total Score; F MSPS Total Score G MSNQ. Fig. S2. Responders for A multi-item and B single-item PROs using recommended meaningful within-individual improvement thresholds. Table S1. Correlation coefficients between change in anchor variables and the change in the corresponding PRO scores.


Observational and experimental studies have suggested that messaging on smoking-related COVID-19 risk may promote smoking abstinence, but evidence from randomized clinical trials (RCTs) is lacking.This was a pragmatic RCT in Hong Kong, China, to compare the effectiveness of communicating smoking-related COVID-19 risk with generic cessation support on abstinence. Both groups received brief cessation advice at baseline. The intervention group received messaging on smoking-related COVID-19 risk and cessation support via instant messaging for three months , which highlighted the increased risk of severe COVID-19 and deaths, and potentially higher risk of viral exposure  for smokers. The control group received generic text messaging support for three months (16 messages). The primary outcomes were biochemically validated 7-day point prevalence abstinence (PPA) at 3 and 6 months. Intention to treat analyses was used.Between 13 June and 30 October 2020, 1166 participants were randomly assigned to an intervention (n=583) or control (n=583) group. By intention-to-treat, validated 7-day PPA did not significantly differ between the intervention and control groups at three months  or six months . A higher perceived severity of COVID-19 in smokers at baseline was associated with a greater validated 7-day PPA at six months, and a marginally significant intervention effect on changes in perceived severity from baseline through 6 months was found (p for group × time interaction = 0.08).Communicating smoking-related COVID-19 risk via instant messaging was not more effective in increasing smoking abstinence than generic cessation support.ClinicalTrials.govIdentifier: NCT04399967The study is registered on  A systematic review of Mendelian randomization studies also showed that smoking traits  were associated with increased COVID-19 hospitalization, severity and mortality4. A potential mechanism is the upregulation of angiotensin converting enzyme-2 receptors (the adhesion site of SARS-CoV-2) in the respiratory tract due to cigarette smoke exposure5. Mask removal and the hand-to-mouth action of smoking may also predispose smokers to viral exposure6. The World Health Organization has recommended smoking cessation to reduce the burden of COVID-197.Systematic reviews and meta-analyses of observational studies have shown that current smokers have a higher risk of severe COVID-19 and death8. Our population-based survey in Hong Kong found that exposure to such misinformation was associated with increased tobacco use9. On the other hand, observational studies in the US and UK showed that a higher perceived risk of COVID-19 related to smoking was associated with increased cessation-related behaviors 11, also shown in our study in Hong Kong12. Several online experiments have found that exposure to messaging on smoking-related COVID-19 risk can increase smokers’ motivations to quit14, which may be mediated by fear arousal15. Nevertheless, our PubMed search (until March 2023) using the keywords ‘risk communication’, ‘health communication’, ‘health warning’, ‘messaging’, ‘COVID-19’, and ‘smoking’ did not identify any randomized clinical trial (RCT) testing the effectiveness of such messaging on smoking abstinence in a real-world setting.Messages regarding the risk of smoking on COVID-19 susceptibility and severity may influence smoking and quitting behaviors. Unverified claims that smoking can protect against COVID-19 have been widely disseminated, especially during the early phase of the pandemic16. Our subsequent trial showed the feasibility of using instant mobile messaging to deliver cessation support amid the COVID-19 pandemic17, in which access to in-person cessation services might be constrained. The current study compared the effectiveness of communicating smoking-related COVID-19 risk using instant mobile messaging with generic cessation support via text messaging to increase abstinence in community smokers.Our previous trial showed the effectiveness of instant mobile messaging in promoting smoking cessation21 in Hong Kong, China. Recruitment took place amid the 3rd wave of the COVID-19 pandemic, with approximately 4200 confirmed cases and 100 deaths in a population of approximately 7.5 million during the period of the recruitment 22. Stringent preventive measures were implemented, including mandatory masking and the restriction of public gatherings to two people, but without a city-wide lockdown23. The compliance rate of mask-wearing was nearly 100%. The Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster approved the protocol. The trial has been registered with ClinicalTrials.gov. The results are reported according to the Consolidated Standards of Reporting Trials (CONSORT-EHEALTH) reporting guidelines.This parallel, 2-arm, pragmatic RCT was conducted under the Hong Kong Council on Smoking and Health Quit-to-Win Contest21, trained smoking cessation advisors proactively approached, screened and recruited smokers at smoking hotspots using the ‘foot-in-the-door’ approach24. Compared with the pre-pandemic period, fewer smokers were observed in outdoor smoking hotspots amid the pandemic6. Therefore, online advertisements were also used to recruit smokers, who were screened by a cessation advisor through video calls (eMethods in Supplementary file).Participants were recruited from smoking hotspots in all 18 districts of Hong Kong or using online platforms. A total of 55 recruitment activities  were organized at 47 community sites. University students and volunteers (n=110) from nongovernmental organizations attended a full-day online workshop and were trained as smoking cessation advisors. Similar to previous trialsEligible participants were Hong Kong residents who were aged ≥18 years, smoked at least 1 tobacco stick [cigarette or heated tobacco product (HTP)] per day or used e-cigarettes daily in the past 3 months, which was verified by a salivary cotinine level of ≥30 ng/mL, who was fluent in Cantonese, owned a smartphone with an instant messaging application installed, and had the intention to quit or reduce smoking. The exclusion criteria were participating in other smoking cessation programs or having physical or cognitive difficulties in communication. All eligible smokers willing to participate signed a written informed consent form.21. Smoking cessation advisors asked the smokers about their smoking history (Ask), warned them about the hazards of smoking using a health warning leaflet (Warn), advised them to quit or reduce smoking as soon as possible (Advice), encouraged them to use a cessation service (Refer), and repeated the above steps if they continued to smoke or had relapsed at telephone follow-up sessions (Do-it-again).All participants received brief cessation advice at baseline guided by the AWARD  model, which was modified from the 5As  model for use in the community settings, as in our previous trials conducted under the Quit-to-Win ContestsParticipants in the control group received a generic health warning leaflet that included shocking pictures of diseases caused by smoking, such as coronary heart disease, stroke, and lung cancer . They also received regular text messages (i.e. participants not able to respond to the messages) with generic cessation advice for three months from baseline, with a tapering schedule from twice a week in the first month to once a week in the following two months . The messages included advice on smoking hazards and quitting benefits, strategies for quitting and coping, psychosocial support, and encouragement to initiate a quit attempt.25, as well as the higher risk of viral exposure because of mask removal, hand-to-mouth action of smoking, clustering of smokers, and secondhand smoke. They also received a combination of regular messages and chat-based cessation support for three months via WhatsApp, an instant messaging application. The schedule of regular messages was the same as that in the control group . The contents were similar to those of the control group, except the messages on smoking hazards focused on smoking-related COVID-19 risk. These messages were adopted from tweets and Facebook posts from the WHO, Centre for Health Protection of the Hong Kong Government, and the University of Hong Kong . Similar to our previous trials on mobile instant messaging support26, the participants could respond to the messages and initiate conversations with a research nurse to receive cessation coaching in real-time during office hours . Behavioral change techniques 27 were used based on the needs of the participants. An experienced doctoral-level researcher monitored the coaching process and discussed it with the research nurse when necessary.Participants in the intervention group received a health warning leaflet that highlighted the smoking-related COVID-19 risk . This included emphasizing the risk of respiratory infection, impaired immunity and COVID-19 complications in smokers A computer-generated randomization list was produced by an independent statistician using a randomized blocking schema . Participants were individually assigned at random to groups with a 1:1 allocation ratio. Blinding the interventionists and participants was not possible because of the nature of the intervention. Outcome assessors and statistical analysts remained masked until the prespecified analyses were completed.28. Secondary outcomes included self-reported 7-day point-prevalence abstinence (PPA), smoking reduction defined by a reduction of at least 50% in daily cigarette consumption compared with that at baseline, and intervention engagement defined as having read the instant messages or text messages in the respective intervention condition .Data were collected by questionnaire at baseline and telephone interviews at 1, 2, 3, and 6 months after intervention initiation. The primary outcome was biochemically verified 7-day PPA at three months (end of treatment) and six months after treatment initiation, verified by salivary cotinine concentrations of <30 ng/mL or exhaled carbon monoxide concentrations of <4 ppm. Research staff visited or video-called participants who reported having abstained from smoking for at least 7 days at 3 and 6 months for a biochemical validation (eMethods in Supplementary file)At baseline and the follow-up sessions, perceived susceptibility (i.e. smoking increased the risk of COVID-19 infection) and severity (i.e. smoking increased the severity of COVID-19 infection) of COVID-19 infection due to smoking were assessed on a scale of 0 to 10, with higher scores indicating greater perceived susceptibility/severity. We also assessed participants’ COVID-19-related information exposure . Process evaluations were conducted by assessing the perceived appropriateness of the messages (yes vs no) and their usefulness in increasing the motivation to quit and quit attempt, each on a scale of 0  to 4 (very useful). Participants in the intervention group were asked if they had engaged in online conversations with the research nurse and the reasons for not doing so. Those who did engage in online conversations rated their satisfaction on a scale of 0  to 10 (very satisfied).29. Based on our prior studies19, we conservatively assumed an additional 10% relative increase in the intervention effect due to messaging on smoking-related COVID-19 risk; the anticipated biochemically verified PPA was 10.1% in the intervention group and 5.0% in the control group. With a type I error of 0.05, a power of 80% and an allocation ratio of 1:1, 421 participants were needed per group. Accounting for a retention rate of 75%, a total of 1122 participants was needed.A meta-analysis of mobile health interventions showed an effect size [risk ratio (RR)] of 1.83 on biochemically verified 7-day PPA at six months30. Sensitivity analyses were conducted for the abstinence outcomes. First, we used complete case analyses by excluding participants with missing outcomes. Second, we used multiple imputation by chained equations to impute missing abstinence outcomes, including study group, sex, age, education level, household income, previous quit attempts, cigarette dependence, and intention to quit. Rubin’s rule was used to pool the estimates from 50 imputed datasets31. Mixed-effect models were used to examine the differences in changes in the perceived susceptibility and severity of COVID-19 due to smoking from baseline through 6 months. All analyses were conducted using Stata V.15.1 , with p<0.05 indicating statistical significance.We used intent-to-treat analyses, and participants with missing outcomes were imputed as smokers with no change in tobacco consumption. Poisson regression models with robust variance estimators were used to calculate the RRs of the intervention effect on the primary and secondary outcomes. The associations of baseline perceived susceptibility/severity with 6-month biochemically verified PPA were examined, adjusting for sociodemographic and known determinants of quittingIn the intervention group, 49.4% (n=288) of the participants had conversations with the research nurse, with a mean satisfaction score of 8.5 (SD=1.9) on a scale of 0 to 10. Being ‘too busy’ (49.5%) was the most common reason for not conversing with the research nurse, followed by ‘don't want to talk about cessation-related topics online’ (32.9%), ‘not interested’ (19.7%), and ‘not useful’ (5.4%).21. A 2019 Cochrane review of 13 RCTs showed that text messaging-based behavioral support was effective in promoting abstinence29. Our findings indicate that communicating messages on smoking-related COVID-19 risk with a research nurse via instant messaging did not confer additional benefits.This is the first RCT testing the effectiveness of messaging on smoking-related COVID-19 risk in increasing smoking abstinence in a real-world setting. Contrary to our expectations, communicating smoking-related COVID-19 risk via instant mobile messaging did not increase biochemically verified 7-day PPA at 3 and 6 months when compared with generic cessation support via text messaging amid the COVID-19 pandemic. However, the 6-month verified PPA (approximately 10%) in both groups was much higher than that of the intervention groups in our previous RCTs conducted under the Quit-to-Win contests before the COVID-19 pandemic (ranging from 5.6% to 9.0%)14. Our secondary analyses also showed that greater perceived severity of COVID-19 due to smoking was associated with 6-month verified PPA, adjusting for known determinants of successful cessation. However, we did not find a significant difference in changes in perceptions between the two groups, which may explain the null effect on abstinence. Subgroup analyses between online and face-to-face recruitment found no significant difference in abstinence, suggesting the similar null effects of interventions in both groups.The intervention was designed to promote cessation by increasing the perceived smoking-related risk of COVID-19, which has been found to be associated with intermediate cessation outcomes such as the motivation to quit in observational and experimental studies12. However, our trial participants showed relatively high levels of perceived susceptibility and severity  at baseline. This ‘ceiling effect’ might have constrained the room for increasing the risk perception level. Second, over 80% of the participants in both groups reported exposure to information on COVID-19 and smoking from any sources during the study period. The control group likely was exposed to such information from other sources, such as publicity by the local health authority and cessation services. Such contamination might have biased the intervention effect toward the null. Finally, participants’ ratings for the messages were significantly lower in the intervention group than in the control group, which suggests that messaging on smoking-related COVID-19 risk was less preferred compared to generic messages and cessation support. Prior qualitative studies on mobile messaging showed that smokers might not be receptive to messages that repeatedly emphasize the hazards of smoking (loss-framed messages)33. Further research is warranted to determine the optimal ‘dose’ to communicate smoking-related COVID-19 risk without demotivating smokers.Several reasons may underlie the failure of the intervention to change smoking-related COVID-19 risk perception. Our survey conducted prior to the trial showed that most smokers did not think smoking increased COVID-19 susceptibility (72%) or severity (58%)14. Likewise, another experiment showed no difference in valence or arousal elicited by COVID-19 or traditional graphic health warnings on cigarette packaging34. The experiment also showed that smokers with lower delay discounting  were more likely to be aroused by COVID-19 warnings34. The much milder impact of COVID-19 in Hong Kong than in most other places worldwide might have led to a lower perceived benefit of cessation in reducing COVID-19 risk and, thus, the abstinence rate.Studies on smokers’ affective responses to messages on smoking and COVID-19 also provide some insights into our null findings. An experiment showed that messages on smoking-related COVID-19 risk  elicited similar levels of reactions  and were perceived to be similarly effective in discouraging smokingThe strengths of the study include the randomized trial design conducted with a large cohort of smokers (n=1166) in a real-world setting with the use of an active comparison group. Another strength is the use of biochemically verified PPA as the outcome with a satisfactory participation rate  despite the difficulties of conducting in-person validation amid the pandemic.35. Third, the secondary outcome of intervention engagement (i.e. having read the instant messages or text messages) was based on self-report. Finally, our trial was conducted in Hong Kong, where the prevalence of smoking is low (9.5%), and smokers are predominantly male36. The generalizability of the findings to other places is unclear.This trial also had several limitations. First, despite a satisfactory retention rate of 71% at 6 months, given the minimal contact between the participants and researchers, non-response bias could not be excluded. However, our sensitivity analyses based on multiple imputations and complete cases yielded similar results to those of the main analyses. Second, as discussed, most participants in the control group were exposed to information on COVID-19-related smoking risks, which might reduce the intervention effect size, if any. However, given the real-world trial design, such contamination is difficult to controlCommunicating smoking-related COVID-19 risk via instant messaging was not more effective in increasing smoking abstinence than generic cessation support via text messaging.Click here for additional data file.


The development of psoriasis and alopecia areata (AA) is multifactorial. The interleukin-17 (IL-17) cytokine is believed to be associated with the pathophysiology of both diseases. This case report demonstrates a 64-year-old female patient who experienced a new onset of AA after the initiation of IL-17A inhibitor, secukinumab, for the treatment of her psoriasis. To our knowledge, there are only three case reports specifically discussing IL-17A inhibitors and AA. This case report highlights a potential rare but significant side effect of IL-17A inhibitors.  The development of psoriasis is multifactorial; it is a consequence of genetic predisposition, environmental triggers, and autoimmune pathogenic traits . AlopeciA 64-year-old Caucasian female presented with a history of chronic plaque psoriasis. Her past medical history was significant for treated chronic hepatitis C, 30 pack-year history of tobacco use, chronic obstructive pulmonary disease , hypertension, and sleep apnea.The initial physical exam demonstrated hyperkeratotic red scaly plaques on the palms, fingers, toes, thighs, and shins. Her condition was previously treated with topical triamcinolone for two years from 2018 to 2020 and narrow-band ultraviolet B phototherapy from November 2018 to January 2019 with minimal improvement. The patient was also treated with acitretin during this time, but she developed flushing and gastrointestinal upset prompting the discontinuation of this therapy. Her primary care physician initiated treatment with adalimumab (unknown dose) in October 2019, which was complicated by the development of generalized pustular psoriasis. Adalimumab was discontinued in May 2020, and she was transitioned to secukinumab 300 mg subcutaneous injection in June 2020 with resolution of pustular psoriasis within one month. However, six weeks after the initiation of secukinumab, the patient called to report a new onset of hair loss. She was seen one week later, and her examination was notable for significant progression of her psoriasis with new onset involvement of her arms and trunk. Additionally, she developed large, confluent, well-demarcated patches of alopecia in the posterior and vertex of her scalp with no other areas of alopecia noted on examination (Figure Treatment of psoriasis has drastically changed since the mid-20th century. Specifically, the introduction of biologic therapies in 2004 made a significant impact on patients with psoriasis refractory to traditional therapies . While sThe IL-17A cytokine is associated with inflammation, which is believed to have a key role in both psoriasis and AA ,7. InterThe underlying mechanism of AA upon IL-17A inhibitor exposure remains to be elucidated. To our knowledge, there are only three case reports specifically discussing IL-17A inhibitors and AA. Interestingly, the patients in these reports developed hair loss after 2, 13, and 24 months succeeding the initiation of the biologic ,10. Our In this case report, we describe a patient who developed AA after initiation of secukinumab for treatment of psoriasis with prompt recovery upon cessation of the biologic. This case report highlights the necessity of continued observation and documentation of potential adverse effects of new-era biologic therapies. Drug reactions such as AA negatively impact patients’ quality of life and psychological health. Providers should be aware of AA as a potential adverse event when they are prescribing secukinumab or other IL-17A inhibitors for the treatment of psoriasis.


Is a theory-informed multifaceted implementation strategy that includes access to an ambulatory blood pressure (BP) monitoring service effective at increasing out-of-office BP monitoring among primary care patients with elevated office BP in accordance with US hypertension screening guidelines?In this cluster randomized trial including 8 safety-net practices and 1186 patients with elevated office BP but no hypertension diagnosis, the implementation strategy modestly increased patient completion of out-of-office BP monitoring.These findings suggest that there is a need for more intensive implementation strategies for increasing adherence to hypertension screening guidelines that recommend out-of-office BP monitoring before hypertension diagnosis. This cluster randomized trial evaluates the effectiveness of a behavioral theory–informed, multifaceted implementation strategy on out-of-office blood pressure monitoring among primary care patients with elevated office BP but no prior diagnosis of hypertension. Few primary care patients complete guideline-recommended out-of-office blood pressure (BP) monitoring prior to having hypertension diagnosed.To evaluate the effectiveness of a behavioral theory–informed, multifaceted implementation strategy on out-of-office BP monitoring (ambulatory BP monitoring [ABPM] or home BP monitoring [HBPM]) among patients with new hypertension.This 2-group, pre-post cluster randomized trial was conducted within a primary care network of 8 practices  and 1186 patients  with at least 1 visit with elevated office BP and no prior hypertension diagnosis between October 2016 and September 2017 (preimplementation period) or between April 2018 and March 2019 (postimplementation period). Data were analyzed from February to July 2023.Usual care (control group) or a multifaceted implementation strategy consisting of an accessible ABPM service; electronic health record (EHR) tools to facilitate test ordering; clinician education, reminders, and feedback relevant to out-of-office BP monitoring; nurse training on HBPM; and patient information handouts.The primary outcome was patient completion of out-of-office BP monitoring within 6 months of an eligible visit. Secondary outcomes included clinician ordering of out-of-office BP monitoring. Blinded assessors extracted outcomes from the EHR.P = .009). Among control practices, the percentage of visits resulting in completed out-of-office BP monitoring changed from 5.4%  to 4.3%  during the corresponding period (P = .94). The ratio of relative risks (RRs) of out-of-office BP monitoring in the postimplementation vs preimplementation periods for intervention vs control practices was 10.5 . The ratio of RRs of out-of-office BP monitoring being ordered was 2.2 .A total of 1186 patients  were included, with a mean (SD) age of 54 (16) years; 808 (68%) were female, and 549 (48%) were Spanish speaking; among those with race and ethnicity documented, 123 (10%) were Black or African American, and 368 (31%) were Hispanic. Among intervention practices, the percentage of visits resulting in completed out-of-office BP monitoring increased from 0.6%  to 5.7%  between the preimplementation and postimplementation periods (This study found that a theory-informed implementation strategy that included access to ABPM modestly increased out-of-office BP monitoring among patients with elevated office BP but no hypertension diagnosis.NCT03480217ClinicalTrials.gov Identifier:  Developing an effective and sustainable model for increasing the use of guideline-recommended out-of-office BP monitoring is well-suited to the emerging area of implementation science, which involves the study of methods to increase the uptake of evidence-based interventions.18Despite the widespread availability of HBPM devices and reimbursement for ABPM, both are infrequently utilized as part of hypertension screening in the United States.19 to develop a multifaceted implementation strategy that addresses barriers to out-of-office BP monitoring as part of hypertension screening. The BCW is a multistep framework increasingly used to design implementation strategies.22 It involves first mapping barriers with stakeholder input and then identifying behavioral theory–informed intervention components for addressing these barriers. We then evaluated the effect of this implementation strategy on out-of-office BP monitoring in patients with elevated office BP but no prior diagnosis of hypertension.In the current study, we used the Behavior Change Wheel (BCW)23 Briefly, EMBRACE was a pre-post cluster randomized trial with randomization at the practice level for practical reasons relevant to clinical implementation and to prevent contamination between clinicians within the same practice. The study protocol (CONSORT Extension) to cluster randomized trials reporting guideline was followed.24Details of the study design and protocol for the Effects of a Multifaceted Intervention on Blood Pressure Actions in the Primary Care Environment (EMBRACE) trial were previously described.protocol  was apprThe trial was conducted in primary care clinics that are part of the Ambulatory Care Network (ACN) of New York-Presbyterian (NYP), a health enterprise affiliated with 2 medical schools, CUIMC and WCM. The preimplementation period took place from October 1, 2016, to September 30, 2017; implementation from October 1, 2017, to March 31, 2018; and postimplementation from April 1, 2018, to March 31, 2019. The ACN serves a predominantly low-income, publicly insured population with substantial numbers of Hispanic and Black or African American patients. The 10 primary care practices in the ACN that serve adult patients, each in geographically distinct locations, are staffed by internal medicine physicians, family medicine physicians, nurse practitioners, and graduate medical education trainees. Office BP was taken by medical assistants using automated devices, with readings manually entered into the electronic health record (EHR). None of the practices had protocols for systematically repeating elevated office BP readings. The practices used 2 different EHR systems: Allscripts (Allscripts) at CUIMC-affiliated practices and Epic (Epic) at WCM-affiliated practices.Primary care practices that served adult patients, were part of the ACN, and whose medical directors agreed to participate were included. Of 10 such practices, the 2 used for pilot testing the implementation strategy were excluded. Patients were identified through the EHR and were included if they were 18 years old or older, had not previously been diagnosed with hypertension, and had high office BP (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) during at least 1 scheduled visit with a primary care clinician at an eligible practice during the relevant time period, hereafter referred to as eligible visits. If multiple BP readings were documented in the flowsheet, the mean was used to determine eligibility. Patients were excluded if they had a prior diagnosis of hypertension; a prior evaluation for white-coat hypertension; prior prescribed antihypertensive medication; office BP less than 140/90 mm Hg; severely elevated office BP (systolic BP ≥180 mm Hg or diastolic BP ≥110 mm Hg); or evidence of target organ damage . As each visit at which patients had elevated office BP represented an opportunity to order out-of-office BP monitoring, patients could be eligible at more than 1 visit.The study principal investigator (I.M.K.) met with the medical directors of all 8 potentially eligible practices to invite their practice to participate, and each agreed. The 8 practices were then matched in pairs according to practice size and patient and clinician characteristics . Randomization was generated by the study’s (blinded) biostatistician (J.E.S.), using a random number generator to assign one practice within each matched pair to the intervention.23 Briefly, patients and primary care clinicians were interviewed to understand barriers to implementation .26 The multidisciplinary implementation strategy design team then used the BCW to develop a preliminary implementation strategy. Medical directors and ACN leaders were then interviewed to determine which implementation strategy components should be retained or added and which should be rejected by virtue of their not meeting one or more APEASE  criteria.27 The final planned strategy for increasing the completion of ABPM/HBPM consisted of a multilevel intervention including (1) access to ABPM; (2) EHR tools tailored to distinct EHR capabilities at WCM- and CUIMC-affiliated practices to facilitate test ordering; (3) educational presentations on why, when, and how to order out-of-office BP monitoring; (4) feedback on the utilization and results of ABPM; (5) reminders to order out-of-office BP monitoring; (6) nurse training on how to teach HBPM to patients, and (7) patient information handouts  was greater in the practices that received the intervention than in the control practices. The same approach was used to evaluate the effect of the intervention on the rate of out-of-office BP ordering. Relative risks (or risk ratios) (RRs) and 95% CIs were based on multilevel Poisson regression analyses adjusted for within-practice clustering. Sensitivity analyses were conducted adjusting for patient age and sex.The percentage of eligible patient visits resulting in ABPM and HBPM being completed in the preimplementation and postimplementation periods was calculated for intervention and control clinics, separately. When reporting condition-by-period rates, simple percentages with 95% CIs were used. Multilevel Poisson regression models,31 For each combination of CV  and correlation (r) between preintervention and postintervention practice-level out-of-office BP completion rates , the power to detect an RR of 3.0 was estimated by (1) generating 10 000 simulated data sets, incorporating the number of eligible patient visits during 2014 in each of the 8 participating practices; (2) performing the multilevel Poisson regression analysis on each simulated data set, and (3) determining the proportion of data sets in which the null hypothesis was rejected  in the hypothesized direction. According to these simulations, the study would have 84% power to detect the hypothesized condition × period interaction effect  if there was no between-practice heterogeneity; 79% to 80% power if CV was 0.10 and r 0.50 or greater, and 75% power if CV was 0.40 and r 0.90.23 Data analysis was conducted with SAS version 9.4 (SAS Institute) from February to July 2023.We estimated the power to detect a 10% increase in out-of-office BP completion rate due to the intervention . For a multilevel Poisson regression model with log link function, this variability depends on the coefficient of variation .A total of 1186 patients  were included, with a mean (SD) age of 54 (16) years, 808 (68%) were female, and 549 (48%) had Spanish as their preferred language. Among those with race and ethnicity documented, 123 (10%) were Black or African American, and 368 (31%) were Hispanic. These patients were treated by 154 clinicians and had 1339 eligible visits . CharactP = .009) (P = .94). Overall, the ratio of these RRs (the prespecified primary parameter of interest) was 10.49 . The same pattern of results was present in analyses adjusted for patient age and sex  to 5.7% of eligible visits  between the preimplementation and postimplementation periods  . Among cP = .02). Among control practices, out-of-office BP test ordering changed from 13 of 149 visits  to 19 of 207 visits  between the preimplementation and postimplementation periods . The ratio of these RRs was 2.22 .Among intervention practices, ordering of out-of-office BP monitoring increased from 15 of 529 visits  to 36 of 454 visits  between the preimplementation and postimplementation periods  and hypertension was diagnosed in 23 visits (5.5%). A similar pattern was found in control practices.P = .03) while decreasing nonsignificantly from 8 of 13 patients (61.5%) to 9 of 19 patients (47.4%) (P = .49) in control practices.In post hoc analyses unadjusted for clustering by practice, of patients with ABPM ordered during the postimplementation period, all from intervention practices, ABPM was successfully completed in 17 of 22 patients (77.3%). Of patients with HBPM ordered, the percentage that completed HBPM increased from 3 of 15 (20.0%) preimplementation to 9 of 14 (64.3%) postimplementation in intervention practices  who completed out-of-office BP monitoring . Too few patients completed out-of-office BP monitoring to compare differences in white-coat hypertension diagnosis between intervention and control practices.32 and support that increasing the accessibility of ABPM, paired with education and reminders, can increase uptake of ABPM in primary care, at least marginally. The value of out-of-office BP monitoring was confirmed, as approximately half of patients who completed out-of-office BP monitoring were diagnosed with white-coat hypertension and potentially avoided inappropriate treatment and chronic disease labeling.In this cluster randomized trial, a theory-informed multifaceted implementation strategy targeting patient-, clinician-, and systems-level barriers increased out-of-office BP monitoring in patients with elevated office BP without a prior diagnosis of hypertension. These improvements were driven by increases in ABPM ordering and completion as well as increases in HBPM completion among those with HBPM ordered. In contrast, no patients had ABPM ordered or completed in usual care practices. These findings are consistent with the low use of ABPM in US-based primary care settings23 Policy-level interventions relevant to billing and reimbursement are likely necessary to spur greater adoption of ABPM in this primary care network. Hard-stop EHR tools that required clinicians to consider out-of-office BP monitoring might also have prompted more action, yet this strategy was not viewed as acceptable in the primary care network where this study was conducted.Although the implementation strategy was effective and could be implemented with fidelity, it only modestly influenced the behavior of clinicians. After implementation, out-of-office BP monitoring was ordered in less than 10% of visits with guideline-eligible patients and completed in only 72% of patients that had testing ordered. Making ABPM available on-site at individual practices may have been a more potent approach. Indeed, training practices to provide ABPM was considered as a potential implementation strategy component, but this component was not viewed as feasible by key stakeholders due to resource limitations in terms of staff time to place, track, and download data from ABPM devices.33While the primary behavioral target for the implementation strategy was clinician ordering of out-of-office BP monitoring, the strategy included patient-focused components that may have increased the percentage of patients at intervention practices successfully completing HBPM from the preimplementation to the postimplementation periods. These components included clinician and nurse training on how to teach patients the correct HBPM protocol, EHR tools to facilitate prescribing of HBPM devices, and links to patient handouts that demonstrated their correct use. While HBPM ordering increased in intervention practices, the magnitude of improvement was small, perhaps due to system-level barriers unaddressed by the implementation strategy. These barriers included limited insurance coverage for home BP devices. In underresourced patient populations, out-of-pocket costs for HBPM devices may continue to serve as a barrier to HBPM testing and may thereby increase health disparities.34 Future interventions should strive to reduce hypertension underdiagnosis in primary care.The predominant action by clinicians for patients with elevated office BP readings was to wait and see. This contributes to the literature showing that hypertension is commonly underdiagnosed in primary care, leading to undertreatment.There are several potential limitations of this study’s findings. Despite matching practices prior to randomization, there were substantial differences in the characteristics and numbers of patients and clinicians between intervention and control practices. This is more likely to happen when, as in this study, only a small number of practices are enrolled. There were also differences in preimplementation test ordering. Nevertheless, comparing the pre-post within-condition changes in out-of-office BP monitoring helped control for these differences and represented a strength of the pre-post cluster randomized design. While cluster randomization was applied at the practice level, some implementation strategy components may have been received by control clinicians; this would have biased results toward the null. The implementation strategy was tested in a small number of hospital-affiliated practices that served an underresourced patient population in one geographic region. Findings might not generalize to other settings. Strategies, such as home BP device loaner programs and increased staff training in provision of out-of-office BP monitoring, that were not viewed as feasible in this network may be effective elsewhere. There may have been differences in the extent to which clinicians in the intervention and control practices documented HBPM, such that differences in HBPM completion should be interpreted cautiously. Also, it was not possible to determine whether patients followed the correct HBPM protocol; patients in intervention practices may have received better training on the proper conduct of HBPM. Finally, just prior to the postimplementation period, the 2017 American College of Cardiology/American Heart Association BP guideline recommended lowering the threshold for diagnosing hypertension from 140/90 mm Hg to 130/80 mm Hg. Future studies should assess the impact of these guideline changes on hypertension screening and their implications for developing implementation strategies.This study found that a theory-informed implementation strategy developed based on the BCW modestly increased out-of-office BP monitoring in patients with elevated office BP and no prior diagnosis of hypertension. Patient-, clinician-, and system-level interventions, such as higher reimbursement and lower out-of-pocket costs for out-of-office BP monitoring, may be needed for greater uptake of hypertension screening guidelines.


Critically ill patients commonly receive proton pump inhibitors (PPIs) to prevent gastrointestinal (GI) bleeding from stress-induced ulceration. Despite widespread use in the intensive care unit (ICU), observational data suggest that PPIs may be associated with adverse outcomes in patients with COVID-19 infection. This preplanned study is nested within a large randomized trial evaluating pantoprazole versus placebo in invasively ventilated patients. The 3 objectives are as follows: (1) to describe the characteristics of patients with COVID-19 in terms of demographics, biomarkers, venous thromboembolism, tracheostomy incidence and timing, and other clinical outcomes; (2) to evaluate the impact of COVID-19 infection on clinically important GI bleeding, 90-day mortality, and other outcomes compared to a propensity-matched non-infected cohort; and (3) to explore whether pantoprazole has a differential treatment effect on clinically important GI bleeding, 90-day mortality, and other outcomes in patients with and without COVID-19 infection.The ongoing trial Re-EValuating the Inhibition of Stress Erosions (REVISE) compares pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important GI bleeding and the primary safety outcome of 90-day mortality. The protocol described in this report is for a substudy focused on patients with COVID-19 infection that was not in the original pre-pandemic trial protocol. We developed a one-page case report form to characterize these patients including data related to biomarkers, venous thromboembolism, COVID-19 therapies, tracheostomy incidence and timing, duration of mechanical ventilation, and ICU and hospital stay. Our analysis will describe the trajectory of patients with COVID-19 infection, a propensity-matched analysis of infected and non-infected patients, and an extended subgroup analysis comparing the effect of PPI among patients with and without COVID-19 infection.Prophylactic acid suppression in invasively ventilated critically ill patients with COVID-19 infection has unknown consequences. The results of these investigations will inform practice, guidelines, and future research.REVISE Trial , COVID-19 Cohort Study . For patients with COVID-19 receiving invasive mechanical ventilation, standard critical care therapies, including prophylactic acid suppression, have unclear consequences. Concerns emerged early in the pandemic that some common medications may predispose to COVID-19 infection or worsen outcomes among infected patients. For example, observational studies suggested that angiotensin-converting enzyme (ACE) inhibitors were harmful as they were associated with increased mortality . HoweverI2 = 66%)   .This study uses a multicenter cohort design embedded within a randomized trial NCT05715567]. This is the first version  of the substudy protocol. Figure 5567. ThiPatients are being enrolled in 63 ICUs worldwide .Patients are eligible for this COVID-19 substudy according to the inclusion and exclusion criteria of the REVISE Trial, as outlined in Table efficacy outcome for REVISE is clinically important GI bleeding occurring in the ICU or resulting in ICU readmission during the index hospital stay. Adjudicator agreement for this metric was excellent in two prior studies ) of the continuous variables will be calculated. Baseline characteristics  will be described. Table For any outcome that is missing for more than 2% of patients, we will perform multiple imputation. Adjustments for multiple comparisons will not be made for these exploratory analyses. All analyses will be performed using the statistical software SAS version 9.4 .New continuous variables added to the REVISE dataset to help characterize the COVID-19 cohort of patients include inflammatory biomarker levels and time until tracheostomy. New dichotomous variables include the incidence of thromboembolic events and treatment with COVID-19-specific therapies. Continuous variables will be summarized using mean ± standard deviation (SD), or median (interquartile range [IQR]), while frequencies and percentages will be used to summarize categorical variables.To explore whether patients with COVID-19 experience different clinical outcomes relative to patients without COVID-19, we will compare the COVID-19 cohort and a propensity-matched non-COVID cohort from REVISE. Propensity score matching attempts to estimate the effect of COVID-19 status by accounting for important covariates that may predict or explain this status. Patients with COVID-19 will be matched with other patients within REVISE using propensity score analysis. We will consider an optimal matching ratio of 2:1 or 1:1 depending on the availability of optimal matches.The propensity score will be generated using potentially important pre-randomization demographic variables, including age, sex, pre-hospital acid suppression (PPIs or histamine-2-receptor antagonists (H2RAs)), COVID-19 vaccination status, ICU admission category of medical or surgical/trauma, and date of enrollment. Propensity matching will only include patients enrolled after the declaration of the COVID-19 pandemic on March 11, 2020. As a sensitivity analysis, we will match only on pre-hospital PPI use, not H2RAs, given limited evidence to suggest that H2RAs influence susceptibility to COVID-19 infection .C. difficile infection, patient-important GI bleeding, renal replacement therapy, ICU and hospital mortality, and duration of mechanical ventilation and ICU and hospital stay. We will adjust all analyses for randomized allocation; mortality outcomes will be adjusted for the APACHE II score.Propensity score matching helps to ensure that the distribution of the foregoing covariates is similar between the compared populations . CompariC. difficile infection, patient-important bleeding, renal replacement therapy, and ICU and hospital mortality, as well as the duration of mechanical ventilation and ICU and hospital stay.We will explore whether pantoprazole in the ICU has a differential treatment effect on clinically important GI bleeding or 90-day mortality for patients with COVID-19 relative to those without COVID-19. This is a subgroup analysis of the primary REVISE trial. However, in addition, we aim to further evaluate the subgroup effects of pantoprazole in patients with COVID-19 across secondary REVISE outcomes including VAP and This analysis will be conducted per the intention-to-treat principle. For time to the primary and secondary binary outcomes, we will use Cox proportional hazards regression, adjusted for pre-hospital use of acid suppression (a stratification variable). Analysis of our mortality outcomes will also be adjusted for the APACHE II score. An interaction term will be included in the model to test for this subgroup effect and results will be interpreted per the ICEMAN criteria . We willThe main REVISE trial was approved in participating hospitals by all relevant ethics committees and regulatory authorities prior to starting enrollment. The Hamilton Integrated Research Ethics Board (HiREB) under Clinical Trials Ontario (CTO Study ID 1360) is the main REB of record, which also approved this substudy. Ethics review for the additional COVID-19-specific data collection was undertaken by the Research Ethics Board of record (the Hamilton Integrated Research Ethics Board), and as needed to comply with local regulations in each participating center. In the absence of any modifications to the REVISE study design, this substudy involved additional data collection to characterize the patients with COVID-19 and facilitate additional future analyses. Therefore, no modifications were made to the consenting process for REVISE patients involved in this embedded COVID-19 study, and no requirements were issued to either reconsent or inform prior REVISE participants of the substudy. Specifically, there was no requirement to inform participants of this substudy, including an additional review of participants’ medical records for new data collection. Participants previously randomized in REVISE were not re-consented to participate in the COVID-19 embedded substudy.After completion of the COVID-19 REVISE substudy, we will rapidly publish the results. All results will be published with open access to ensure wide dissemination and accessibility of study findings. We plan to publish and present the COVID-19 substudy work at an international congress. We will disseminate a lay summary of findings to the general public through health networks of patient advocates and persons with lived or living experiences. We will generate lay language summaries and visual abstracts for traditional  and social media. We will also host videoconferences and regional rounds. We will disseminate structured abstracts and slide decks to local ICU quality councils, provincial organizations , national policymakers , and professional societies. Participating organizations, sponsors, and university institutions will be provided with press release briefs to disseminate to their respective audiences.This study, embedded within a global, randomized trial of stress ulcer prophylaxis, will fill important knowledge gaps in the literature that prompted our three research questions and three study objectives. The first is a descriptive analysis of the COVID-19 cohort in REVISE. The second is a propensity-matched analysis of patients with and without COVID-19. The third is an extended subgroup analysis of the REVISE trial, evaluating the effect of pantoprazole on a range of additional clinical outcomes among patients with and without COVID-19.Evidence describing the association between acid suppression and poor prognosis among patients with COVID-19 has emerged, but results have been variable. To prevent complications among critically ill patients with COVID-19, interim WHO guidance in 2020 suggested H2RAs or PPIs for patients with risk factors for GI bleeding, including mechanical ventilation for ≥ 48 h, coagulopathy, renal replacement therapy, liver disease, multiple comorbidities, and higher organ failure score . SurviviLimitations of this substudy include the risk of missing 90-day outcomes due to high levels of inter-hospital transfers experienced during COVID-19 . PatientStrengths of this study include the timely development of a protocol addressing essential research questions relevant to a high-risk subgroup of critically ill mechanically ventilated patients that emerged during the pandemic. The main REVISE Trial [NCT03374800], and this COVID-19 Cohort Study [NCT05715567] are registered. We have specified a priori hypotheses for each of the 3 objectives. As this study was developed after the REVISE Trial began recruitment, we are using both retrospective and prospective data collection methods to identify relevant patients with COVID-19. All necessary data is derived from the hospital stay, except 90-day mortality for those discharged alive; thus, we anticipate minimal missing data.As of June 1, 2023, more than 90% of relevant data for REVISE patients with COVID-19 are in the REVISE database to inform this work. REVISE enrollment is anticipated to close byNovember 2023; 90-day follow-up, chart closure, and analyses for this study will follow later in 2024.


Health-seeking behaviour refers to patients’ choices regarding their preferred healthcare destination and the timing of seeking assistance for treatment. Patients with TB usually first approach the private sector and/or lose several months’ time in inappropriate diagnosis and treatment due to lack of awareness regarding the availability of standard treatment protocols. This can lead to poor outcomes such as drug-resistant TB (DR-TB) and/or death.A cross-sectional study was conducted to examine the health-seeking pathway and delays in diagnosis and initiation of DR-TB treatment among patients registered with the DR-TB centre in Vadodara District (India).n = 20, 21.5%). The median delay in reaching the first healthcare facility was 12 days (IQR 7.5–30). Delay in reaching second- and third-level care was respectively 25 days (IQR 9–68) and 16 days (IQR 4–67).A total of 93 patients were enrolled in the study; the median age was 35 years (IQR 24–45). For the first visit, 59 (63%) patients chose a public healthcare facility, mainly because the facility was near their residence . The median duration from symptom onset to the first healthcare contact fell within the timeframe for screening symptoms in standard diagnosis. TB is a continuing public health problem in India . Moreover, India has the highest burden of multidrug-resistant TB (MDR-TB) cases in the world. The estimated number of MDR-TB and extensively drug-resistant TB (XDR-TB) cases were respectively 4 and 1/100,000 according to the 2021 WHO Global TB Report.Delay in diagnosis and the subsequent delayed treatment initiation can lead to greater DR-TB resistance, as well as increased mortality among TB patients. Delay in the diagnosis and initiation of treatment could be attributed to health-seeking behaviour of the patient and delay in diagnosis from the provider’s side.4Health-seeking behaviour for TB can be described as patients’ preference for the healthcare facility and the timing of seeking treatment according to their own choices.7Regarding the provider delay documented by Kelkar-Khambete et al., the evidence indicates that patients had to visit multiple healthcare facilities due to the limitations of each facility in terms of diagnosis and available treatment.A cross-sectional study was carried out among patients with DR-TB  registered with the DR-TB Centre, Vadodara District.In India, as per the programmatic guidelines for TB elimination, the government established DR-TB Centres, with the aim of having one in each district.According to the recent PMDT guidelines, patients are required to register themselves at a DR-TB centre for pre-treatment evaluation before commencing DR-TB treatment.11Exposure variable such as sociodemographic details of the patients, symptoms, first healthcare facility contacted and outcome of the disease were collected. Questions pertaining to the pathway prior to reaching our DR-TB centre  before diagnosis and treatment inititaion were assessed to aid in pathway analysis.Contact details of the patients were obtained from patients records after due permissions. Data were collected using a pre-tested semi-structured questionnaire in a single telephone interview. A second call was made in case of incomplete information. Data were entered in MS Excel , and the health-seeking pathway with median duration and delay in diagnosis and overall treatment initiation were presented in graphs. Patient-side delay was determined by assessing the time patients took to reach the initial healthcare facility, while provider-side delay was calculated based on the time taken to initiate treatment after arriving at the first healthcare facility. Interviews were conducted within 21 days of treatment initiation to rule out recall bias.The study was conducted after obtaining permission from The Institutional Ethics Committee for Human Research (IECHR) and the NTEP. Patients were contacted and telephone consent for the interview was obtained; if patients were not available at the time of the interview, the telephone interviews were conducted at their convenience.Interviews were conducted after ensuring due confidentiality. Data were entered in a pre-designed data capture format based on the information recorded in the registers. As unique identification numbers were assigned to patients, no names were mentioned and confidentiality was maintained. Hard copies of data were kept under lock and key in a cupboard designated for this specific research, while the electronic records were secured using password-protected files, allowing limited access to soft copies and hard copies. The Principal Investigator was personally responsible for data collection; these data were shared with co-investigators after removing individual identifiers for analysis purposes. Records will be maintained for 5 years after completion of study.At the conclusion of each in-depth interview, a simplified information sheet in the local language was presented orally. This sheet provided an overview of MDR-TB, stressed the significance of adhering to the treatment, and informed the participants about the Direct Benefit Transfer and other available support schemes during their treatment.Presumptive DR-TB refers to individuals eligible for screening for rifampicin  resistance at the time of TB diagnosis or during treatment for drug-susceptible TB (DS-TB). This category also includes those with isoniazid  mono/poly DR-TB. It comprises all reported TB patients, whether from the public or private sector, follow-up cases with positive microscopy results, including those who have experienced treatment failure with standard first-line treatment and those on the INH mono/poly DR-TB regimen. It also covers clinical non-responders, including paediatric non-responders.12n = 90, 96.8%) had pulmonary TB. The study comprised 55 (59.1%) males, and the majority  were identified as Hindu. Furthermore, 79 (84.9%) of the patients had received some level of education, and 65 (69.9%) resided in urban areas. The median delay for seeking care did not differ significantly across various parameters, including age groups, sex, religion, educational level, occupation, socio-economic status and residence (P > 0.05) . The majority of these patients ( > 0.05) . To noteThe health facilities frequented by DR-TB patients, illustrating their healthcare-seeking journey, were categorised into four main groups. Of the 93 patients, 16 received a diagnosis and commenced treatment without being directed to another facility as they initially visited the DR-TB centre as their primary point of care. In our study, patients consulted with as many as four different levels/centres before receiving a diagnosis and starting treatment. Forty-eight patients required only one referral to reach the point of diagnosis and treatment initiation. Twenty-two patients (23%) underwent two referrals. The majority of patients (86/93) received their diagnosis and started treatment at the second referral level. Five patients needed a third referral, while two required four referrals before their DR-TB diagnosis and treatment initiation.Among the total of 93 patients, 77 (82%) opted to visit a healthcare facility of any type (public or private). The remaining patients favoured home remedies and Ayurvedic preparations, as well as obtaining direct medications from a pharmacy, which accounted for 10 (11%) and were screened by field workers, totalling 6 (7%).n = 23), community healthcare centres (CHCs) (n = 5), district hospitals (n = 15) and tertiary care hospitals associated with medical colleges (n = 16). The most common reasons for selecting a public healthcare facility for diagnosis and treatment were its proximity to their residence , previous experience with treatment at a public health facility  and affordable costs .For their initial visit, 63% of patients had chosen public healthcare facilities, including primary healthcare centres/urban primary healthcare centres (PHCs/UPHCs) , the facility being that of their family physician  and the expectation of better healthcare services   . The med% . The mn = 77) were for specific treatment of DR-TB , for treatment of TB , lack of improvement of symptoms  and treatment not affordable . Reason for referral to second (n = 32) and third (n = 7) healthcare facility/setup were also similar; for specific treatment of DR-TB , lack of improvement of symptoms  and treatment not affordable  The reasons for referral are mentioned in The reasons for first referral  for patients to reach the DR-TB centre and commence treatment. Specifically, the delay in reaching the second level was 25 days (IQR 9–68) and for the third level, it was 16 days IQR 4–67). The cumulative delay from the providers’ side amounted to 31 days (IQR 5–75). –67. The DR-TB represents a dual challenge as it impacts patient treatment duration, disease transmission,Our study aimed to unveil the health-seeking trajectories and the delays in obtaining diagnoses and DR-TB treatment among patients who visited the DR-TB centre affiliated with a medical college’s tertiary care hospital. An improved understanding of the pathways taken by DR-TB patients could pave the way for enhanced care access, ultimately reducing both delays and treatment expenses.In our investigation, it was observed that a majority of patients, two-thirds, required a visit to a second-level healthcare facility before receiving a diagnosis and commencing DR-TB treatment. For a small number of patients, five in total, a visit to a third-level healthcare facility was necessary, and just two patients had to access a fourth-level healthcare facility. Notably, 16 patients were diagnosed and started treatment during their first healthcare encounter, possibly due to direct referral by healthcare workers or their prior knowledge of the diagnostic and treatment process. This prior knowledge might have resulted from knowing individuals with TB within their social circles or having previous experience with TB treatment, although this aspect was not explored in depth in our study. Describing the health pathways of patients with previous TB experience could be a valuable avenue for future research.The overall median delay was 60 days (IQR 26–122) before treatment initiation, and a median delay of 12 days (IQR 7.5–30) in reaching the first healthcare facility from the patient’s perspective. Other studies conducted in India reported different figures, with Rathi et al. finding a median delay of 30 days for public health facilities and 20 days for private health facilities,16The substantial delay in treatment initiation suggests a lack of knowledge or prompt referral services for diagnosis and treatment initiation.We found that only 16% of patients initiated treatment at the DR-TB centre during their first visit, having gone directly to the district DR-TB centre, while the majority of patients required two or more referrals. A study conducted in Ghana by Queri et al. in 2014 also reported that more than half of the patients began treatment at facilities other than DOTS centres.Multiple referrals were primarily linked to treatment affordability issues, and there was a significant difference in the median delay in treatment between patients who visited public healthcare facilities and those who chose private facilities. Private facilities are often associated with higher care costs, leading to referrals to other healthcare facilities. Despite the national health programme’s aim of zero catastrophic costs for TB treatment and a standard of care in public healthcare facilities, there may be a lack of awareness about these provisions, resulting in patients seeking care in the private sector. Studies have also indicated that patients prefer private facilities due to the fear of being stigmatised as having TB.16The median delay from the providers’ side in our study was 31 days (IQR 5–75). A systematic review by Getnet et al. in 2017 reported provider-side delays ranging from 2 to 128.5 days (IQR 12–34).20Studies conducted in Bangladesh and Kerala, India, reported delays of respectively 68.5 days and 78 days.These delays may be attributed to factors such as patients’ knowledge of the disease, awareness of available services, self-medication practices, and occupational commitments, as mentioned in other studies.The importance of conducting more studies and analysing health-seeking behaviour cannot be understated, as it will contribute to the design and implementation of patient-centred approaches to TB/DR-TB diagnosis and management. We acknowledge the limitation of not collecting data related to TB contacts and individuals with previous TB episodes. This information could be pertinent and may reduce delays among individuals with previous TB experiences, warranting exploration in future studies.The primary limitation of our study was our inability to contact all the patients registered within the specified time frame. Given that our study was conducted during the COVID-19 pandemic, the number of patients registered during the designated study period was limited. Consequently, we extended the study duration and conducted interviews over the phone, being careful to collect the required data. Our study focused on questions related to the health pathway before treatment initiation, potentially introducing recall bias. Moreover, our study did not differentiate between diagnostic delays and delays in treatment initiation, which could be examined in future studies.