CMV infection is a common complication in allogeneic hematopoietic stem cell transplantation (HSCT). We investigated the association of clinically significant CMV (CS‐CMV) infection with clinical outcomes and healthcare resource utilization in allogeneic HSCT patients in Finland.This retrospective study included adult patients who received their first allogeneic HSCT between January 1, 2013, and December 31, 2018, at the Turku University Hospital. Data were collected from the hospital data lake. Clinical and healthcare outcomes were investigated at one year and mortality up to three years.1–Q3, 27.0–45.0). Recipient and donor seropositivity, and lymphoproliferative diseases were associated with higher, and HLA identical sibling donors with lower CS‐CMV infection risk. CS‐CMV infection was not associated with mortality in three years of follow‐up. One hundred thirty‐three (89.8%) and 75 (72.8%) patients with and without CS‐CMV infection, respectively, were readmitted to the hospital. Patients with CS‐CMV infection had more hospital readmissions  and patients with one CS‐CMV infection  or ≥2 infections had longer length of hospital stay .The study included 251 patients. CMV seroprevalence was 69.7%. CS‐CMV infection occurred in 59.0% of the patients, and of those, 14.2% had ≥2 infections. The median time to CS‐CMV infection was 34.5 days (QCMV seroprevalence is relatively high among Finnish allogeneic HSCT patients. CS‐CMV infection was common and associated with a higher readmission rate and longer length of hospital stay.  CMVcytomegalovirusCSclinically significantDdonorGVHDgraft‐versus‐host diseaseHRhazard ratioHSCThematopoietic stem cell transplantationIRRincidence rate ratioORodds ratioPCRpolymerase chain reactionPETpre‐emptive therapy1–Q3Qlower and upper quartilesRrecipient1CMV infection is a common complication in allogeneic hematopoietic stem cell transplantation (HSCT).Allogeneic HSCT patients are commonly monitored for CMV replication by polymerase chain reaction (PCR) in blood or urine samples. If clinically significant CMV (CS‐CMV) infection is observed, pre‐emptive therapy (PET) with antivirals is often initiated to prevent CMV disease. Established anti‐CMV drugs include ganciclovirDonor (D) and recipient (R) CMV serostatus are significant risk factors for CMV infection in allogeneic HSCT,CMV infection, CMV disease, and PET have been reported to associate with higher clinical burden and increased healthcare resource utilization. Retrospective single‐center studies have reported that a greater economic burden is associated with CMV treatment.There are no published data on CMV seroprevalence or CS‐CMV infection among allogeneic HSCT patients in Finland. A study from the Finnish Maternity Cohort serum bank reported a decline in CMV seroprevalence from 84.5% in 1992 to 71.5% in 2012.22.1This single‐center, retrospective, observational cohort study with Finnish allogeneic HSCT patients investigated the association of CS‐CMV infection with clinical outcomes and healthcare resource utilization. The study included adult patients who received their first allogeneic HSCT  between January 1, 2013, and December 31, 2018, at the Hospital District of Southwest Finland. Patients who had participated or were considered to participate in the letermovir phase 3 CMV reactivation prophylaxis studyThe data collected at baseline and/or during follow‐up included: age, gender, date of allogeneic HSCT, R and D CMV serostatus, combined D/R CMV serostatus, donor type , the primary reason for allogeneic HSCT , preconditioning regimen  if non‐normally distributed. The normality of the empirical distributions was tested using the Kolmogorov‐Smirnov test. Discrete variables were presented using observed frequencies and proportions.The continuous variables in the data were described using means and standard deviations if normally distributed and as medians along with lower and upper quartiles  between patients with and without CS‐CMV infection were analyzed using Mann‐Whitney U‐test for numerical variables and Pearson's chi‐squared of Fisher exact test categorical attributes. The association of different patient characteristics and the occurrence of CS‐CMV infection  were analyzed using simple logistic regression.U‐test.Simple and multiple Cox proportional hazards models were used to analyze the overall survival of the patients. CMV infection‐free survival, relapse‐free survival, and GVHD‐free survival were analyzed using a simple and multiple proportional hazards model for the subdistribution of a competing risk because death or non‐relapse‐related death were considered competing risks. The Schoenfield residuals were checked to confirm the proportional hazards assumption, and if the assumption was not met, the Kaplan‐Meier estimator and log‐rank test were used for overall survival and the cumulative incidence function, and Gray's test for events with competing risks. Healthcare resource utilization due to CS‐CMV infection was further analyzed with a simple negative binomial model. The use of anti‐CMV medication between patients with one versus multiple infections as well as acute GVHD grade 0–2 versus 3–4 was analyzed using Pearson's chi‐squared or Fisher's exact test and the differences in total dosage were analyzed with Mann‐Whitney In all analyses where CS‐CMV infection or GVHD were used as independent variables, sensitivity analyses were performed and the model selection was based on the smallest value of the Akaike information criterion. For further details of the sensitivity analyses, see Supporting Information.p‐values and corresponding 95% confidence intervals when applicable. p‐values less than 0.05 were considered statistically significant. Statistical analysis, tables, figures, and listings were all produced with R version 3.6.3  using RStudio Server in Auria Clinical Informatics’ secure operating environment.The results of the Cox proportional hazard models were presented using the average hazard ratios (HRs), and the results of logistic and negative binomial regression were presented as odds ratios (ORs) and incidence rate ratios (IRRs), respectively. The results of the log‐rank and Gray's test were reported using the chi‐squared test statistic together with the degrees of freedom. All results were presented with 2.5This study was approved by the Administration of the Hospital District of Southwest Finland (T94/2020) in the role of the data controller and was conducted in compliance with applicable national legislation. According to the Act of Secondary Use of Health and Social Data, informed consent is not required for studies based on patient records. MSD had oversight of the study. MSD had an initiative in the conception of the study, and MSD participated, together with other investigators, in the design of the study, and interpretation of the results, and MSD was responsible for the publication development. MSD did not participate in the data collection and analysis.33.1Between January 1, 2013, and December 31, 2018, a total of 276 patients were identified. Twenty‐five patients were excluded from this study: 22 patients participated or had been considered for participation in the letermovir CMV reactivation prophylaxis study,Baseline characteristics are presented in Table 3.2One‐hundred forty‐six patients 58.1%) and 148 (59.0%) had CS‐CMV infection by week 24 and one year, respectively, and the median time to the first CS‐CMV infection was 34.5  days     Figure , but rec) Figure . The hap) Figure . Other cp = .463) (Table p < .001) (Table p = .050) (Table p < .013)  Table . A graft3) Table  and multp = .034), presence of acute GVHD , and grade 2–3 chronic GVHD   Table . Age was1) Table .3.3p = .569) or three years  2 1.17, p = .279) or three years  of follow‐up  Figure . Also, Cp Figure .3.4p = .936) or at one year . However, the risk of GVHD was higher in patients with ≥2 CS‐CMV infections compared to those without GVHD by one year  , but the risk of GVHD was higher in patients with ≥2 CS‐CMV infections,  compared to those without CS‐CMV infection. CS‐CMV infection was not associated with relapses at one year  or three years .CS‐CMV infection did not increase the risk of GVHD at 24 weeks  Figure . In the 3.51–Q3) 3.0 (2.0–5.0) vs. 2.0 (1.0–3.5), IRR 1.38, 95% CI 1.10–1.73, p = .005]. Correspondingly, the number of hospital readmissions was higher in patients with ≥2 CMV infections compared to those without CMV infection   patients were readmitted to the hospital. One hundred thirty‐three (89.8%) and 75 (72.8%) patients with and without CS‐CMV infection, respectively, were readmitted during the first year after the transplantation Table . The num1] Table .1–Q3) 27.0 (14.8–53.0) vs. 14.0 (4.0–37.0); IRR 1.48, 95% CI 1.12–1.94, p = .005]. Also, patients with ≥2 CS‐CMV had longer additional length of hospital stay .The additional length of hospital stay was longer in patients with CS‐CMV infection compared to those without CMV infection [median days  patients received PET. One hundred twenty‐four patients received PET for one CMV infection, and 21 patients received PET for ≥2 CMV infections Table .Frequencies and the medians of total doses for all anti‐CMV drugs are detailed in Table p = .004)  Table . There w4) Table .p = .020), and the total dose of foscarnet was higher compared to the patients with grade ≤2 acute GVHD (Table Patients with grade 3–4 acute GVHD received more often foscarnet (51.0% vs. 33.2%, HD Table . There wHD Table .4This retrospective single‐center study investigated clinical and healthcare burdens due to CS‐CMV infection in allogeneic HSCT patients by one year after allogeneic HSCT, and mortality rate up to three years. This is the first study reporting CMV infection rate and CMV seroprevalence in Finnish allogeneic HSCT patients. CMV seroprevalence was 69.7%, and CS‐CMV infection occurred in 59.0% of all patients, and 77.1% of the CMV seropositive patients. Also, 14.2% of the patients with CS‐CMV infection experienced ≥2‐CMV infections during the first year after the transplantation. CS‐CMV infection was associated with greater healthcare resource utilization, indicated by higher readmission rates and longer length of hospital stay.D/R CMV serostatus has a significant impact on the risk of CMV infection and clinical outcomes after allogeneic HSCT.CMV seroprevalence was 69.7% in the study cohort. Observed CMV seroprevalence is in line with the CMV seroprevalence reported from the Finnish biobank cohort of pregnant women, with CMV seroprevalence of 84.5% in 1992 and 71.5% in 2012.CMV seropositivity and CMV infection have been reported to associate with negative clinical outcomes in allogeneic HSCT patients.Previous studies report that D+/R+ serology is associated with a lower incidence of acute GVHD in chronic myeloid leukemia, whereas D/R serology or CMV infection is not associated with acute GVHD in other diseases.In our study, the malignancy relapse rate was 19.5% and 29.9% by one year and three years, respectively, and CS‐CMV infection was not associated with relapse. CMV infection has been postulated to reduce relapses in certain hematological malignancies, possibly by activating the graft and tumor immunity,Healthcare costs due to CMV infection have been compared with costs in patients with acute GVHD.In contrast, a single‐center retrospective study investigating costs in 310 allogeneic HSCT patients did not report an association between CMV infection and changes in healthcare costs.Allogeneic HSCT patients report a negative impact on the quality of life in many dimensions of quality‐of‐life questionnaires, including physical, psychological, social, and role functions, especially during the first year after the transplantation.In conclusion, CMV seroprevalence is relatively high among allogeneic HSCT patients in Finland. Clinically significant CMV infection was common, occurred within three months after the transplantation, and repeated CMV infection was associated with GVHD. CMV infection was associated with a higher hospital readmission rate and longer length of hospital stay.JR received the Principal Investigator fee, and Turku University Hospital District received institutional research funding for this study. RK is an employee of MSD Finland Oy and owns stocks of Merck & Co., Inc., Rahway, NJ, USA.Supporting informationClick here for additional data file.Supporting informationClick here for additional data file.Graphical AbstractClick here for additional data file.


Closed spatial mark–recapture models estimated plausible densities that varied with elevation. Preferred elevations differed between species, with density averaging 0.63 ha−1 for Vespadelus darlingtoni (high elevation), 0.43 ha−1 for V. pumilus (low elevation), 0.19 ha−1 for Chalinolobus morio (high elevation), and 0.08 ha−1 for V. regulus (high elevation). Overall, densities were higher than most previous published estimates for bats. Forest disturbance history (past timber harvesting) had no detectable effect on density. Density also varied substantially across years, and although annual maximum temperature and rainfall were not supported in models, some time periods showed an apparent relationship between density and annual rainfall (+ve) and/or annual maximum temperature (−ve). The most notable change was an increase in the density of V. pumilus after 2013, which tracked an increase in annual temperature at the site, reflecting a warming climate. Bat densities in forests outside of climate refugia are likely to be more sensitive to climate change, but more studies are needed in different habitats and continents and outside climate refugia to place the densities we estimated into a broader context.For many species, estimating density is challenging, but it is important for conservation planning and understanding the functional role of species. Bats play key ecological roles, yet little is known about their free‐ranging density. We used a long‐term banding study of four species caught in an extensively forested climate refuge and spatial capture–recapture models (SCR) to estimate density and its change over time. Between 1999 and 2020, there were 3671 captures of four bat species, which were all edge‐space foragers. Recaptures represented 16% ( A long‐term banding study of four bat species caught in an extensively forested climate refuge was used with spatial capture–recapture models to estimate species density and changes over time. Models estimated plausible densities that varied with elevation and across years. Our results suggest that bat densities in productive forests may be substantially higher than previously appreciated with variation over time inconsistently related to climate patterns. These studies were undertaken in cool temperate climate zones of Europe, but very different densities could be expected in other climate zones or other habitats, potentially driven by productivity and/or anthropogenic disturbance  models are an alternative contemporary approach for estimating density based on recaptures of marked animals from multiple known locations  fell within an experimental section (450–940 m elevation) of Chichester State Forest, 200 km north of Sydney, Australia . The experimental section, which comprises eight small (13–97 ha) catchments, was established in 1974/75 to investigate the effects of logging on water flow and quality  (43%), silvertop stringybark (E. laevopinea) (23%), and pure and mixed rainforest communities (32%), where crabapple (Schizomeria ovata), sassafras (Doryphora sassafras), and corkwood (Quintinia sieberi) were the primary species . Dominant tree species included Sydney blue gum , large forest bat Vespadelus darlingtoni (6 g), southern forest bat Vespadelus regulus (5 g), and eastern forest bat Vespadelus pumilus (4 g). Each belongs to the Vespertilionidae family and forages in edge spaces, usually within forested communities in south‐eastern Australia.The four most commonly captured species were the subject of analyses. The species varied in body mass: chocolate‐wattled bat 2.2Six to nine  permanent trapping clusters were sampled annually in autumn (~4 months after parturition) over 21 years (1999–2020). We standardized trapping effort at each site using a cluster of one to three harp traps set within a 200 m length along a 4WD trail. We attempted to keep the precise location of traps consistent between years, but locations sometimes varied slightly due to track maintenance. In each trap year, we trapped for two consecutive nights at each cluster to minimize trap avoidance, except that occasionally banding trips were repeated when rain affected trapping. The first 2 years of the study were an exception, in that three trapping events were employed in autumn (separated by ~ 2 weeks) for the purpose of maximizing the number of bands in the population for recapture and survival analysis in later years . Band injuries on recaptured bats were noted . We recorded <1% of recaptures with a swelling that required us to shift the band to the other forearm, indicating that band injuries were rare .2.3https://www.longpaddock.qld.gov.au/silo/). Data were lagged by one‐year preceding trapping in March of each year.Annual climate in the study area was collated for comparison with longitudinal trends in bat density. Rainfall data were collected in gauges on‐site while maximum temperature was interpolated to the mid‐point of the study area using SILO data  and σ . In the case of the hazard rate function, an additional home range shape parameter, z, gives the detection function extra flexibility. Once the functional form was selected, the influence of explanatory variables on g0 and σ was explored , conventional SCR also assumes that animal home ranges are distributed randomly in space, and the population is closed and detection events are independent. Depending on the time of year, bats are known to live in colonies which may violate assumptions of independent detection events, as well as home range centers being distributed randomly. However, our surveys were timed (in autumn) to coincide with a season during which bats congregate to a lesser extent than in the spring–summer maternity season, so this assumption is met. A closed population is also assumed, but the mobility of bats and the long‐time series suggests the population was open even though previous analyses confirm that a high proportion of bats are resident at the study site in autumn  and cluster‐level (1999–2020: trap‐level information was collapsed for the period 2018–2020) capture events. However, all confidence intervals overlapped between the two models, because mostly traps within a cluster were separated by small distances (<200 m) relative to a bat's home range. Therefore, only the cluster‐level models are presented here.33.1The study area experiences high rainfall with a long‐term average (since 1958) just above 1500 mm. This varied over the study period but remained at ~1000 mm and 750 mm during drought years of 2002 and 2019, respectively , there were 3671 capture events of s Figure . Recaptus Figure . The maxV. darlingtoni, 9 years for V. regulus, 7 years for V. pumilus, and 8 years for C. morio. If a bat was recaptured multiple times, it was typically captured at the same location regardless of whether it was captured within the same year or between years.Bats were typically caught just once, or if multiple times, typically in a single year only, but some individuals were recaptured over a 4‐ or 5‐year period. Some of these individuals were captured up to eight times and the longest time to recapture was 11 years for 3.3Model selection results for density are provided for the cluster‐level analysis over the full study period (Table 3.4V. pumilus banded across the study. The best model predicted density to vary with year factor and elevation (high/low), g0 with elevation, and other parameters constant . On average, the species was estimated to have a higher detection probability at low elevation (g0 = 0.43 ± 0.06) compared with high elevation (g0 = 0.25 ± 0.04). The second model fell within two AIC, and it provided support for the same covariates, except g0 was constant. Annual maximum temperature was not supported as significantly influencing density across the study period and models with annual rainfall failed to converge.There were 586 unique V. pumilus for the whole time series using the best‐fitting cluster‐level model shows density averaged four times higher at low elevation (0.43 bats ha−1) than at high elevation (0.12 bats ha−1)  Figure . Density) Figure .3.5V. darlingtoni banded across the study. The best model allowed density to vary with year factor and elevation, g0 to vary with elevation, and other parameters to remain constant . On average, for the cluster‐level model, the species was more likely to be detected at higher (>600 m) than lower elevation (<600 m) with an elevation‐specific g0 value estimated for low elevation (0.24 ± 0.04) and high elevation (0.37 ± 0.05). Annual maximum temperature was not supported as influencing density across the study period and models with annual rainfall failed to converge.There were 1048 unique V. darlingtoni for the whole time series using the best‐fitting cluster‐level model shows density averaged more than five times higher at high elevation (0.62 bats ha−1) than at low elevation (0.12 bats ha−1) . On average, for the cluster‐level model, the species was more likely to be detected whether its activity center was at higher elevation (>600 m) than at lower elevation (<600 m) with an elevation‐specific g0 value estimated for low elevation (0.11 ± 0.03) and high elevation (0.78 ± 0.12). A second model within 2.04 AIC   Figure . Density) Figure . Density3.7C. morio banded across the study. The best model predicted density to vary with year factor and elevation, with other parameters constant . On average, for the cluster‐level model, the species was estimated to have a low, but constant detection . Annual maximum temperature was not supported as influencing density across the study period and models with annual rainfall failed to converge.There were 364 unique C. morio for the whole time series using the best‐fitting cluster‐level model shows density averaged almost two times higher at high elevation (0.19 bats ha−1) than low elevation (0.10 bats ha−1)  Figure . Density4Despite deploying a trapping network comprised of only six to nine  permanent site clusters that were sampled annually, SCR modeling yielded plausible density estimates for each species. These results provide one of the first estimates of density for tree‐hollow roosting bats in large contiguous forests, and these were an order of magnitude larger than density estimates for bats in a recent global review , 0.43 ha−1 for V. pumilus (4 g), 0.19 ha−1 for C. morio (8 g), and 0.08 ha−1 for V. regulus (5 g). Density estimates were comparable, but slightly lower than the density of female V. pumilus estimated elsewhere around maternity roosts (0.5–0.7 ha−1) based on roost emergence counts and estimated foraging distance . Positive relationships with cooler, high elevations among the remaining species may reflect their more temperate, southern origins and also a productivity gradient with elevation in warmer months  for g0 (detection) for V. darlingtoni (+ve), V. pumilus (−ve), and V. regulus (+ve), though alternative models with constant g0 also had some support, suggesting this effect may not be strong. Better detection at certain elevations may be related to species‐specific activity levels, which varies with elevation at our study site , low constant detection for C. morio (often higher‐flying), and intermediate values that increased with elevation for V. darlingtoni and V. regulus.Elevation also influenced V. darlingtoni and C. morio), a positive effect for one (V. pumilus), and negative for the other (V. regulus), although overall the effects were minor  and decreases in some hot, dry years (V. regulus) or hot years (C. morio—and the coolest year of the study). Vespadelus pumilus exhibited the most marked response with an increasing trend since 2013 that paralleled an increase in temperature in the study area. This subtropical species, which occurred at higher densities at low elevation, may benefit from a warming climate, whereas density of V. regulus, a cool temperate species, remained low after 2017 when temperatures peaked in our study. While these trends were mostly weak, our wet montane study area is a climate refuge, and so climate extremes over the course of the study were generally buffered ; funding acquisition (lead); methodology (lead); project administration (lead); writing – original draft (lead); writing – review and editing (lead). Traecey Brassil: Data curation (lead); formal analysis (supporting); investigation (supporting); project administration (supporting); writing – original draft (supporting); writing – review and editing (supporting). Roland Proud: Formal analysis ; software ; writing – original draft (supporting). Joanne Potts: Formal analysis ; software ; writing – original draft (supporting).The authors declare no conflict of interest.Funding over the course of the study was provided by the NSW Government.Appendix S1Click here for additional data file.


How clinicians treat patients with terminal dyspnea widely varies, which could hamper quality care. We visualized comprehensive pharmacological treatment delivered by palliative care physicians.To examine adherence to a comprehensive pharmacological treatment algorithm for patients with terminal dyspnea, and to explore its outcomes during 48 h.A multicenter cohort study at five sites (February 2020 to June 2021).We prospectively enrolled consecutive patients with advanced cancer, Eastern Cooperative Oncology Group performance status 3–4, and moderate/severe dyspnea. Participating palliative care physicians initiated algorithm‐based treatment. The primary outcome was the proportion of adherence to the treatment algorithm over 24 h . We evaluated the adherence, goal achievement, and dyspnea level with a numerical rating scale (NRS), as well as adverse events over 48 h.n = 72; p < 0.001), and 7.2 (0.3) at the baseline to 4.6 (0.4) at 48 h . Most adverse events were mild to moderate.All 108 patients received algorithm‐based pharmacological treatment. Among 96 and 87 patients who were alive at 24 and 48 h, respectively, 96  and 82  continued to receive the algorithm treatment, respectively, and 66  and 64  achieved the treatment goals, respectively. Using a complete case analysis with paired t‐tests, mean dyspnea NRS scores significantly reduced from 7.3  at the baseline to 4.9 (0.3) at 24 h (The comprehensive pharmacological treatment algorithm was feasible, and the study data supports its preliminary efficacy and safety. The use of this algorithm may help clinicians improve care for patients with terminal dyspnea. We visualized a comprehensive pharmacological treatment algorithm that includes various treatment options for cancer patients with terminal dyspnea. This multicenter cohort study showed that the treatment algorithm was highly feasible, and correlated with a significant improvement in dyspnea with rare adverse events. Secondary aims were to examine its efficacy and safety over 48 h. We hypothesized that the treatment algorithm would be feasible, effective, and safe for patients with terminal dyspnea.22.1We conducted a multicenter prospective cohort study involving advanced cancer patients seen by palliative care physicians in inpatient consultation teams and inpatient hospices/palliative care units at five sites in Japan. All assessment and interventions were conducted within routine practice. The study was conducted based on the ethical standards of the Helsinki Declaration and the ethical guidelines for medical and health research involving human subjects presented by the Ministry of Health, Labour, and Welfare in Japan. We obtained approval by the Institutional Review Boards (IRBs) of the main institution  and all the other study sites. The requirement for written informed consent in this observational study was waived by the IRBs based on the ethical guidelines.2.2We enrolled patients consecutively from February 2020 to June 2021. Inclusion criteria included: age ≥ 18 years old; advanced cancer; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 3; moderate‐overwhelming dyspnea ; maintained communication capacity ; and initiation of parenteral opioids by continuous administration the first time for dyspnea. Patients were excluded if they received treatment for dyspnea caused by etiologies unrelated to cancer, or if they were scheduled to undergo an intervention that would markedly influence dyspnea intensity . The patients were followed for 1 month or until death, whichever came first.2.3We chose morphine, oxycodone, and hydromorphone as frequently used opioids for dyspnea in Japan.2.4We recorded measurement variables at the baseline, 24 h, and 48 h by responsible physicians.2.4.1Baseline data of the patients included patients' basic demographics, etiologies of dyspnea, comorbidities, and various signs and symptoms. We also collected laboratory data to evaluate baseline renal and hepatic functions. Other variables including the prior use of opioids and use of the treatment algorithm were obtained.2.4.2We calculated the percentage of patients who were provided with the algorithm‐based treatment, and percentage of those who continued to receive it over 48 h . We also documented whether the algorithm was discontinued because of dyspnea relief or adverse events. The treatment algorithm was considered feasible a priori if the adherence rate was greater than 70%. We chose an adherence rate of 70% or greater as our feasibility threshold, as our previous pilot study that explored the feasibility of a visual treatment algorithm of parenteral opioids applied the same cut‐off, and showed that the threshold of 70% could be achieved in cancer patients with terminal dyspnea.2.4.3The dyspnea intensity was evaluated with a numerical rating scale (NRS) by patients, and NRS and IPOS scores rated by physicians at the baseline (worst over 4 h) as well as at 24 and 48 h (worst over 2 h at each time‐point).2.4.4Achievement of treatment goals was operationally defined as “the case where dyspnea is alleviated or is acceptable to the patient, and the patient does not wish for further adjustment of treatment for dyspnea” based on clinical experiences. If the patient had difficulty communicating, and his or her family was present, the responsible physician asked the family if the patient looked comfortable and would not wish for further adjustment based on observation. If the patient had difficulty communicating and the family was not present, the responsible physician determined whether the treatment goals shared by the patient/family at the initiation of treatment had been achieved.2.4.5We assessed the modified Richmond Agitation‐Sedation Scale (RASS) to examine the consciousness level, and CCS item 4 to assess communication capacity. The modified RASS is a reliable and valid tool that measures the severity of agitation and sedation on a 10‐point scale .2.4.6The severity of adverse events including nausea, delirium, and apnea was assessed with the Common Terminology Criteria for Adverse Events version 4.0 over 48 h.2.5The primary outcome was the rate of adherence to the treatment algorithm over 24 h. The secondary outcomes included adherence at 48 h as well as efficacy, goal achievement, modified RASS, CCS item 4, and adverse events at 24 and 48 h.We used descriptive statistics to summarize baseline data and outcomes over time. We then performed paired t‐tests to demonstrate changes over time in patients who remained alive at 24 and 48 h as compared with the baseline. In some patients, NRS scores become unevaluable essentially due to the development of cognitive impairment. Thus, we first analyzed existing data without conducting imputation . Next, we conducted sensitivity analysis with the missing data replaced by the last observation data of the same patients , as complete case analysis could lead to selection bias. Dyspnea relief at 24 and 48 h was defined as dyspnea IPOS score of 0 or 1.To assess a balanced outcome, we grouped patients based on the dyspnea intensity and communication capacity as followsWe used Kaplan–Meier methods to calculate the median survival time from the day when parenteral opioids were started for dyspnea. Those who remained alive at 1 month were treated as censored.p‐value<0.05 (two‐sided) was considered significant. The Statistical Package for the Social Sciences, version 25.0  was used for statistical analyses.To achieve an adherence rate ≥ 70%, 81 patients would be required to calculate accuracy within a 20% width at a 95%CI. Considering potential missing data and attrition in patients close to death, we aimed to enroll 100 patients. A 3A total of 108 patients were enrolled (Table 3.1All 108 patients (100%) received the algorithm‐based treatment Table . Among 9As parenteral opioids for dyspnea, morphine was used in 66 (61%) patients, followed by oxycodone and hydromorphone in 34 32%) and 8 (7.4%) patients, respectively , and 7.2 (0.3) at the baseline to 4.6 (0.4) at 48 h . The results were similar when the unevaluable data of patient‐rated NRS scores at 24 and 48 h were replaced with the last observation data. Similar trends were noted when dyspnea intensity was evaluated by physician‐rated NRS and IPOS (Table Table nd 7.2 0. at the b3.2.2p = 0.006 at 24 h and p < 0.001 at 48 h) and CCS item 4 scores significantly increased over time (p = 0.002 at 24 h and p < 0.001 at 48 h)  Table .Table 3.2.3Among 96 and 87 participants who were alive at 24 and 48 h, respectively, 66  and 64  achieved goals of dyspnea relief, respectively  in 49 (51%) and 56 (64%) patients, respectively , 36 (42%), 19 (22%), 5 (5.9%), and 11 (13%) patients, respectively, at 24 h. At 48 h, complete relief, partial relief, persistent dyspnea, being unable to communicate, and death were noted in 15 (18%), 32 (38%), 9 (11%), 10 (12%), and 19 (22%) patients, respectively.3.3Most adverse events were mild to moderate (CTCAE = 1–2), including nausea and delirium Table .44.1In this multicenter, prospective, cohort study, we found that a comprehensive pharmacological treatment algorithm is highly feasible, effective, and safe for terminal dyspnea in cancer patients.4.2The main significance of this study is the implementation of a visual flow chart of a comprehensive pharmacological treatment algorithm for terminal cancer dyspnea. Although international clinical guidelines suggest opioids and benzodiazepines for patients with terminal dyspnea, they do not show how to use them in clinical practice, leading to marked variability in practice even among palliative care specialists.Notably, the multiple outcomes suggested the preliminary efficacy of the treatment algorithm. Patient‐reported outcomes are the gold standard, but not always available, as patients with terminal cancer and severe dyspnea often lose consciousness as death approaches and thereby cannot communicate.In contrast, approximately a third of participants did not experience dyspnea relief within 48 h. Similar findings were repeatedly reported by prior studies on terminal dyspnea.4.3The study's strengths include patient enrollment at multiple sites, consecutive sampling, utilization of reliable and valid outcomes, and a novel effort to comprehensively visualize the pharmacological management by palliative care specialists, many of whom are involved in the development of national and international guidelines for cancer dyspnea.However, several limitations should be noted. First, due to the observational nature and absence of a comparison arm, whether treatment with the algorithm is more effective than treatment without it could not be confirmed. Second, as the treatment was provided by palliative care specialists, the study findings might not be directly applied to general oncology settings. Thus, randomized controlled trials and well‐designed observational studies with comparison arms are required to confirm the effects of the treatment algorithm. Third, while our operational definition of goal achievement reflects clinical practice, it has not been validated. The use of palliative care physician determination that treatment goals were achieved in lieu of patient/family determination when patient could not communicate could be biased. Future research is needed to establish scales to measure the achievement of personalized symptom goals for patients with terminal dyspnea and impaired cognition. Fourth, several efficacy outcomes such as physician‐rated dyspnea NRS, IPOS, and physician‐rated improvement were assessed by treating physicians. While this reflects real‐world practice, there could potentially be a bias in reporting. Lastly, as the study was conducted only in Japan, the treatment algorithm may require future modification when used in other countries with different practice patterns.5In summary, the comprehensive pharmacological treatment algorithm is feasible, and may be effective and safe for cancer patients with terminal dyspnea. The algorithm could be easily instituted in other settings such as oncology and primary care globally. Its use may not only help clinicians improve care for such patients, but also help interdisciplinary professionals discuss goals of care with patients and families. Future studies are needed to demonstrate the effectiveness of the treatment algorithm in various primary palliative care settings.Takashi Yamaguchi: Conceptualization ; data curation ; investigation ; methodology ; project administration ; resources ; writing – review and editing . Kozue Suzuki: Conceptualization ; data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Yoshinobu Matsuda: Conceptualization ; data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Ryo Matsunuma: Conceptualization ; data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Hiroaki Watanabe: Conceptualization ; data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Tomoo Ikari: Conceptualization ; data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Yoshihisa Matsumoto: Conceptualization ; investigation ; methodology ; project administration ; writing – original draft ; writing – review and editing . Kengo Imai: Conceptualization ; data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Naosuke Yokomichi: Conceptualization ; data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Satoru Miwa: Conceptualization ; data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Toshihiro Yamauchi: Data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Soichiro Okamoto: Data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Satoshi Inoue: Data curation ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Akira Inoue: Conceptualization ; investigation ; methodology ; project administration ; resources ; writing – original draft ; writing – review and editing . Tatsuya Morita: Conceptualization ; data curation ; investigation ; methodology ; project administration ; resources ; supervision ; writing – original draft ; writing – review and editing . Eriko Satomi: Conceptualization ; funding acquisition (supporting); investigation ; methodology ; project administration ; resources ; supervision ; writing – original draft ; writing – review and editing .This work was supported in part by Japan Hospice Palliative Care Foundation, Health, Labour, and Welfare Sciences Research Grant , and JSPS KAKENHI Grant Number 20 K20618.No conflict of interest to declare.


Acinetobacter baumannii up to 32‐fold, without observing toxic effects.Over recent decades, the pipeline of antibiotics acting against Gram‐negative bacteria is running dry, as most discovered candidate antibiotics suffer from insufficient potency, pharmacokinetic properties, or toxicity. The darobactins, a promising new small peptide class of drug candidates, bind to novel antibiotic target BamA, an outer membrane protein. Previously, we reported that biosynthetic engineering in a heterologous host generated novel darobactins with enhanced antibacterial activity. Here we utilize an optimized purification method and present cryo‐EM structures of the Bam complex with darobactin 9 (D9), which served as a blueprint for the biotechnological generation of twenty new darobactins including halogenated analogs. The newly engineered darobactin 22 binds more tightly to BamA and outperforms the favorable activity profile of D9 against clinically relevant pathogens such as carbapenem‐resistant  Structural evaluation of the Bam complex with darobactin 9 using cryo‐EM combined with bioactivity evaluation led to biosynthetic engineering of novel derivatives with enhanced activity against Gram‐negative pathogens, including clinically relevant isolates. The currently most promising derivative darobactin 22 verified the structure and activity guided approach, exhibiting up to 128‐fold increased activity compared to natural darobactin A. Escherichia coli (E. coli), Acinetobacter baumannii (A. baumannii), Klebsiella pneumoniae (K. pneumoniae), and Pseudomonas aeruginosa (P. aeruginosa) continuously rises.Acinetobacter strains (Table Acinetobacter baumannii (CRAB), where most of the commonly used antibiotics are not active (Table S4). Here, the activities of DA, D9 and D22 were compared to colistin (COL), the antibiotic of last resort to treat infections caused by CRAB, which can cause nephrotoxicity.As D22 distinguishes itself by its superior activity, especially against tested −1)  Table , displayE. coli MG1655  within 2 to 4 h. The observed initial bacteriostatic effect can possibly be explained by Ritzmann et al., which demonstrated that binding of darobactin on the lateral gate leads to an increased stability by “freezing” BamA and consequently no immediate bactericidal effect.E. coli MG1655, and the extent of bactericidal activity was concentration‐dependent. Nevertheless, re‐growth of bacteria was observed at 2x and 4x MIC conditions after 24 h, while this was not the case at 8x MIC . Imai et al. did not report re‐growth of E. coli after DA treatment, however, the timeframe in their reported experiment was limited to 8h with 16x MIC, making direct comparison challenging.−1 in E. coli, which is fully in line with our findings for DA and D22 having MBCs of 16 and 8 μg mL−1, respectively.8 CFU mL−1) we were able to show that surviving bacteria are likely persistersA. baumannii NCTC13301, D22 shows its clear superiority over DA .In addition, time‐kill kinetics of DA and D22 at 2x, 4x and 8x MIC in A.baumannii easily acquires resistance, making CRAB a WHO priority one pathogen for antibiotic development,[−1 , which emphasizes the potential for application and encourages further development towards proof of concept in humans.Considering that elopment,8, 26 l‐tryptophan exhibiting similar or higher activity than DA .Preceding darobactin SAR studies focused on native darobactins16, 21According to our findings, structural changes at position 4 appears to have only a minor influence, while positions 6 and 7, necessary for interactions with β‐hairpins of BamA, seem to have a major influence on activity and could be used as a potential starting point for improvement of pharmaceutical properties through structural changes. The most promising compound developed to date, based on our SAR study is the biosynthetically engineered new darobactin D22, which surpasses the antibacterial activity of all identified native darobactins. This is remarkable, as natural products are produced in co‐evolution over millions of years, resulting in structural diversity and target specificity for fungi, eukaryotes and bacteria.A. baumannii strains, of which a co‐structure with darobactins has not yet been solved. However, our activity and toxicity data of D22 are encouraging to advance into further preclinical studies. While currently established protocols for cultivation in E. coli are favorable for fast and robust generation of novel, even halogenated, darobactins in quantities suitable for research and development purposes,[E. coli. Changing the heterologous producer to a Gram‐positive strain such as Bacillus subtilis, which has been successfully applied in industrial fermentations, might enable higher darobactin titers. Alternatively, very recently published total syntheses reported for DA may be applicable but currently suffer from yield issues as well.[Future studies should also include a comparison to the structurally variable BAM complex of purposes,16, 19To summarize, our SAR approach presented structural knowledge about the MoB of the darobactins and resulted in novel derivatives with up to 32‐fold increased activity against CRAB, compared to the most potent known derivative D9.The authors declare no conflict of interest.1As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.Supporting InformationClick here for additional data file.


Commercially produced complementary foods (CPCF), including ready‐to‐eat CPCF purées and meals, are gaining popularity among caregivers of older infants and young children (IYC) as a convenient alternative to home‐prepared foods in low and middle‐income countries. However, there is growing concern regarding the suitability of these products for older IYC, as they can contain high levels of sugar and/or sodium. Given the rapidly evolving market in Southeast Asia, it is crucial to monitor the appropriate composition and promotion of CPCF in the region. This study examined the nutrient composition and labelling practices of CPCF purées and meals sold in 2021 in the capital cities of seven Southeast Asian countries: Phnom Penh (Cambodia), Jakarta (Indonesia), Manila (Philippines), Bangkok (Thailand), Vientiane (Lao PDR), Hanoi (Viet Nam), Kuala Lumpur . The study adapted a nutrient profiling model from the WHO Regional Office for Europe to determine the proportion of products suitable for promotion for older IYC. The proportion of CPCF purées and meals that would require a high sugar front‐of‐pack warning based on the percentage energy from total sugar was also determined. Of the 459 CPCF purées/meals assessed, only 37.7% of the products met all nutrient composition requirements and none met all labelling requirements. In addition, most CPCF purées and meals were identified as having high total sugar content. To ensure that older IYC consume appropriate CPCF products, Southeast Asian countries need to implement and enforce regulations concerning the nutrient composition and labelling practices of CPCF purées and meals. This study examined the nutrient composition and labelling practices of commercially produced complementary food (CPCF) purées and meals sold in 2021 in the capital cities of seven Southeast Asian countries. Of the 459 CPCF purées/meals assessed, only one‐third of the products met all nutrient composition requirements and none met all labelling requirements, and most CPCF purées and meals were identified as having high total sugar content. Only one‐third of CPCF purées/meals were identified as nutritionally suitable for promotion for older IYC, with performance varying by sub‐category, and over three‐quarters of products contained high levels of total sugar.None of the CPCF purées/meals presented fully appropriate labelling practices, with the use of inappropriate claims the most prevalent issue. Further, one‐third of products recommended an age of introduction of less than 6 months.To ensure that CPCF purées/meals sold in Southeast Asia have appropriate nutrient composition and labelling practices, it is essential that national standards are in accordance with global guidance and enforced. The WHOAt present, in Southeast Asia, there is a lack of national and regional guidance on what constitutes appropriate nutrient composition and package labelling for CPCF purées/meals, and limited evidence is available on the current landscape of CPCF purées/meals sold in the region. Using information provided on the product labels, this study aimed to provide a comprehensive assessment of the nutrient composition and labelling practices of CPCF purées/meals sold in seven Southeast Asia capital cities. The objectives were to assess CPCF purées/meals to determine: (1) the proportion with suitable nutrient composition and labelling practices and (2) the proportion that would require a ‘high sugar’ warning due to excessive total sugar content.22.1A cross‐sectional assessment was conducted among CPCF purées/meals purchased between August and December 2021 in the capital cities of Cambodia, Indonesia, Lao People's Democratic Republic (PDR), Malaysia, Philippines, Thailand and Viet Nam. Specifically, purchases were made in Phnom Penh in August, Bangkok in August–September, Hanoi in October and Jakarta, Vientiane and Kuala Lumpur in November. Capital cities were selected due to their expected extensive availability of CPCF, being major urban centres, and because they are where UNICEF national offices are present and national researchers could therefore be engaged. In the Southeast Asian region, Singapore was excluded due to the absence of a UNICEF presence in the country and Myanmar because of a national emergency. Purchased products were benchmarked against nutrient composition and labelling requirements of an adapted version of the WHO Europe NPM for CPCF (adapted NPM for CPCF) to assess their suitability for promotion for children 6–36 months of age. Adaptions were made to the 2019 WHO Europe NPM  found in Kuala Lumpur, around half (n = 21) of the chain stores per store category and nine independent stores were selected, prioritizing those with the broadest CPCF variety. Store selection for each country was adapted in response to the COVID‐19 pandemic. For safety reasons, only online platforms of physical retailers were visited in Bangkok (n = 31), Jakarta (n = 25), Kuala Lumpur (n = 30), and Hanoi (n = 21). In Phnom Penh, both online platforms (n = 6) and physical outlets (n = 22) were visited. In Vientiane, due to low COVID‐19 incidence and limited online shopping availability, only physical outlets (n = 22) were surveyed.In Cambodia, Lao PDR, Indonesia, Malaysia, Thailand, and Viet Nam, stores that sold CPCF were identified through a web‐based search and consultation with local experts, and a list of chain and independent retail outlets  was developed. For each chain outlet, the largest physical location was selected, together with all independent retail stores. A web search was conducted to determine if major outlets offered online platforms or physical‐only outlets, and online retailers without physical stores were excluded from the study. Given the significant number of retail outlets (https://ona.io/home/products/ona-data/features/). The ONA Data App was used as a centralized platform to ensure uniform and efficient data collection.National researchers involved in product purchasing and data extraction underwent a standardized training, remotely administered by a dedicated technical team. The training included the identification of CPCF, the categorization of CPCF, the methodology to search for CPCF in physical and online stores and, finally, step‐wise instructions on how to collect data concerning CPCF in a mobile application called ONA Data app  were recommended for introduction at an age of less than 3 years; (2) were labelled with the words ‘baby’, ‘infant’, ‘toddler’, ‘young child’ or a synonym; (3) had a label with an image of a child who appeared to be younger than 3 years of age or who was feeding with a bottle; or (4) were in any other way presented as being suitable for children under 3 years of age WHO, . Images The list of CPCF products available in the Philippines was sourced from the Access to Nutrition Initiative (ATNI) CPCF analysis study conducted in 2020  Dry, powdered and instant cereal/starchy food, (2) Soft–wet spoonable, ready‐to‐eat foods, (3) meals with chunky pieces, (4) Dry finger foods and snacks, (5) Juices and other drinks and (6) other  no added sugar/sweeteners , and nonsugar sweeteners), (2) percentage of fruit content, (3) energy density, (4) fat content, (5) protein content and (6) sodium content. The presence of added sugars/sweeteners and the percentage of fruit content were determined from the ingredient lists, while the proportions of energy from fat and protein were calculated using the Atwater factor system. If salt content was listed instead of sodium, the sodium content was determined by dividing the salt content by 2.5. Products were required to meet all six requirements to pass the nutrient composition assessment. Any product without nutrient content information relative to one of the six requirements was noted as having failed that specific requirement. Although not part of the pass/fail assessment, the adapted NPM for CPCF also requires products to provide a front‐of‐pack high sugar warning if the percentage energy from total sugar exceeds the specific threshold for each subcategory. These thresholds are set at ≥40% for dairy‐based foods, ≥30% for fruit purées and vegetable purées, ≥20% for puréed vegetables and cereals, and ≥15% for puréed meals and meals with chunky pieces. Products were assessed based on this additional criterion, and the results reported separately.2.4.2The adapted NPM for CPCF includes 17 labelling requirements for the CPCF purées/meals category. These requirements cover: the protection and promotion of breastfeeding, claims, product name and ingredient list clarity, messages on products with a spout, and age restrictions on puréed foods. All applicable labelling requirements were required to pass this assessment. Products lacking information for any applicable requirements failed that labelling requirement. Claims were classified into five categories: nonpermitted compositional claims, nutrient content claims, nutrient function claims, disease risk reduction claims, other claims.2.5The software program Stata (version 14.2) was utilized to perform the analysis. Descriptive statistics were calculated and presented using proportions and frequencies.33.1Among all CPCF products, the proportion sold that were purées/meals varied across the seven countries. The highest percentage was in the Philippines (57.1%), followed by Cambodia (40.5%), Viet Nam 32.6%), Thailand (30.6%), Lao PDR (26.3%), Malaysia (14.4%) and Indonesia (12.1%). With the exception of Lao PDR, where the most common subcategory was chunky meals with meat/fish/cheese, across all countries, fruit purées were the predominant CPCF. Fruit purées accounted for 60.9% of CPCF purées/meals in Cambodia, 48.5% in Indonesia, 67.9% in Malaysia, 56.7% in the Philippines, 39.7% in Thailand, and 55.0% in Viet Nam. Table .6%, Thai3.2n = 173) met all relevant nutrient composition requirements (Table n = 40) failed to meet the no added sugars/sweeteners requirement. In addition, despite being typically considered savoury foods, 20.0% (n = 6) of puréed meals without meat/fish and 21.6% (n = 11) of puréed meals with meat/fish contained at least one added sugar/sweetener. Although most CPCF purées/meals  did not exceed the maximum threshold for added fruit, over one‐third of vegetable purées with cereals and puréed meals with cheese failed to meet this requirement. Additionally, over a third  of all CPCF purées/meals failed to meet the energy density requirement, with only 24.0% (n = 6) of vegetable‐only purées and around half of vegetable purées with cereals , puréed meals with meat/fish , and puréed meals without meat/fish  providing minimum energy density. The performance of CPCF purées/meals against the sodium threshold also varied by subcategory. Excessive levels of sodium were found in two‐thirds of chunky meals with meat/fish/cheese , which had a median sodium content of 46 (IQR 23–66) mg per 100 g of product (Table n = 11), puréed meals with meat/fish  and puréed meals without meat/fish  exceeded the sodium threshold. The vast majority  of CPCF purées/meals met the total fat requirement. Most products performed poorly against the protein requirement, which only applied to puréed and chunky meals, with less than half  of these products meeting the requirement.Of the 459 CPCF purées/meals assessed, approximately one‐third  were identified as having high total sugar. This included almost all fruit purées (98.7%), 84.4% of dairy‐based desserts, and over two‐thirds (69.6%) of vegetable only purées. The median total sugar content of fruit purées and dairy‐based desserts was 10.6 (IQR: 8.8–12.1) g and 8.8 (IQR: 6.4–10.0) g per 100 g of product, respectively  did not present a message on the importance of continued breastfeeding to 2 years or beyond. Furthermore, around one‐third of the products recommended an age of introduction of less than 6 months  or were marketed as suitable for children under 6 months . The fruit purées and vegetable‐only purées were the subcategories that performed most poorly against these last two requirements. The use of claims on CPCF purées/meals was widely prevalent, with only seven products (1.5%) not including any claims on their labels. Nonpermitted compositional claims  were the most commonly displayed type of claim across all subcategories, occurring on almost all products . Furthermore, ‘other claims’ were also particularly prevalent and included ‘easy to swallow texture’, ‘fresh and delicious as mom cooks’, ‘easy to carry anywhere’. Conversely, no products included disease risk reduction claims and only 3.9% (n = 18) included nutrition function claims.Of the 459 CPCF purées/meals, none passed all labelling requirements (Table n = 112) of CPCF purées/meals met all four labelling requirements relative to product name and ingredient list clarity. Approximately two‐thirds of the products had a name that reflected their ingredients in descending order as per the ingredient list . Only 26.9% (n = 70) of the products included the percentage of added water in their ingredient lists, with fruit purées performing most poorly against this requirement . In addition, nearly one‐third  of the products that contained fruit did not state the percentage of fruit in the ingredients list. Despite most relevant products including protein by percentage weight in their ingredient lists, 43.3% (n = 13) of puréed meals without meat/fish failed to meet this requirement. Among products with a spout, most  presented a warning that the cap is a choking hazard. However, only 17.6% (n = 44) of the products with a spout included the message ‘not to suck from the container’. Finally, almost all puréed products  did not include a maximum recommended age of use of 12 months on their labels.Less than a quarter  in the adapted NPM for CPCF guarantee that any named protein sources are not ‘bulked’ or replaced by cheaper alternatives and that meal products provide a minimum amount of protein. Our finding that more than half of CPCF purées/meals listing a protein source on the front of pack name failed to meet the protein requirement mirrored findings from the United Kingdom  across seven countries in Southeast Asia through primary data collection, product identification was limited to capital cities of each country. Therefore, the sample of CPCF purées/meals obtained may not be exhaustive of all products available in the market in these countries. Moreover, due to COVID‐19 pandemic, in Indonesia, Malaysia, Thailand and Viet Nam, the search for CPCF was restricted to online platforms. This meant that store categories without online platforms, such as pharmacies, independent supermarkets and baby stores, were not sampled. However, as most major CPCF retailers in these countries operated online, this approach is believed to have had a limited influence on the results. Finally, the sample of CPCF assessed was collected in 2021 and may not fully capture the current market landscape, as products may have been altered, discontinued, or replaced, and new CPCF may have been introduced.The study has some limitations. Even though data were obtained on a large number of commercial CPCF purées/meals (Jessica Blankenship and Alissa M. Pries designed the study. Anzélle Mulder and Alissa M. Pries conducted the data management. Alissa M. Pries analysed the data. Eleonora Bassetti wrote the paper, and all authors provided substantial review.The authors declare no conflict of interest.


The systematic molecular associations between the peripheral blood cells and brain in Alzheimer's disease (AD) remains unclear, which hinders our understanding of AD pathological mechanisms and the exploration of new diagnostic biomarkers.Here, we performed an integrated analysis of the brain and peripheral blood cells transcriptomics to establish peripheral biomarkers of AD. By employing multiple statistical analyses plus machine learning, we identified and validated multiple regulated central and peripheral network in patients with AD.By bioinformatics analysis, a total of 243 genes were differentially expressed in the central and peripheral systems, mainly enriched in three modules: immune response, glucose metabolism and lysosome. In addition, lysosome related gene ATP6V1E1 and immune response related genes  were significantly correlated with Aβ or Tau pathology. Finally, receiver operating characteristic (ROC) analysis revealed that ATP6V1E1 showed high‐diagnostic potential for AD.Taken together, our data identified the main pathological pathways in AD progression, particularly the systemic dysregulation of the immune response, and provided peripheral biomarkers for AD diagnosis. Here, we performed an integrated analysis of brain and peripheral blood cells transcriptomics to establish peripheral biomarkers of AD. By employing multiple statistical analyses plus machine learning, we identified and validated multiple regulated central and peripheral network in AD patients, which provided rich resources for understanding the pathogenesis of AD and large‐scale biomarker validation. Immune response, glucose metabolism, and lysosomes may be closely related to the progression of AD. Lysosome‐associated genes ATP6V1E1 and immune response‐related genes  were significantly correlated with Aβ or Tau pathology, which may be candidate targets for AD treatment. Receiver operating characteristic (ROC) analysis revealed that ATP6V1E1 showed high‐diagnostic potential for AD.22.1http://www.alzdata.org/),All the datasets used for the exploration of brain and peripheral specific expression profiles in mild cognitive impairment (MCI) and patients with AD are from the National Biotechnology Information Center (NCBI) Gene Expression Comprehensive Database (GEO).2.2p < 0.05, |log2 Fold change (FC)| > 0.1375 (EC brain region), |log Fold change (FC)| > 0.0415  were defined as differentially expressed. To show the apparently altered pathophysiological processes in AD, WEB‐based GEne SeT AnaLysis Toolkit  were performed for biological process (BP), Kyoto Encyclopedia of genes and genomes (KEGG), and Wiki pathway enrichment analyses with differentially expressed genes (DEGs). Cytoscape 3.8.2 and STRING  plug‐in were used for visual analysis of protein–protein interaction (PPI) network, and Molecular Complex Detection (MCODE) analysis was performed to seek the core DEGs set.Genes with 2.3www.mouseac.org).40 and phosphorylated Tau semi‐quantitative analysis, of which 165 brain tissue samples with Aβ pathological grading from four AD transgenic mice with human APP, PSEN1 mutant , and 42 brain tissue samples with Tau pathological grading from TAU transgenic mice (MAPTP301L mutant).To study the correlation between module‐related genes and Aβ or Tau pathology, we examined the potential genes mRNA expression and the corresponding Aβ and Tau pathological grading scores in the 2AD mouse models brain tissues  were used to evaluate the efficiency of candidate biomarkers to discriminate between AD and normal subjects. All the data have been tested for normality with the D'Agostino & Pearson test. Non normally distributed data were analyzed by the non‐parametric equivalent. The Student's 33.1The research flowchart is shown in Figure 3.2A total of 1547 DEGs were found in EC brain regions and 4053 DEGs were found in peripheral blood cells, of which 243 DEGs were coaltered Figure . Biologi3.3To further identify key modules and related molecules, we conducted Molecular Complex Detection (MCODE) analysis based on PPI networks. Modules analysis showed that the coaltered genes were mainly related to immune response, glucose metabolism, and lysosomes Figure . Interes3.4r = −0.189, p < 0.05; Figure r = 0.170–0.415, p < 0.05; Figure To determine the association between MCODE‐related genes and AD progression, we analyzed the expression of MCODE‐related genes in AD mice and correlated them with Aβ and Tau pathology Figure . V‐type 3.5To investigate whether the Aβ/Tau correlated genes have diagnostic potential, we analyzed their expression levels in the brain and peripheral blood cells Figure . With thp < 0.001, Specificity = 0.744, Sensitivity = 0.718; GSE63060: AUC = 0.759, p < 0.001, Specificity = 0.481, Sensitivity = 0.916; GSE63061: AUC = 0.677, p < 0.001, Specificity = 0.540, Sensitivity = 0.739; Figure To analyze the performance of candidate biomarkers in brain and the peripheral blood cells to distinguish patients with AD or MCI from controls, we performed a ROC analysis. ROC analysis found that ATP6V1E1 showed good discrimination in both brain and peripheral blood cells  is the most common neurodegenerative disease, and with the acceleration of population aging, the prevalence of AD has increased dramatically. Therefore, the convenient and non‐invasive peripheral biomarkers for AD early diagnosis is an urgent need. In this study, we focused on the transcriptome data of the EC and peripheral blood mononuclear cells (PBMC), as the EC brain region is the earliest lesion area of AD,The cross‐talk between glial cells in the central system and peripheral immune cells invading the brain is closely related to the progression of AD,In the early stage of AD, glucose utilization in the cortex gradually declines, and the degree is closely related to the AD process,Lysosomes are widespread within eukaryotic cells, which mediate the degradation of metabolic waste, toxic proteins, and damaged organelles enclosed by autophagosomes and endosomes,5In sum, we have integrated the molecular connections between brain and blood cells through a systems biology approach, providing a valuable data resource for the early diagnosis and treatment of AD. Bioinformatics analysis suggested that we should focus on immune response, glucose metabolism, as well as lysosome dysfunctions in future studies of AD. The lysosomal ion channel protein ATP6V1E1 may be an ideal candidate biomarker for AD diagnosis. Overall, the exploration of integrating central and peripheral transcriptomics reflects the application of omics‐driven precision medicine in AD.Experimental design: Haitao Yu, Dongdong Jia and Gao‐shang Chai. Experimental methods: Haitao Yu, Dongdong Jia, Jia‐jun Wu and Gao‐shang Chai. Data analysis: Haitao Yu, Fangzhou Wang, Jia‐jun Wu, Juan Gong, Yumin Mao and Shuguang Bi. Manuscript‐writing: Haitao Yu, Dongdong Jia and Gao‐shang Chai.The authors declare that they have no conflict of interest to disclose.Appendix S1.Click here for additional data file.


Since the coronavirus outbreak became a global health emergency in 2020, various immune‐based effects, such as inflammatory arthritis (IA), have been recorded. This study aimed to determine the role of COVID‐19 severity on post‐COVID arthritis.We systematically reviewed 95 patients who developed arthritis after severe and non‐severe COVID‐19 infection by searching the databases, including PubMed, SCOPUS, and EMBASE. We used the term “COVID‐associated arthritis” because there was no definite diagnostic method for classifying arthritides after COVID‐19 infection, and the diagnosed arthritis types were based on the authors' viewpoints.After evaluating the data between the two severe and non‐severe COVID‐19‐infected groups of patients, the results showed that the COVID‐19 severity may affect the pattern of joint involvement in IA. In both groups, combination therapy, including oral nonsteroidal anti‐inflammatory drugs with different types of corticosteroids, was the most common treatment. In addition, the mean age and comorbidities rate was higher in the severe COVID‐19 group. Even though the patients in the severe COVID‐19 group developed more serious COVID‐19 symptoms, they experienced milder arthritis with better outcomes and more delayed onsets that required less aggressive therapy.We conclude that there may be an inverse relationship between COVID‐19 severity and arthritis severity, possibly due to weaker immunity conditions following immunosuppressant treatments in patients with severe COVID‐19. This study compares COVID‐associated arthritis in two non‐severe COVID‐19 and severe COVID‐19 categories by collecting data from 95 cases. We conclude that the prevalence of COVID‐associated arthritis may increase with COVID‐19 severity. However, there is an inverse relationship between COVID‐19 severity and arthritis severity, probably because of weaker immunity conditions following immunosuppressant therapy in patients with severe COVID‐19. Common types of IA comprise reactive arthritis (Re‐A), rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PA), and gout arthritis (GA).Viral infections such as the SARS‐CoV‐2 virus can solely trigger musculoskeletal manifestations with a nonimmune pathway by directly invading joint tissues and cells; this event is called viral arthritis. Diagnosing and confirming viral arthritis can be challenging because, up to this date, there are no accepted diagnostic criteria to distinguish viral arthritis from post‐viral Re‐A.Here we have systematically reviewed COVID‐associated arthritis in patients after severe and non‐severe COVID‐19 infection by aggregating both post‐COVID inflammatory and viral arthritides studies.2All procedures used in this systematic review have complied with the preferred reporting items for systematic review guidelines (PRISMA).2.1To claim the cases, PubMed (MEDLINE/PMC), SCOPUS, EMBASE, and other valid resources, were comprehensively searched by using the following keywords: “Inflammatory Arthritis” OR “Post‐Infectious Arthritis” OR “Reactive Arthritis” OR “Reiter's Syndrome” OR “Sacroiliitis” AND “COVID‐19” OR “SARS‐CoV‐2” OR “Coronavirus Disease‐19.” Additional data are given in Supporting Information: S2 File.2.2Published articles in English on both IA  and viral arthritis occurring after COVID‐19 infection; which reported COVID‐19 severity were included. Although numerous papers clearly stated that their patients were diagnosed with severe or non‐severe COVID‐19, some did not. To classify these unidentified patients, intensive care unit admission or hospitalization due to COVID‐19 was considered a positive criterion for COVID‐19 severity.2.3Cases or articles with undetermined laboratory diagnostic tests  for COVID‐19 were excluded. Arthralgia was the only complication of some patients; these patients were also excluded.2.4We collected the following data for each study: first author and published year, nationality, age and sex, type of arthritis, COVID‐19 severity, number and pattern of involved joints, the basis of COVID diagnosis test, the interval between initiation of COVID‐19 infection and the onset of arthritis, basis of arthritides diagnosis, synovial fluid analysis , consisting auto‐antibodies rheumatologic antibodies and human leukocyte antigen B27 (HLA‐B27), history of RMDs, history of non‐RMD comorbidities, treatment, outcome, sexually transmitted disease (STD) tests results, extra‐articular manifestations, and history of recent vaccine injection. We summarized the extracted data by classifying the results into two main groups; COVID‐associated arthritis following non‐severe COVID‐19 and COVID‐associated arthritis following severe COVID‐19. The JBI checklist was used to assess the quality of selected studies in parallel by two reviewers (M. Z. and P. A.), then the results were structured in a qualitative synthesis.33.1Our search primarily included all published articles in any language until Febuary 20, 2023, and 271 papers were collected. Duplicate reports were initially removed; then, the titles, abstracts, and full texts were separately reviewed by two authors (M. Z. and P. A.). Non‐English, review, and irrelevant articles were excluded. Cases with post‐COVID arthritis, including case reports, case series, letters, editorial papers, comments, and conferences, were included for eligibility assessment, and documents with inadequate clinical data were excluded. Finally, 41 case reports  are summarized in Table While six patients were diagnosed with RMD flare‐ups,The most prevalent pattern of joint involvement was the peripheral form, reported in 72 patients. Twelve patients experienced axial involvement, and 6 had the peripheral pattern simultaneously. Articular involvement of the peripheral type comprised monoarthritis (in 20 patients), oligoarthritis (in 21 patients), and polyarthritis (in 20 patients). The most frequently involved joints were the knee, reported in 30 cases ; the ankle, in 27 patients ; small joints of hands or feet in 21 patients; and wrist, reported in 20 patients; all affected joints are listed in Table Extra‐articular manifestations like skin rashes,The interval between COVID‐19 infection and the onset of arthritis differs from zero days (simultaneous with COVID‐19) to 16 weeks. While the onset of arthritis in 14 cases occurred less than 1 week (≤1 week) after COVID‐19 symptoms,Nonsteroidal anti‐inflammatory drugs (NSAIDs) (in 50 cases) and corticosteroids in 38 cases) were the most prevalent prescribed drugs for arthritis treatment. Monotherapy with NSAIDs and steroids was used in 20 and 4 patients, respectively. NSAIDs were most commonly used orally; the topical form was used in only one patient.8 cases wAlthough 57 patients gained complete or significant remission after treatment and follow‐up, 7 patients acquired partial remission, 1 experienced a relapse of symptoms,3.4A total of 18 cases that reported the onset of arthritis after severe COVID‐19  are summarized in Table While three patients were diagnosed with RMD flare‐ups and had an RMD history,The prevalent form of joint involvement was the peripheral form reported in 18 patients, and three experienced axial involvement simultaneously. The peripheral form types comprised monoarthritis (in 4 patients), oligoarthritis (in 9 patients), and polyarthritis (in 4 patients). The most frequently involved joints were as follows: the knee, reported in 10 patients , and the ankle, in 7 patients ; All affected joints are listed in Table Only one patient experienced extra‐articular manifestations, including bilateral conjunctivitis, psoriatic skin lesions, oral lesions, and vulvitis,The interval between COVID‐19 symptoms and the onset of arthritis differs from zero days (simultaneous with COVID‐19) to 3 months. The onset of arthritis in 2 cases occurred less than 1 week (≤1 week) after COVID infection,Corticosteroids (in 10 cases) and NSAIDs (in 9 cases) were the most prevalent prescribed drugs for arthritis treatment. Monotherapy with steroids and NSAIDs was used in 4 and 5 patients, respectively. Corticosteroids were administered in different types comprising oral route in 6 patients,χ2 tests (Table p > .05).Patients' characteristics in both severe and non‐severe groups are summarized in Table ts Table . No asso4Re‐A, RA, AS, PA, and GA are common subgroups of IA that frequently arose after COVID‐19 infection. Re‐A and AS were repeatedly reported after infection with viruses such as SARS‐CoV‐2 and were presented as the first episode of arthritis in patients without RMD history. Re‐A often occurs with asymmetric oligoarthritis of the lower limbs, especially the knee joint; AS is mainly copresent with axial involvement, called sacroiliitis; both AS and sacroiliitis are considered subgroups of spondyloarthropathies, that are associated with the HLA‐B27 genetic marker.In this systematic review, we compiled all published data on patients with COVID‐related arthritis. We summarized 95 included patients in two categories: COVID‐associated arthritis following non‐severe COVID‐19 and COVID‐associated arthritis following severe COVID‐19 Table . We usedFollowing our computation, 81.05% of the patients experienced asymptomatic, mild, or moderate COVID‐19, and 18.95% underwent severe or critical COVID‐19 infection, similar to the COVID‐19 severity rate (19%).All patients in the severe COVID‐19 group were adults with a mean age of 53.05 ± 15.27 years, and 55.56% of them had at least one non‐RMD comorbidity; on the other hand, in the non‐severe COVID‐19 group, 7.79% of cases were juveniles, and the mean age was 41.43 ± 16.45 years; and 32.46% mentioned at least one non‐RMD comorbidity; which shows the fact that age and comorbidity are the most potent risk factors for severe COVID‐19 outcomes.According to the authors' reports, 92.21% of patients in the non‐severe COVID‐19 group were diagnosed with non‐RMD arthritis and 7.79% with RMD flare‐ups; however, 11.69% of them declared a history of RMDs and 7.79% had positive rheumatic autoantibodies. We included all COVID‐related arthritides, not solely Re‐A, to avoid missing any related data or cases. In the severe COVID‐19 group, 16.67% of patients were diagnosed with RMD flare‐ups and reported a history of RMDs with positive rheumatic autoantibodies; the rest experienced their first episode of IA. Despite the fact that there were no significant differences in HLA‐B27 positivity between the two groups and most of the positive HLA‐B27 patients were cases with sacroiliitis or cases of non‐axial Re‐As.Furthermore, two patients who experienced arthritis after non‐severe COVID‐19 declared a history of recent vaccine injections. One of them reported a SARS‐CoV‐2 vaccine (Biontech/Pfizer) injection 9 days before arthritis, whereas the onset of COVID‐infection occurred 8 weeks before arthritis,While in the non‐severe COVID‐19 group, common peripheral joint involvement patterns consist of oligoarthritis (27.27%), monoarthritis (25.97%), and polyarthritis (25.97%), in the severe COVID‐19 group, the proportion of each pattern was different, oligoarthritis (50%) was the most prevalent, monoarthritis (22.22%), and polyarthritis (22.22%) were following ones Figure ; we assuAs the treatments of arthritis were based on age, comorbidities, RMDs history, arthritis severity, and other personal conditions, we cannot precisely define the best treatment; nevertheless, in both groups, polytherapy (or combination therapy) was more common than monotherapy, and it often included oral NSAIDs with different types of corticosteroids Figure . More agMany reviews have been conducted to collect COVID‐related arthritis before,Besides all the new data and evaluations, our study had some limitations too; for example, no observational study was done, there were a lot of unmentioned data in some papers, and some cases were better documented than others, leading to variations in the quality of papers. To decrease the risk of bias and improve the quality of evaluations, we listed the case reports and the case series in two separate tables Tables  and 2.5This study compares COVID‐associated arthritis in two non‐severe COVID‐19 and severe COVID‐19 categories by collecting data from 95 cases. We conclude that the prevalence of COVID‐associated arthritis may increase with COVID‐19 severity. However, there is an inverse relationship between COVID‐19 severity and arthritis severity, probably because of weaker immunity conditions following immunosuppressant therapy in patients with severe COVID‐19. We suggest that all non‐severe COVID‐19 patients, even asymptomatic ones, need nonaggressive immunosuppressant treatments (during COVID‐19 infection) to alleviate the immune‐based complications, specifically IA.Mahsa Zarpoosh contributed to searching databases, collecting data, and writing the manuscript. Parsa Amirian contributed to searching databases, collecting data, and revision the manuscript.The authors declare no conflict of interest.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.


The etiology and pathophysiological mechanisms of sudden sensorineural hearing loss (SSNHL) remain unclear, but it is generally believed to be associated with viral infections, vascular diseases, and autoimmune disorders. Considering that coronavirus disease 2019 (COVID‐19) is promising candidates for SSNHL, we studied the immune cells changes by COVID‐19 in patients with SSNHL.We collected data from 47 patients with SSNHL and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) positive. Patients were divided into ineffective or effective groups based on the degree of hearing recovery at discharge. Clinical information was collected and processed for both groups. Logistic regression models were used to determine the risk factors for an unfavorable prognosis in COVID‐19‐related SSNHL. Receiver operating characteristic (ROC) curves were used to estimate the predictive value.p < 0.05). In the logistic regression model, high levels of SII and NLR were associated with treatment ineffectiveness, pre‐ and postcorrectively . And ROC curve analysis showed higher AUC of 0.765 for SII, 0.697 for NLR,0.681 for CRP, and 0.553 for platelet‐to‐lymphocyte ratio (PLR) in predicting treatment outcomes.There was statistically significant difference in C‐reactive protein (CRP), auditory curve, degree decline, pretreatment hearing, posttreatment hearing, systolic blood pressure, diastolic blood pressure, total bilirubin, neutrophil‐to‐lymphocyte ratio (NLR), systemic immune‐inflammation index (SII), indirect‐bilirubin and platelet count between groups  is associated with inflammation. λSystemic immune‐inflammation index (SII), neutrophil‐to‐lymphocyte ratio, and C‐reactive protein could serve as predictive markers of unfavorable outcomes in COVID‐19‐related SSNHL. λSII may be considered an independent risk factor for poor prognosis in COVID‐19‐related SSNHL. Following the initial outbreak in China, there has been a notable escalation in the quantity of reports pertaining to the outbreak. Additionally, certain individuals have exhibited a negative prognosis. Hence, we conducted a comparative analysis of the clinical characteristics and prognostic outcomes among individuals diagnosed with COVID‐19 and sudden deafness within a clinical cohort. Additionally, we examined pertinent inflammatory markers, thereby offering novel perspectives and potential avenues for the management and prognosis of sudden deafness in the context of viral infection.22.1From November 2022 to March 2023, 47 patients with COVID‐19 complicated with sudden deafness in the Clinical Medical College of Yangzhou University were retrospectively analyzed. The following were the criteria for inclusion: (1) Positive results for SARS‐CoV‐2 in polymerase chain reaction (PCR) testing of oropharyngeal and nasopharyngeal swabs; (2) Aged 18 years or older; (3) Sudden onset of sensorineural hearing loss within 72 h, with a minimum continuous decrease of ≥20 dBHL in at least three consecutive frequencies; (4) Mostly unilateral, with a few bilateral or sequential cases; (5) Patients may exhibit symptoms including tinnitus, ear stuffy, and echo; (6) Patients may experience disorientation, vertigo, nausea, and vomiting; (7) No prior treatment received before the onset of symptoms.The exclusion criteria were as follows: (1) Patients with accompanying diseases or injuries that could cause hearing loss, such as Ménière's disease, chronic suppurative otitis media, other central nervous system diseases, head trauma, or the use of ototoxic drugs; (2) Patients were confirmed to have the posterior cochlear space‐occupying lesion as evidenced by magnetic resonance imaging (MRI) of the skull or middle inner ear, or computed tomography (CT) scan of the temporal bone; (3) Patients with a history of previous hearing loss or tinnitus; (4) Patients with a history of otologic pathology or ear surgery.2.2In this investigation, all patients received comprehensive treatment, which included systemic corticosteroid therapy, intravenous administration of neurotrophic drugs, and dexamethasone was injected into the tympanic cavity of the affected ear, once a day, a total of three times, 5 mg each time. In accordance with the 2015 Chinese Medical Association's Guidelines for the Diagnosis and Treatment of Sudden Deafness,Before and after treatment, pure tone audiometry was conducted to evaluate the therapeutic effect. If the pure‐tone audiometric (PTA) of the affected frequencies improved by at least 15 dB or if the affected ear reached the same level as the normal or unaffected ear, the treatment was deemed efficacious. If the improvement in PTA was less than 15 dB, the treatment was deemed ineffective.2.32 Each case was assigned a neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and systemic immune‐inflammation index (SII). SII was calculated using the following formula: SII = N × P/L. The research was sanctioned by the Hospital Ethics Committee (2023ky052).Patients' baseline characteristics , vital signs , clinical history, SSNHL‐related information, and laboratory parameters were retrieved from hospital records. Body mass index (BMI) was calculated using the following formula: BMI = Weight (Kilograms)/Height (Meters)2.4n, %). Rank‐sum tests were utilized to analyze ranked data. Continuous variables with a normal distribution were expressed as mean standard deviation (SD) and compared using t‐tests on samples from independent groups. Alternately, quartiles  were used to represent continuous variables that did not have a normal distribution, and rank‐sum tests were used to compare between groups. On the basis of clinical indicators of patients, logistic regression models were used to control for potential confounding variables. Model I included adjustments for age, gender, and diabetes. Model II added SBP and DBP to Model I as additional modifications. Model III added TBiL, indirect bilirubin, Cr, and cholesterol to Model II as adjustments. To assess the predictive value of SII, NLR, PLR, and CRP for treatment outcomes, receiver operating characteristic (ROC) curves were constructed. The significance level was set to 0.05, and a test with two hypotheses was conducted. SPSS 26.0 was used to perform statistical analysis.The chi‐square test was utilized to analyze count data presented as percentages (3p > 0.05). The ineffective group had a slightly higher average age (53.32 ± 12.25 vs. 46.05 ± 17.10) and a higher prevalence of diabetes (21.4% vs. 0.0%) compared to the effective group, but these differences were not statistically significant (p > 0.05). The ineffective group had significantly higher levels of CRP (14.64 ± 8.02 vs. 9.35 ± 6.34) and showed significant differences in the auditory curve (p < 0.05). The ineffective group had a higher proportion of patients with a degree decline of 2 (92.9% vs. 57.9%), which was statistically significant (p < 0.05). The ineffective group had higher pretreatment hearing (83.25 ± 14.49 vs. 68.42 ± 19.40) and posttreatment hearing (81.61 ± 14.34 vs. 35.58 ± 20.77) compared to the effective group, and these differences were statistically significant (p < 0.05). Additionally, compared to the effective group, the ineffective group had higher levels of SBP (136.61 ± 17.07 vs. 125.47 ± 8.39), DBP (85.79 ± 7.35 vs. 77.05 ± 5.45), TBiL (17.02 ± 5.04 vs. 6.21 ± 1.00), NLR (5.86 ± 2.89 vs. 4.08 ± 1.54), SII (1129.24 ± 693.55 vs. 595.75 ± 275.36), indirect bilirubin (12.58 ± 4.95 vs. 3.73 ± 0.70), and platelet count (198.14 ± 77.54 vs. 146.95 ± 40.05), with statistically significant differences (p < 0.05) , albumin, lymphocyte count, creatinine (Cr), platelet volume, Fibrinogen (FIB), cholesterol, triglyceride, high‐density lipoprotein (HDL), low‐density lipoprotein (LDL), BMI, D‐Dimer (DD), and glycosylated hemoglobin, Type A1C (Hba1c) (p = 0.005) and NLR  were associated with treatment ineffectiveness. After adjusting for other confounding factors, this study used three logistic regression models to explore the relationship between SII, NLR, and treatment outcomes . In Model II, SBP and DBP were added as additional adjustments to Model I, and it was found that high levels of SII  and NLR  were also significantly associated with treatment ineffectiveness . In Model III, TBiL, indirect bilirubin, Cr, and cholesterol were added as adjustments to Model II, and it was found that high levels of SII  and NLR  remained significantly associated with treatment ineffectiveness   of 0.765 for SII, 0.697 for NLR, 0.681 for CRP, and 0.553 for PLR, indicating that PLR had a lower predictive value, while NLR and CRP had some predictive value for treatment ineffectiveness, and SII had a good predictive value for treatment ineffectiveness , vertigo , dizziness , and ear tightness . The prevalence of tinnitus is shown to be high, as indicated by Xiangming Meng et al.This study involved a retrospective analysis of 47 patients who presented with acute deafness associated with COVID‐19. The study observed a range of median ages between 46 and 54. The sample consisted of 22 male participants and 25 female participants, with no statistically significant variation in incidence rates across genders. These findings align with prior studies.To determine the factors influencing the prognosis of COVID‐19 patients with SSNHL, 47 patients were divided into effective or ineffective group. The results of these two groups demonstrated that the type of audiometric curve at the onset of SSNHL and the degree of hearing loss were related to the prognosis of COVID‐19 patients with SSNHL. The recovery rate for low‐frequency SSNHL was greater compared to flat‐frequency SSNHL and total impairment of SSNHL in patients with severe and profound hearing loss on their initial audiogram. Consistent with previous research on the prognostic factors of SSNHL, these findings indicate that patients with more severe hearing loss tend to have poorer recovery outcomes.PLR has been demonstrated to be predictive of cardiovascular diseases such as peripheral arterial occlusive disease.The NLR, or Neutrophil‐to‐Lymphocyte Ratio, is a recognized indicator that may be utilized to assess the presence of inflammation in both cardiac and noncardiac disorders.NLR and CRP had values between 0.65 and 0.70 based on the area under the ROC curves, implying a moderate correlation with a poor prognosis in COVID‐19 patients with SSNHL. These two markers play a role in prognosis prediction. However, the area under the ROC curve for SII was greater than 0.70, indicating that it is a reliable indicator for predicting the prognosis of COVID‐19 patients with SSNHL. Patients with elevated NLR, CRP, and SII should therefore consider corticosteroid use a necessary intervention. Nevertheless, corticosteroids may have adverse effects. Therefore, for patients with extremely high SII values or other COVID‐19 complications, alternative treatment methods such as high‐dose intravenous methylprednisolone therapy (200 mg for 3 days) can be considered, or they can be referred to the appropriate departments for anti‐inflammatory treatment. We also recommend investigating additional inflammatory markers in patients with high SII suspected of viral infection to understand further the relationship between inflammatory markers and viral COVID‐19‐related SSNHL. In addition, COVID‐19 patients with elevated NLR, CRP, and SII levels should be vigilant for concurrent SSNHL, and appropriate measures, such as anti‐inflammatory treatment, should be implemented to facilitate early intervention and reduce disability rates.4.1In this study, the peripheral blood inflammatory markers of COVID‐19 patients with SSNHL were evaluated. The assessment of hearing loss was conducted exclusively through the utilization of pure tone audiometry (PTA), in accordance with the 2015 Chinese Guidelines for the Diagnosis and Treatment of Sudden Deafness. This particular method of hearing assessment is widely employed and recognized as the most prevalent approach. In accordance with the guidelines outlined in the International Audiology report, it is important to take into account the speech recognition score (SRS) as a measure. The SRS not only provides information about the patient's hearing ability, but also offers insights into the functional status of their auditory nerve conduction pathway and auditory center.To enhance the existing understanding of the clinical manifestations and inflammatory indicators linked to SSNHL in the context of COVID‐19, future investigations should encompass a more extensive cohort of COVID‐19 patients affected by SSNHL. Additionally, it would be valuable to gather data on patients with sudden‐onset sensorineural hearing loss (SRS) and their respective time of COVID‐19 diagnosis.It will aid in early intervention and disability rate reduction, as well as facilitate individualized treatment.5Our research indicates that inflammation is linked to the prognosis of COVID‐19 patients with SSNHL. Patients with severe and pervasive hearing loss on the initial audiogram, those with low‐frequency SSNHL, and those with elevated levels of NLR, CRP, and SII may have a poor prognosis, with CRP, NLR, and SII being predictive of poor outcomes. SII is an independent risk factor associated with a poor prognosis in COVID‐19 SSNHL patients. Consequently, it is our recommendation for giving high‐dose steroid therapy to individuals exhibiting elevated levels of inflammatory markers. The risks and benefits of corticosteroid treatment must be evaluated for patients with elevated NLR, CRP, and SII levels, and alternative treatments or anti‐inflammatory therapies may be utilized. In addition, patients with COVID‐19 should closely monitor these inflammatory markers. Patients with elevated levels of NLR, CRP, and SII were subjected to early anti‐inflammatory intervention and individualized treatment to reduce the risk of SSNHL and its impact on disability. Additional large‐scale studies are required to better comprehend the clinical characteristics of SSNHL caused by viral infection, as well as the significance and predictive value of SII and other inflammatory markers.Xu Zhang: Conceptualization; data curation; formal analysis; investigation; methodology; resources; writing—original draft. Li Chen: Data curation; formal analysis. Bing Guan: Funding acquisition; supervision; validation; writing—review and editing.The authors declare no conflict of interest.The study was approved by the Ethics Committee of the Ethics Review Committee of the Clinical Medical College, Yangzhou University  and conducted according to the Declaration of Helsinki.