Cancer is related to not only physical but also mental suffering. Notably, body image disturbances are highly relevant to cancer-related changes often persisting beyond recovery from cancer. Scalable and low-barrier interventions that can be blended with face-to-face psychotherapy for cancer survivors are highly warranted.The aim of the study is to investigate whether smartphone-based bodily interventions are more effective to improve the mood of patients with cancer than smartphone-based fairy tale interventions (control intervention).We recruited patients with cancer in 2 Swiss hospitals and conducted daily, fully automated smartphone-based interventions 6 times a week for 5 consecutive weeks, blended with weekly face-to-face group body psychotherapy. We applied 2 types of smartphone-based interventions using a within-subject design, randomly assigning patients daily to either bodily interventions or fairy tales. Each intervention type was presented 3 times a week. For this secondary analysis, 3-level mixed models were estimated with mood assessed by the 3 Multidimensional Mood Questionnaire subscales for good-bad mood, wakefulness, and calmness as key indicators. In addition, the effects on experience of presence, vitality, and burden assessed with visual analog scales were investigated.s=732 interventions performed by 36 participants, good-bad mood improved , and participants became calmer  following smartphone-based interventions. Wakefulness did not significantly change from pre- to postsmartphone–based intervention . This was true for both intervention types. There was no interaction effect of intervention type with change in good-bad mood , calmness , or wakefulness . Experience of presence  and vitality  increased from pre- to postsmartphone–based intervention, while experience of burden decreased . Again, these effects were present for both intervention types. There were no significant interaction effects of intervention type with pre- to postintervention changes in experience of presence , experience of vitality , and experience of burden .Based on the data from Our results suggest that both smartphone-based audio-guided bodily interventions and fairy tales have the potential to improve the mood of cancer survivors.ClinicalTrials.gov NCT03707548; https://clinicaltrials.gov/study/NCT03707548RR2-10.1186/s40359-019-0357-1 Cancer is an often life-threatening disease, posing multiple challenges. Although cancer is increasingly curable and the number of survivors has grown, it still remains one of the most feared diseases . PatientMobile mental health has become a topic of considerable interest for patients with cancer to promote self-management of their chronic disease . PreviouThe goal of this randomized clinical trial component nested in a convergent parallel design was to explore changes in mood after smartphone-based bodily intervention compared to fairy tale intervention (comparator). It was hypothesized that the mood of cancer survivors improves from pre- to postsmartphone–based bodily interventions. Furthermore, we expected that mood improvement was greater following bodily interventions as compared to fairy tales (comparator). Due to a small study sample, we have performed exploratory analyses of our hypotheses.Presented data originated from a nested randomized controlled trial, embedded in a nonrandomized study registered in ClinicalTrials.gov (NCT03707548). The aim of this larger nonrandomized study was to evaluate the treatment effects of a BPT group intervention.We recruited patients between September 3, 2018, and May 12, 2019, in 2 Swiss hospitals . All participants signed an informed consent before study participation. We kindly refer to a previous publication  for moreThe entire nonrandomized study, including the present nested randomized controlled trial component, is designed according to the Declaration of Helsinki, the Human Research Act, and the Human Research Ordinance. The Ethikkommission Zentral- und Nordwestschweiz  has approved the study. In addition, we obtained ethical approval from the Kantonale Ethikkommission Zürich. Consistent with good clinical practice, we informed patients about participation in the larger nonrandomized study, the planned secondary analysis of data, and the implications of participation. All participants signed an informed consent form before study participation. Informed consent from the original, larger nonrandomized study allows the present analysis of secondary outcomes without additional consent. Participation was voluntary and could be withdrawn at any time during the entire study. Participants did not receive any compensation. Data were treated confidentially and were strictly analyzed in deidentified form.Inclusion criteria for the entire nonrandomized study were (1) age≥18 years, (2) sufficient knowledge of spoken German, (3) having received curatively intended treatment for any malignant neoplasm, (4) suffering from bodily disturbances, (5) primary treatment being completed at least 3 months prior to recruitment, (6) an Eastern Cooperative Oncology Group performance score of 0-1 , (7) an The smartphone-based digital intervention was embedded in a nonrandomized study with face-to-face psychotherapy, consisting of 6 group BPT sessions, 90 minutes each. As part of the nested randomized controlled trial component, participants received either an audio instruction of bodily interventions (3 times a week) or audio recordings of fairy tales as unspecific intervention and comparator (3 times a week) via smartphone between sessions, over a period of 5 consecutive weeks. There was no smartphone-based intervention on the day of the group BPT session. The smartphone-based bodily intervention offered audio clips consisting of BPT tools, experiences, and strategies that reflected the content of the face-to-face sessions. For more details on the contents of these bodily interventions, please refer to The Clinical Trial Unit of the University Hospital Basel independently generated the random sequences using R software , applying a block design to ensure that each patient received both interventions 3 times a week. This allowed individual daily randomization of each participant to either the bodily or the fairy tale intervention (within-subject randomization). Trial participants were blinded to randomization up until the moment at which the intervention was provided; body psychotherapists were also blinded to randomization.To familiarize participants with the smartphone-based interventions, all patients received an invitational email with a link to an introductory audio file and the request to complete the questionnaire at the end of the first group BPT session. Data collected during this training were not included in the analyses.Patients could freely choose the time of day they participated in the digital intervention. The time window started each day at 7 AM with the invitational email including the day-specific hyperlink giving access to the intervention. This hyperlink expired at midnight of the same day. We used on the web Questback software (Questback Ltd)  to conduThe detailed procedure of each smartphone-based intervention was as follows: (1) participants used their own smartphones to get connected via internet browser to the Questback server, using a day-specific personalized hyperlink provided in the daily invitational email. We instructed patients to log into their email once a day. (2) We asked patients to enter their individual self-generated personal code, which allowed for verifying subject identity. (3) Participants replied to a short questionnaire (“pre”) described in more detail below. (4) To start the session, patients were asked to click on the “play” button of the audio player. (5) Participants listened to the audio clip using either headphones or the smartphone speaker and eventually performed the bodily intervention. (6) Participants again replied to the short questionnaire (“post”). (7) The session finished by thanking the patients for their participation in that day’s session.We assessed mood pre- and postsmartphone–based interventions via web-based questionnaires. We applied the German version of the “Multidimensional Mood Questionnaire” Short-Form A (MDMQ) ,22. The We screened patients for eligibility at baseline assessment (T0), including standardized questionnaires and a semistructured interview. Included patients with cancer who are in posttreatment underwent a waiting period of approximately 6 weeks followed by a pre-face-to-face psychotherapy questionnaire assessment (T1). After the face-to-face group session, a postpsychotherapy assessment (T2) with standardized questionnaires and a second semistructured interview took place. The smartphone-based part of the study applied ecological momentary assessments taking place daily along the face-to-face psychotherapy sessions .We conducted a secondary analysis of data collected in the larger nonrandomized study. The primary outcome analysis of the entire study is reported elsewhere . Accordit tests for independent samples. To investigate the association between age and frequency of participation in digital interventions, the Pearson correlation coefficient was calculated. We estimated gender-specific differences in participation in the digital interventions by using t tests for independent samples. The data for normal distribution by histograms and qq-plots were visually inspected. We summarized sample characteristics using descriptive statistics. We followed the CONSORT  guidelines to report results  using chi-square tests and  results .haven [tidyverse [lme4 [effects [We used R Studio   for all haven . For datidyverse  in additse [lme4  was used[effects  was usedP=.70), gender (P=.43), and baseline distress (P=.44). We screened 171 patients, of whom 40 were scheduled to take part in the face-to-face group BPT  and that patients became significantly calmer  of the smartphone-based bodily interventions and in 70% (378/540) of the smartphone-based control interventions . The frequency distribution of interventions per category over all patients is depicted in r34=0.08; P=.64) and with gender . Pre- and postsmartphone–based intervention, mean and SD of the MDMQ subscales and the 3 VAS items are depicted in Results of this secondary analysis were based on a total of The aim of this exploratory secondary analysis was to evaluate the potential of smartphone-based bodily interventions focusing on related mood changes from pre- to post-EMI in cancer survivors with body image disturbances. We compared smartphone-based bodily interventions with smartphone-based fairy tale interventions (comparator) using a within-subject design. Over the course of 5 consecutive weeks, participants were randomly assigned daily to either the bodily or fairy tale intervention (comparator). We blended face-to-face psychotherapy with this smartphone-based intervention. It was hypothesized that the mood of cancer survivors improves from pre- to postsmartphone–based bodily interventions. Furthermore, we expected that mood improvement was greater following bodily interventions as compared to fairy tales (comparator). Results indicate that the mood of patients with cancer who are in posttreatment improved following smartphone-based interventions, irrespective of the intervention type. Accordingly, results support the first part of our hypotheses but not the second. Hence, listening to fairy tales might have equally soothing and calming effects on people’s moods as bodily interventions . NotablyIn addition, we found no indication of an association between the patients’ age and the frequency of applying the smartphone-based intervention. Hence, there was no indication that younger patients were more skilled or motivated to use smartphone-based interventions as compared to older patients. Notably, the identified participation rates of between 65.5% and 70.0% can be seen as largely satisfactory, yet still indicate relevant potential for improvement, for example, by extending the time window in which patients were granted access to the daily digital interventions or by applying daily smartphone push notifications to remind patients to take part in the digital interventions. Importantly, mood differences from pre- to postsmartphone–based interventions were statistically significant but rather small in magnitude, indicating that a sequence of digital interventions with accumulating treatment effects  may be rOverall, the findings of this study indicate that blending face-to-face BPT for cancer survivors with smartphone-based interventions is not only feasible—in line with previous reports on group therapy for depression , but is Our study has several strengths. First, we used common technology  to provide daily and easily available body psychotherapeutic interventions, facilitating the uptake and translation of the interventions into routine clinical practice. Second, patients were free with regard to the timing of the smartphone-based interventions during everyday life, allowing a rather flexible integration of the smartphone-based intervention into daily routines. Third, smartphone-based interventions were designed to be very intuitive and straightforward to use, not requiring high internet or smartphone literacy of patients, further facilitating the uptake of the technology. Notably, the application of this kind of smartphone-based intervention could be particularly interesting for older patient populations and people with little smartphone or internet-related knowledge. Limitations of this study include a rather small number of included patients, which was only partially compensated by the up to 30 smartphone-based intervention sessions per patient. Our study was also limited by the fact that women with breast cancer were overrepresented. Although our group BPT was open to all patients with cancer who are in posttreatment with any malignant neoplasm, only 4 men participated. This should be taken into consideration when generalizing our findings. Furthermore, we could not blind participants with regard to the intervention. Hence, it is possible that patients were aware of what was the intervention of interest (bodily intervention) and what was the comparator . This may have resulted in biased mood assessments pre- and postsmartphone–based interventions. Nevertheless, we did not inform patients that the overall goal of the smartphone-based interventions was to compare the effects of bodily interventions with that of fairy tales on mood. Importantly, we measured changes in mood but not in bodily disturbances in relation to the smartphone-based interventions. Changes in bodily well-being were merely assessed at baseline (T0) and pre- (T1) and post- (T2) group face-to-face BPT intervention . Thus, iThe number of patients surviving cancer continues to rise. For example, there were 16.9 million cancer survivors in the United States on January 1, 2019 . Many ofThe results of this study suggest that smartphone-based bodily interventions, which can be combined with face-to-face psychotherapy in terms of blended therapy may represent such an innovative intervention. This study underlines the feasibility and acceptance of smartphone-based interventions in postcancer survivors with bodily disturbances. These represent a new, promising treatment model that can be offered as a low-threshold supplement to face-to-face psychotherapy.


The rapid emergence of immune-evading viral variants of SARS-CoV-2 calls into question the practicality of a vaccine-only public-health strategy for managing the ongoing COVID-19 pandemic. It has been suggested that widespread vaccination is necessary to prevent the emergence of future immune-evading mutants. Here, we examined that proposition using stochastic computational models of viral transmission and mutation. Specifically, we looked at the likelihood of emergence of immune escape variants requiring multiple mutations and the impact of vaccination on this process. Our results suggest that the transmission rate of intermediate SARS-CoV-2 mutants will impact the rate at which novel immune-evading variants appear. While vaccination can lower the rate at which new variants appear, other interventions that reduce transmission can also have the same effect. Crucially, relying solely on widespread and repeated vaccination (vaccinating the entire population multiple times a year) is not sufficient to prevent the emergence of novel immune-evading strains, if transmission rates remain high within the population. Thus, vaccines alone are incapable of slowing the pace of evolution of immune evasion, and vaccinal protection against severe and fatal outcomes for COVID-19 patients is therefore not assured. As the COVID-19 pandemic continues to rage worldwide, it is generally hypothesized that the next phase of the crisis will involve a widely circulating disease with limited virulence ,3. This With the rapid worldwide spread of the Omicron variants, public-health authorities have stepped up their efforts to increase vaccination rates, with a particular focus on boosters ,11. Two At this point in time, a case can be made that a crucial determinant of the eventual resolution of the crisis phase of the pandemic will hinge on the ongoing rate of viral evolution. Each new variant brings with it a set of unknowns in terms of key viral properties—the transmissibility, the degree of immune evasion, the superspreading, and infection fatality rate (see Table S3 in ). A scenIn this context, some reports have emphasized that widespread vaccination is critical for slowing viral evolution ,30,31. TWe thus sought to examine the impact of a public-health strategy that relies solely on vaccine uptake on the rate of viral evolution. To do this, we created a stochastic computational model to investigate the emergence of new immune escape variants with multiple mutations to answer the question “what factors determine the rate of emergence of novel immune-evading variants?”. We then used this model to study the impact of vaccination on the emergence of new variants, answering the question “what rate of vaccination would be required to blunt this rate of emergence?”.TR. The simulation starts with one individual infected by a SARS-CoV-2 variant with a single mutant, and each transmission event has a 1 × 10−5 probability of creating a new variant with an additional mutation. This mutation rate was estimated from a ~1 × 10−3/yr SARS-CoV-2 evolutionary rate inferred from phylogenetic analyses  .TR of SARS-CoV-2 by reducing the number of uninfected contacts to which an infected individual can successfully transmit the virus. Disregarding demographic and geographic effects on interpersonal contacts and assuming individuals are well-mixed with regards to vaccine or immunity status, the immunity-adjusted TR’ is TR is the base transmissibility, assuming no immunity, rf and vf are the fractions of individuals who are immune after recovering from prior infection and vaccinated, respectively, and vε is the efficacy of vaccination in preventing infection. Here, we assumed that prior infection confers perfect immunity against subsequent infections.Immunity due to previous infection or vaccination lowers the transmissibility TR is constant over time. We also simulated situations where viral transmission rates decrease over time, to model a wave of SARS-CoV-2 transmission that eventually wanes due to herd immunity or the implementation of interventions such as social distancing. For these simulations, we assumed that the transmission rates for all variants in the population decrease exponentially over time at rate δ. Therefore, the time-dependent transmission rate is t is the time elapsed since the beginning of the simulation, when the first single mutant appears in the population.For the initial set of simulations, we assumed that the viral transmission rate TR ranging from 1 to 5.7 and is countered by a vaccine with a 70% or 100% efficacy against transmission. Each infected individual has a rate of 1 × 10−5 per day of generating a new double-mutant infection  model of viral transmission and immunity from our previous work, which includes a description of the system of differential equations used to simulate the model . BrieflyWe adapted our published computational model  of SARS-X new hosts after a fixed amount of time . Here, X is a Poisson-distributed random variable with mean TR, corresponding to the current SARS-CoV-2 reproduction number. Using this framework, we simulated the multistep creation of a new variant with more than one point mutation, which mirrors the process that generates new immune-evading variants [TR, until the lineage goes extinct. We assumed new mutations occur in this intermediate single-mutant lineage at a rate of 10−5 per transmission event , increasing the transmission rate decreases the amount of time necessary for generation of the double mutant , this wave is shorter and involves fewer infections  can reduce the SARS-CoV-2 transmission rate. However, many of these interventions reduce fections A. Limiti is high B.Our simulations suggest that, if SARS-CoV-2 transmission is not controlled, new variants will continue to emerge relatively quickly. If these new variants can partially or fully evade the adaptive immune response to previous SARS-CoV-2 variants, sequential waves of transmission driven by new variants will occur. If these sequential outbreaks occur close together in time, it may be difficult to control and prevent these transmission waves by developing and deploying vaccine boosters against each variant.R0 is 3.32)  A. Howeveis 3.32) B. These Another mechanism by which vaccination could slow SARS-CoV-2 evolution is by reducing the rate at which new beneficial mutants are produced within infected hosts. Our previous work has shown that viral load kinetics impact within-host evolution, with more viral replication leading to higher rates of variant generation . Using oWe previously showed that generation of variants with more than one new mutation happens much faster in individuals with prolonged infections . We founIn this work, we have taken a first-principles approach rooted in the evolutionary theory to examine the impact of SARS-CoV-2-targeting vaccines on the rate of the variant emergence. Our results suggest that the critical determinant of the rate of SARS-CoV-2 variant emergence in a broadly vaccinated population is the impact of the vaccine on viral fitness. While the rate of evolution of resistance has been demonstrated in other settings to be proportional to the strength of the selection pressure ,39, in tTsR ranging from approximately 1 to 3 [TsR values facilitate viral evolution by providing greater leeway for intermediate variants with reduced fitness to propagate. This finding illustrates a critical flaw in the public-health strategy during the current pandemic: relaxing restrictions in response to increased levels of vaccination within the population without implementing countervailing containment strategies speed up the emergence of vaccine-resistant variants. Notably, this outcome does not arise in the hypothetical case of broad population coverage with a vaccine that dramatically reduces transmission  in supporting vaccines to slow viral evolution. NPIs complement vaccines in slowing viral evolution by limiting the transmission of novel vaccine-evading mutants . In the  typical  or prolo typical . The latPopular misconceptions about viral evolution have repeatedly undermined the public-health response to this pandemic. Early in the pandemic, there was a widely held belief ,46,47 thIn this work, we draw attention to another common misconception about SARS-CoV-2 viral evolution, that is, widespread vaccination will help to slow it down. Our work suggests that the opposite can be true in certain settings—viral evolution can be facilitated by levels of vaccination in the population that are higher than those seen currently  of the US population has received a first booster dose, and around 7% (23.5 million) has received a second booster dose . VaccineOur work has a few key limitations. First, we assumed that new variants were created through the stepwise accumulation of point mutations, either with multiple mutations occurring within a single host or with mutations in the same viral lineage occurring in different hosts. Since many previous major SARS-CoV-2 lineages have arisen through the accumulation of point mutations ,58, we dIn summary, our work points to two unmet needs with the current public-health strategy for SARS-CoV-2. First, there is a need for better prophylaxis in order to bring SARS-CoV-2 under control. Vaccines  that prevent infection and transmission are an urgent need at this point. Rapid viral evolution will continue to complicate the public-health response to the pandemic, will undermine new biomedical interventions as they become available , and mayThree years into the pandemic, we face a virus that is evolving rapidly and is substantially more transmissible than it was at the outset. A clear-eyed understanding of the limitations of the tools at our disposal is crucial at this point for formulating public-health strategies. Our work highlights the importance of looking beyond the current crop of vaccines in finding measures to slow SARS-CoV-2 viral evolution.


After the debut of the results of the effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) and Sotagliflozin in Patients With Chronic Kidney Disease and Type 2 Diabetes (SCORED) trials at the American Heart Association’s 2020 Scientific session, sotagliflozin became the first drug and the third sodium glucose co-transporter-2 (SGLT-2) inhibitor to be approved for heart failure (HF) across the spectrum of ejection fraction (EF). In light of this recent major U.S. Food and Drug Administration (FDA) approval of sotagliflozin, we conducted a systematic review to compare the cardiovascular mortality rates between sotagliflozin and dapagliflozin in patients with HF.To find relevant articles, we extensively searched major research literature databases and search engines such as PubMed, MEDLINE, PubMed Central, Google Scholar, Embase, and Cochrane Library. We compared the results of significant trials involving sotagliflozin with the trials studying dapagliflozin to provide comprehensive mortality results of both drugs. The results showed that the timely initiation of sotagliflozin in HF cases significantly reduces cardiovascular mortality, hospitalizations, and urgent HF visits. Comparative trials with dapagliflozin indicate enhanced mortality reduction associated with greater initial symptom burden. The results of these major trials cannot be overlooked due to the large size of the combined trials, the randomized design, and the high standards with which they were conducted. The pathophysiology behind the cardioprotection offered by these agents is complex and multifactorial, but it is believed that due to the diuretic-like function, SGLT-2 inhibitors reduce glycemic-related toxicity, promote ketogenesis, and exert antihypertrophic, antifibrotic, and anti-remodeling properties. The benefits of dapagliflozin on cardiovascular death and worsening HF in patients with mildly reduced or preserved EF appeared especially pronounced in those with a greater degree of symptomatic impairment at baseline. Sotagliflozin led to a rise in the count of days patients were alive and not hospitalized (DAOH), which offers an extra patient-centered measure to assess the impact of the disease burden. The data in our article will help future researchers conduct large-scale trials with sotagliflozin to identify and implement it in the treatment of patients with HF as a mortality-reducing drug and to improve the quality of life for patients with HF. On May 26, 2023, there was a remarkable update in the field of cardiology. On the basis of the phase three results of the effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) and Sotagliflozin in Patients with Chronic Kidney Disease and Type 2 Diabetes (SCORED) trials, the U.S. Food and Drug Administration (FDA) approved sotagliflozin, making it the first dual sodium-glucose co-transporter 1 and 2 (SGLT 1 and 2) inhibitor authorized for the treatment of heart failure (HF) in both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) [HF which is a leading cause of morbidity and mortality is a progressive and complex syndrome of left ventricular dysfunction. The term left ventricular ejection fraction (LVEF) categorizes systolic dysfunction, with LVEF >50% as normal .Few advancements in the field of cardiometabolic medicine have had as significant an impact as sodium-glucose cotransporter-2 (SGLT-2) inhibitors . SGLT-2 SGLT-2 and SGLT-1 receptors, which are in charge of about 90% and 10%, respectively, of glucose reabsorption in the kidney proximal tubule, are inhibited by SGLTi to enhance urine glucose excretion. While SGLT-1 receptors are more extensively expressed and are primarily found in the colon and heart/skeletal muscle, SGLT-2 receptors are virtually entirely localized in the kidneys.As of June 2023, 13 large-scale trials involving >90,000 participants, including the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), explored SGLT-2 inhibitors in type-2 diabetes, HF, and kidney disease. While 12 trials reduced hospitalizations for HF, only these two demonstrated a significant reduction in cardiovascular mortality, highlighting uncertainties due to limited subgroup analysis in individual trials [Sotagliflozin is a novel and unique diabetic medication that has dual inhibition of SGLT-1 and SGLT-2 receptors. SGLT-1 inhibition has been shown to delay postprandial intestinal glucose absorption and can also enhance levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). The ability to inhibit SGLT-1 molecules makes sotagliflozin different from the other SGLT-2 inhibitors which have been known for a while. The Emperor-reduced trial and DAPA-HF trials mentioned above have shown evidence of the cardiovascular benefits of SGLT-2 inhibitors. Both trials included patients with HFrEF, irrespective of their type-2 diabetes mellitus (T2DM) status. These trials demonstrated the decreased risk of hospitalization for HF and death from cardiovascular causes among patients with stable HF. However, there was no trial or data available on the effects of these drugs if initiated immediately after an episode of decompensated HF. The SOLOIST-WHF trial demonstrated the mortality benefits and significant cardiovascular outcomes of sotagliflozin when initiated immediately after a decompensation event. The results of this trial cannot be overlooked due to the large size of the combined trials, its randomized design, and the high standards with which it was conducted .In light of the recent data from the SOLOIST-WHF and SCORED trials followed by the FDA approval of sotagliflozin, we conducted a systematic review to compare the cardiovascular mortality rates between sotagliflozin and dapagliflozin. Our primary outcome is to compare the differences in cardiovascular mortality or death rates in patients treated with sotagliflozin and dapagliflozin. The secondary outcomes include differences in HF hospitalization and the requirement for urgent admission for HF.MethodsThis systematic review adheres to the outlines prescribed by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) .Search StrategyTo find relevant articles for our study, we conducted thorough searches using major research literature databases and search engines including PubMed, MEDLINE, PubMed Central, Google Scholar, Embase, and Cochrane Library. We used appropriate keywords and Medical Subject Headings (MeSH) to ensure comprehensive coverage and find articles related to our specific topic. To find the most pertinent articles, we combined the keywords in various combinations using Boolean operators "AND", "OR", and "NOT". This extensive approach helped us identify relevant and up-to-date literature for our study.An overview of the databases that were reviewed for article collection and the corresponding search strategies employed are elaborated in Table Inclusion and Exclusion CriteriaThe inclusion criteria for our review encompassed randomized controlled trials, systematic reviews, and meta-analyses that were published in the English language within the past 10 years, with a specific focus on the adult population comprising individuals aged 18 years and above and relevant to our research question. We excluded articles focusing on the pediatric population (<18 yrs.), case reports, letters to editors, animal studies, and unpublished or grey literature.Analysis of Study Quality/BiasAfter conducting a thorough assessment using standardized quality evaluation tools, we identified 11 out of the 12 selected studies as medium or high quality. These 11 studies were deemed suitable for inclusion in our review due to their credibility and robustness. Two different tools were employed for the assessment: the Assessment of Multiple Systematic Reviews (AMSTAR) tool for systematic reviews and meta-analyses, and the Cochrane risk-of-bias assessment tool for randomized controlled trials (RCTs).A comprehensive evaluation of the quality of each study that was included in our review is shown in Table Table ResultsIn our initial search of PubMed, MEDLINE, PubMed Central, Embase, and Cochrane Library databases, we found a total of 227 articles. After applying relevant filters according to our eligibility criteria , we removed 15 duplicate articles, leaving us with 212 unique articles. These remaining articles were then screened by two independent investigators based on titles, abstracts, full-text, and detailed inclusion and exclusion criteria.After this meticulous screening process, we were left with 11 articles. A single additional article was added by searching the relevant keywords on the Cochrane Library database. A total of 12 articles were chosen to undergo a comprehensive quality and bias assessment utilizing standardized quality assessment tools. Following the quality appraisal process, one study was excluded, and the final systematic review included a total of 11 studies. One study was excluded after quality appraisal, and the final 11 studies were included in this systematic review. Of the 11 included studies, three were systematic reviews and meta-analyses, two were purely meta-analyses and the remaining six articles were randomized controlled trials. The quality of the systematic review and meta-analyses were evaluated using the AMSTAR-2 checklist. The Cochrane Risk of Bias Assessment Tool was used for assessing the bias risk in the randomized controlled trials. The PRISMA 2020 flow diagram is depicted in Figure DiscussionHF is a significant global health concern, characterized by substantial morbidity and mortality . SGLT-2 Several major cardiovascular outcome trials evaluated and demonstrated the beneficial cardioprotective effects of SGLT-2 inhibitors. The major ones were the Empagliflozin Cardiovascular Outcome Trial (EMPA-REG) trial which studied Empagliflozin, Canagliflozin Cardiovascular Assessment Study (CANVAS) which showed a significant reduction in HF hospitalization with Canagliflozin, the Dapagliflozin Effect on Cardiovascular Events Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial and the most recent one being the effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial which demonstrated a significant reduction in the risk of death from cardiovascular causes or hospitalization for heart failure with the use of sotagliflozin .Dual SGLT 1 and 2 Inhibition: MechanismsSodium-glucose co-transporters can be classified based on their modulatory sites with SGLT-2 predominating in the kidney and SGLT-1 in the intestine. SGLT-1 transporters have dual functions in the body. They are involved in absorbing glucose from the small intestine during digestion, and they also reabsorb approximately 10% of the filtered glucose from the kidney’s proximal tubule back into the bloodstream . The posThe usual renal threshold for reabsorption of glucose is a serum glucose concentration of 180mg/dl. However, interestingly, in diabetics, the SGLT-2 protein becomes upregulated which may contribute to the worsening of the hyperglycemia. The inhibition of the SGLT-2 receptors prevents glucose reabsorption in the kidneys, thus allowing for better control of glucose in the diabetic population. Sotagliflozin is particularly unique for its dual ability to inhibit SGLT-1 and SGLT-2 receptors. SGLT-1 inhibition has been shown to cause a delay in postprandial intestinal absorption of glucose and increase levels of GLP-1 and GIP. This dual function along with the many beneficial cardiovascular outcomes discussed further make Sotagliflozin a novel drug of choice for patients with heart failure.In an efficient and elaborate study done by Lee et al, comprising 52,607 patients from 10 trials, it was shown that in patients with heart failure, the SGLT-2 inhibitors with low selectivity towards SGLT-1 and SGLT-2 had a greater impact on reducing the risk of hospitalization for heart failure (HHF) compared to agents with higher selectivity .Effect of SGLT-2 Inhibitors on Cardiovascular Outcomes in HFAccording to the 2022 guidelines of the American Heart Association, American College of Cardiology, and Heart Failure Society of America, SGLT-2 inhibitors have been designated as Class I, level A drugs for the management of heart failure with reduced ejection fraction and as Class II A, level B for treating heart failure with mildly reduced ejection fraction  or preserved EF  . While tWhile earlier trials such as the DECLARE-TIMI 58 trial involving Dapagliflozin and Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease (VERTIS-CV) trial testing Ertugliflozin failed to demonstrate significant cardiovascular outcomes in patients with HF with ejection fraction >45%, we noticed that recent trials such as SOLOIST-WHF have shown significant outcomes in patients with HF and LVEF >50% with Sotagliflozin. However, the limited number of occurrences or events makes it unreliable to fully assess the treatment’s potential benefits .Larger trials such as EMPEROR-PRESERVED (5988 patients) and DELIVER (6263 patients) are the two largest trials to date evaluating the benefits of SGLT-2 inhibitors in patients with HF with LVEF >40% ,21. EachHasan et al. analyzed a total of 13 randomized controlled clinical trials including 75,287 patients demonstrating that SGLT-2 inhibitors significantly reduce the risk of hospitalization in patients with HF irrespective of their diabetes status but showed a significant reduction in mortality risk only in diabetics (Relative Risk (RR) =0.87,95% Confidence Interval (CI): 0.77-0.99) [In an extensive meta-analysis conducted by Lu et al., which included eight large trials involving 16,640 patients with HF, SGLT-2 inhibitors were found to significantly decrease the risk of cardiovascular disease and hospitalization for heart failure (CVD/HHF) by 23% across a diverse range of heart failure patients . In contIn a meta-analysis of 15 trials including over 20,000 patients conducted by Cardoso et al., SGLT-2 inhibitors were shown to significantly reduce all-cause mortality and cardiovascular mortality in patients with HF stratified by age, sex, race, renal function, diabetic status, the functional class of HF and ejection fraction . The stuTable Cardiovascular Mortality and Other Significant Outcomes With Sotagliflozin Bhatt et al. conducted the effect of sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post-Worsening Heart Failure (SOLOIST-WHF) trial, a multicenter, double-blinded, randomized, and placebo-controlled study. This trial aimed to compare the effects of sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, with placebo in patients with type 2 diabetes and reduced or preserved left ventricular ejection fraction who had recently been hospitalized due to worsening HF . During The study population included patients with type 2 diabetes who were recently hospitalized for worsening of HF. The main focus or primary endpoint of the study was to measure the combined total of cardiovascular deaths and hospitalizations or urgent visits related to heart failure. In the sotagliflozin group, the primary endpoint event rate was 51.0 per 100 patient-years, while in the placebo group, it was 76.3 per 100 patient-years . When the total number of deaths that occurred due to cardiovascular causes and hospitalizations for HF was studied as a secondary endpoint excluding the urgent visits for heart failure, the results obtained were statistically significant and similar to the results of the primary endpoint  [A summary of the randomized controlled trials assessing sotagliflozin is presented in Table The SOLOIST-WHF trial established that in patients with diabetes and worsening heart failure, the administration of Sotagliflozin, a dual SGLT 1 and 2 inhibitor, was associated with a notably reduced total number of cardiovascular deaths when compared to the placebo group. There was also a statistically significant reduction in hospitalizations and urgent visits for heart failure.Following the positive findings of the previous study, Szarek et al. conducted a study to assess whether the use of sotagliflozin improved the prespecified efficacy outcome of "days alive and out of the hospital" (DAOH) in the SOLOIST-WHF trial . They diAnother ongoing major trial studying sotagliflozin is the Sotagliflozin in Heart Failure With Preserved Ejection Fraction Patients (SOTA-P-CARDIA) trial which was accepted in May 2023. The study aims to demonstrate the benefits of sotagliflozin in non-diabetic HFpEF patients when administered on top of their prescribed HF treatment. The primary endpoint that will be assessed would be the reduction in the left ventricular mass by Sotagliflozin assessed by cardiac MRI at baseline vs. six months and compared with placebo. The study is ongoing and the expected results are that the previous results and benefits of sotagliflozin in diabetic patients would also be seen in non-diabetic HFpEF patients.Some of the unique features of the SOLOIST-WHF trial are the inclusion of hospitalized patients as well as patients with preserved ejection fractions or LVEF>50% which was different from previous trials which only included patients with reduced ejection fractions. However, some significant limitations were the early termination and the small sample size of the subgroup which had LVEF>50%. In the comparatively larger Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease (SCORED) trial, sotagliflozin resulted in a 26% lower risk of the same redefined outcome as SOLOIST-WHF . Thus, tThus, the SOLOIST-WHF and the SCORED trials were two large-scale randomized clinical trials that evaluated the cardiovascular effects of the dual SGLT 1 and 2 inhibitor Sotagliflozin and have demonstrated the cardiovascular benefits of mortality reduction with Sotagliflozin.Comparative Mortality and Other Significant Outcomes With DapagliflozinOne of the noteworthy trials investigating Dapagliflozin was the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial conducted by Kosiborod et al. . The uniAs part of the DELIVER trial, Peikert et al. conducted another study focusing on the safety and efficacy outcomes in different age categories of patients with heart failure and mildly reduced or preserved ejection fraction . This stThe Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF) is an international, multi-center, randomized double-blinded controlled trial to determine the safety and efficacy of SGLT-2 inhibitor dapagliflozin added to the conventional heart failure therapy in patients with heart failure with reduced ejection fraction . The DAPThus, extensive research with SGLT-2 inhibitors has helped us arrive at this position with HF management.A comprehensive summary of the randomized controlled trials assessing dapagliflozin is presented in Table LimitationsThis systematic review encounters some limitations. Firstly, the majority of the information provided in this review is based on articles, studies, and clinical trials published within the last 10 years. Furthermore, this review relied solely on free full-text articles accessible from various databases to gather information. Publications in languages other than English were excluded during the screening process for this review. Studies involving minors including the pediatric population , were not included in this review. Studies in which animal models have been used to test the efficacy and safety of SGLT-2 inhibitors have been excluded from the review. Since some trials with sotagliflozin are still ongoing, more data are required to make definitive conclusions. In certain included clinical trials, subgroup analyses were conducted without adjusting for multiple comparisons. The prespecified inclusion and exclusion criteria in some trials may have limited the enrolment of some very high-risk patients which could affect the generalizability of the results. Lastly, we must account for information bias due to the non-availability of certain data collected from various databases worldwide.This systematic review was carried out to compare the cardiovascular mortality rates between sotagliflozin and dapagliflozin in patients with heart failure. With the significant FDA approval of the dual SGLT 1 and 2 inhibitor sotagliflozin, we conducted a review that compared the cardiovascular mortality rates between sotagliflozin and dapagliflozin. In our review, we found that sotagliflozin if initiated immediately after an episode of decompensation of HF significantly reduces the cardiovascular mortality rates. Dapagliflozin's impact on reducing cardiovascular death or worsening heart failure was more prominent in patients with a greater baseline symptom burden. We did not find any comparative review articles focusing on sotagliflozin and we hope that this article helps provide future researchers with the information they need to conduct more large-scale trials involving this unique medication. We also advocate conducting more clinical trials in the context of studying the benefits of sotagliflozin in patients with type 1 diabetes and low glomerular filtration rates to obtain more information on the safety and efficacy of the drug.


Gallbladder cancer (GBC) and cholangiocarcinoma are common cancers of the biliary system and are associated with a poor prognosis. Surgery and chemotherapy provide limited benefit to patients with advanced biliary tract carcinoma. Novel immunotherapies and molecularly targeted therapies are more effective options; however, few patients benefit and drug resistance is a concern. Here, we report five cases of advanced GBC with either high programmed death-ligand 1 (PD-L1) expression or a high tumor mutation burden (TMB-H). The patients were treated with a combination therapy of tislelizumab and S-1. The tumors were effectively controlled in most patients. One patient developed immune-related pneumonia (irP) during treatment, which resolved after hormone therapy, and the patient underwent surgery. Tislelizumab and S-1 were administered again after surgery; however, recurrent irP required discontinuation, and the tumor progressed after drug withdrawal. These cases demonstrate that combined therapy of anti-programmed cell death protein-1 (PD-1) antibodies and S-1 is a safe and effective regimen with few side effects for GBC patients, especially for sensitive populations . To our knowledge, this is the first time that tislelizumab in combination with S-1 has been used to treat patients with advanced GBC. The Immunotherapy and targeted therapy have shown good therapeutic promise for cancer in recent years , 10. TheHere, we report our experience treating five GBC patients with high PD-L1 expression or high tumor mutation burden (TMB-H) who received a combination of tislelizumab and S-1. We present the comprehensive clinical evaluations and relevant histories of the patients and highlight the possible association between immunotherapy markers and efficacy. All patients achieved good therapeutic results and showed good treatment tolerance.22.1A 64-year-old man sought medical attention in September 2020 for marasmus. The physical examination showed no yellow pigmentation of the patient’s skin or sclera and no abdominal tenderness. Contrast-enhanced computed tomography (CECT) and positron emission tomography-computed tomography (PET-CT) of the abdomen showed a significant mass in the gallbladder and left hepatic region. Further, there were multiple metastatic nodules in the omentum and multiple metastases in the hilar and retroperitoneal lymph nodes  and the abdominal metastases disappeared   )  and the patient’s neck mass disappeared.   and progression-free survival (PFS) (median PFS 7.2 months vs. 5.7 months) compared with chemotherapy alone . Unfortuvia HAIC with the 3cir-OFF regimen, which is comprised of oxaliplatin, 5-fluorouracil, and folinic acid. The median PFS and OS of patients receiving this regimen were 9.8 months and 14.2 months, respectively  are potential biomarkers for immunotherapy –35 and tGiven the superiority of immune and targeted combination therapy shown by published studies, several clinical trials on immunotherapy and targeted therapy in patients with GBC are ongoing .The TOPAZ-1 study showed that combination therapy did not have significantly different survival benefits based on PD-L1 expression . HoweverBecause the patient in Case 1 developed irP, we changed the treatment from tislelizumab to nivolumab. However, his irP recurred, and his tumor continued to progress. Therefore, it appears that switching medications after the patient develops immune-related adverse events does not decrease the severity of the side effects. In addition, while waiting to start nivolumab, the patient developed drug resistance. In Case 2, after the medication was effective and the surgical criteria were met, the patient chose to continue medication instead of surgery. Although the patient showed good clinical results, we still cannot determine whether it is feasible to forgo surgery after response to combination therapy. Further, if the patient opts to continue treatment, determining how to judge whether there is tumor activity by CECT and how long to discontinue the drug after the development of adverse events remains a problem. In Case 3, considering the patient’s high risk of postoperative recurrence, we administered the combination of tislelizumab and S-1 to the patient postoperatively. Currently, the patient has not experienced a relapse for 19 months. The patients in cases 4 and 5 developed tumor progression after surgery. After which they received tislelizumab + S-1 and the tumor shrank. Combining the results from the three patients , we suggest that timely postoperative drug administration for patients with medication indication may reduce tumor progression and the recurrence rate.Only the patient in case 1 developed irP; the rest of the patients had no immune-related adverse events. Four of the five patients profiled in this study underwent surgery, and all of them recovered smoothly with no significant postoperative complications. In our study of immunotherapy for GBC, we found only one case of irP, but our team also found immune-related liver damage and immune-related myocarditis in immunotherapy for liver cancer. Deaths occurred in these two patients. This study has several limitations. First, the samples size of our study is too small to draw general conclusions. Thus, further studies are required to establish the effectiveness of the combined treatment with tislelizumab plus S-1. Second, we did not recheck the PD-L1 and TMB status of patients which go on to form metastases in continued immunotherapy. We think it may be beneficial to test the PD-L1 and TMB status of patients’ specimens if patients show resistance to anti-PD-1 immunotherapy.4The five cases we report show that the combination of anti-PD-1 and S-1 therapy is a safe and effective treatment option for patients with advanced GBC and may be more useful for those with a high expression of immunotherapeutic markers .The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.SL, LF, and BL contributed to the conception and design of the study. SL, LF, and BL contributed to the administrative support of the study. FZ, JL, SL, LF, and BL contributed to the provision of study materials for patients. YL contributed to the collection and assembly of data for the study. YZ and YL contributed to the data analysis and interpretation of the study. All authors contributed to the article and approved the submitted version.


Testicular germ cell tumors (TGCTs) are the leading cause of cancer-related death in males between the ages of 20 and 40. In the advanced stages, the combination of cisplatin-based chemotherapy and surgical excision of the remaining tumor can cure many of these patients. Vascular procedures may be required during retroperitoneal lymph node dissection (RPLND) in order to achieve the complete excision of all residual retroperitoneal masses. Careful assessment of pre-operative imaging and the identification of patients who could benefit from additional procedures are important for minimizing peri- and postoperative complications. We report on a case of a 27-year-old patient with non-seminomatous TGCT, who successfully underwent post-chemotherapy RPLND with additional infrarenal inferior vena cava (IVC) and complete abdominal aorta replacement using synthetic grafts. Testicular cancer is the most common cancer among young men between 20 and 40 years of age, and even though it accounts for <1% of all tumors in men, its incidence is gradually rising . The sucpcRPLND can be a difficult surgical procedure due to the complex anatomy of the retroperitoneal space. It requires expert surgeons who are well-versed in retroperitoneal anatomy and capable of performing surgical techniques on the vascular and intestinal structures ,10,11. CDonohue first described the split and roll technique over the aorta and vena cava, dividing the lumbar vessels in order to easily retract the great vessels and safely resect the retroperitoneal tumors during RPLND . HoweverHerein, we report a case of a 27-year-old patient with a residual retroperitoneal mass after chemotherapy for non-seminomatous TGCT, who underwent pcRPLND with complete replacement of the infrarenal inferior vena cava (IVC) and abdominal aorta using synthetic grafts. We also review relevant literature on clinical and anatomical characteristics that could help to predict the need for major vascular surgery in these patients.A 27-year-old patient was initially diagnosed with testicular cancer after experiencing severe scrotal pain radiating to his back. On physical examination, a painless mass was palpated in the right testicle and confirmed on scrotal ultrasound, measuring 7.5 cm. A right orchidectomy was immediately scheduled and performed. Histopathological diagnosis of the resected mass was consistent with a non-seminomatous yolk sack tumor (95%) with a minor component of teratoma (5%).3 and bilateral pulmonary metastatic lesions. Serum marker assessment disclosed a significantly elevated AFP of 1620 ng/mL with a β-hCG of 573 mIU/mL and an LDH level of 1190 IU/L. The patient was initiated on platinum-based chemotherapy for stage IIIB intermediate-risk disease and received four cycles of a standard bleomycin, etoposide, and cisplatin (BEP) regimen. Reimaging with CT CAP after the completion of systemic therapy showed a complete response of the pulmonary metastatic sites but no significant size reduction in the retroperitoneal mass. Postoperative serum marker assessment was consistent with the normalization of AFP at 33.4 ng/mL, as well as β-hCG (0.1 mIU/mL) and decreased levels of LDH at 402 IU/L.Computed tomography (CT) of the chest, abdomen, and pelvis (CAP) revealed a retroperitoneal lymph node mass measuring 14 × 13 × 8.4 cmDuring preoperative assessment, the patient underwent CT angiography, which showed infiltration and compression of the inferior vena cava (IVC), as well as encasement of the abdominal aorta (AA) and the proximal part of both iliac arteries. Complete resection of the total infrarenal length of both major vessels up to the mid-iliac arteries and veins was discussed and thoroughly planned with the Vascular Surgery and Anesthesiology teams during the tumor board review of the case. Finally, the patient underwent RPLND with total replacement of the IVC and AA with synthetic grafts.Intraoperatively, careful mobilization of the retroperitoneal mass, IVC, and abdominal aorta from the renal vessels to common iliac vessels was performed .Vascular clamps were placed inferior to the renal arteries and veins and bilaterally at the bifurcation of the common iliac veins and arteries. Complete resection of the retroperitoneal mass alongside the IVC and aorta, as well as the proximal part of both iliac arteries and veins, was achieved . An endoSubsequently, a replacement of the aorta and the common iliac arteries using a bifurcated 16 × 8 mm PTFE graft  was performed with end-to-end anastomoses and the arterial blood flow was restored. A successful restoration of the veins was also performed using a bifurcated 24 × 12 mm PTFE graft  .A tissue-traction-related injury to the right ureter was treated with the placement of a double J-stent end-to-end anastomosis. During the entire procedure, the patient was transfused with six units of packed red blood cells but remained hemodynamically stable and was transferred to the intensive care unit (ICU) postoperatively for monitoring. Prophylactic anticoagulation with enoxaparin 8.000 anti-Xa IU twice daily was started to reduce the thrombotic risk in the reconstructed inferior vena cava system. Post-op CT angiography did not disclose any complications, while revealing the full patency of both vascular grafts .The hospital course was complicated by prolonged lymphatic leakage from the draining tube for an additional six-day period after discharge (corresponding to Grade I severity according to Clavien–Dindo classification). Moreover, a subcutaneous hematoma at the incision site required drainage after bedside removal of the surgical clips (Grade II complication). The patient was cleared for discharge by both Urology and Vascular Surgery teams on post-op day 12, starting rivaroxaban 20 mg once daily for 6 months to maintain the patency of the venous graft. The patient was re-evaluated 30 days postoperatively with serum biomarkers showing a further decrease in AFP within the normal range at 1.62 ng/mL, while adequate patency of the vascular grafts was confirmed via color Duplex ultrasonography. Histopathological evaluation of the resected masses showed the presence of viable teratoma with minor components of yolk sac tumor in the retroperitoneal mass, and therefore, the patient was started on second-line chemotherapy with paclitaxel-ifosfamide-cisplatin (TIP).pcRPLND is an integral part of the treatment algorithm for patients with advanced non-seminomatous TGCTs. It is a complex surgical procedure, and occasionally, patients may require additional procedures, including vascular surgical resections, usually involving the IVC. NSGCT residuals are often found attached to the vascular wall, but in some cases, they may be located within the lumen of great vessels. After chemotherapy, the incidence of intraluminal thrombi in RPLND can be as high as 5.8% . When thIf lesions cannot be separated from the great vessels or are located inside the lumen, vascular surgery techniques must be employed. These techniques may include cavotomy and thrombectomy, partial or complete cavectomy, aortic resection, or complete vascular replacement. Caldarelli et al.  suggesteIVC reconstruction may help to prevent complications that can develop after IVC ligation, and certain clinical and intraoperative factors may play key roles in the decision on IVC reconstruction. According to Ehrlich et al. , there aen bloc with the aorta and IVC to achieve an R0 resection. A vascular reconstruction was then successfully performed using synthetic PTFE grafts, followed by long-term anticoagulation to sustain the patency of the venous graft.Regarding aortic involvement, infiltration of the aorta by the residual mass is an absolute indication for complete resection and replacement with a synthetic graft. Aortic resection may be indispensable for achieving an R0 resection, in addition to the fact that peeling the tumor from the aorta may leave the aorta with a thin wall ,19. SeveEven though laparotomy is the standard approach for patients with excessive retroperitoneal residuals and cases where vascular replacement is needed, recent studies have demonstrated advances in laparoscopic surgical techniques that have made vascular reconstruction during laparoscopic RPLND feasible. Aufderklamm et al.  studied There is currently an unmet need to develop and prospectively validate predictive markers which could help to identify patients who are likely to need vascular surgery during RPLND. According to the German Testicular Cancer Study Group, the risk factors for vascular involvement include intermediate- or poor-risk germ cell tumors, according to the International Germ Cell Cancer Collaborative Group risk classification, and the presence of residual masses that exceed 5 cm after chemotherapy . PatientThe long-term sequelae of IVC resection during RPLND after a median follow-up of over 7 years were reassuring, without long-term disability in three-quarters of patients . In addipcRPLND encompasses complex surgical procedures with potential vascular involvement, depending on certain clinical (poor-risk ICCCGC classification) and anatomical parameters . Concomitant aorto-caval reconstruction, when necessary, as in our case, increases the complexity and concern regarding the patency of aorto-caval bypass grafts and the avoidance of lower extremity ischemia or edema. Therefore, adequate preoperative evaluation may help to identify those patients who will benefit from vascular reconstruction, while careful planning and execution of the procedure in high-volume centers of reference could minimize post-operative complications and improve oncological outcomes.


Infant motility assessment using intelligent wearables is a promising new approach for assessment of infant neurophysiological development, and where efficient signal analysis plays a central role. This study investigates the use of different end-to-end neural network architectures for processing infant motility data from wearable sensors. We focus on the performance and computational burden of alternative sensor encoder and time series modeling modules and their combinations. In addition, we explore the benefits of data augmentation methods in ideal and nonideal recording conditions. The experiments are conducted using a dataset of multisensor movement recordings from 7-month-old infants, as captured by a recently proposed smart jumpsuit for infant motility assessment. Our results indicate that the choice of the encoder module has a major impact on classifier performance. For sensor encoders, the best performance was obtained with parallel two-dimensional convolutions for intrasensor channel fusion with shared weights for all sensors. The results also indicate that a relatively compact feature representation is obtainable for within-sensor feature extraction without a drastic loss to classifier performance. Comparison of time series models revealed that feedforward dilated convolutions with residual and skip connections outperformed all recurrent neural network (RNN)-based models in performance, training time, and training stability. The experiments also indicate that data augmentation improves model robustness in simulated packet loss or sensor dropout scenarios. In particular, signal- and sensor-dropout-based augmentation strategies provided considerable boosts to performance without negatively affecting the baseline performance. Overall, the results provide tangible suggestions on how to optimize end-to-end neural network training for multichannel movement sensor data. Developments in wearable electronics, and especially in integrated sensors with inertial measurement units (IMUs), have made automatic human activity recognition (HAR) feasible in various use scenarios. Typical HAR systems aim at detecting various everyday activity patterns of a person . These data can then be used for various purposes ranging from personal activity logs  to medicIn our previous work ,12, we dIn the previous study , classiforted in . FurtherIn this work, we take a more principled approach to the technical development of a infant movement classifier from wearable IMUs. More specifically, we investigate different end-to-end neural network architectures for multisensor IMU data processing in infant movement analysis. We also analyze the utility of different training data augmentation strategies for classifier performance and robustness. Different system variants are tested in conditions that simulate issues encountered in practical out-of-the-lab use scenarios, such as sensor dropout or packet loss due to real-time wireless data transfer issues. We also compare performance of different system architectures to their memory footprint and computational complexity. As a result, we find many such strategies in sensor signal encoding and time series modeling that may benefit also many other HAR applications that are based on multisensor setups.The Maiju jumpsuit reported in  records The general neural network architecture presented in  can be tThe HAR literature contains multiple proposals to perform raw-input feature extraction for the encoder model e.g., ,13), and, and13])Finally, the recording setup of Maiju performs real-time streaming of the raw data to the controlling device (a mobile phone) over Bluetooth. This means that the real-life recordings might suffer from packet loss and/or sensor dropout. It has been well documented that data augmentation methods can improve model robustness in image and audio processing applications ,18 as wewww.movesense.com, accessed 6 March 2023) sensors with proximal limb placements. The accelerometer measures linear acceleration in m/sThe “Maiju” smart jumpsuit is a full body garment that allows spontaneous unrestricted movements of approximately 4–16-month-old babies. The jumpsuit performs triaxial accelerometer and gyroscope recordings at a 52 Hz sampling rate from four Suunto Movesense  process to obtain the most likely one-hot labels for the movement categories . In IAR,The data preprocessing and windowing process is illustrated in We utilize the SVM classifier reported in our previous study  as a perThe overall schematic of the processing pipeline is presented in The “dense” encoder structure, presented in The 1-dimensional CNN system Conv1D; b is a siThe previous encoder systems (dense and 1-D CNN) work under the assumption that the same learned features can be extracted from the parallel accelerometer and gyroscope signals. In reality, the accelerometer and gyroscope sense complementary inertial information that potentially benefit from individualized features. The “2-D CNN with individual paths”  absolute model performance or (2) model robustness in expected real-world settings. We aim to investigate both of these effects with a number of augmentation methods (with modifications) that were previously proposed in .Dropout is generally a popular deep learning method to increase model generalization: During training, a binary dropout mask is applied to a given layer, which sets a given percentage of its activation values to zero. Effectively, this forces the neural network to learn robust distributed representations for the same input. For the present study, we experimented with dropout at two different positions: (1) in the input tensor, and (2) in the bottleneck features between the encoder and time series modeling modules. The first case can be thought of data augmentation for the case of packet loss that might occur during a real-world recording. The dropout probability for both cases is set to 30% in the present experiments.Sensor dropout aims to increase model robustness by randomly dropping one IMU sensor of a minibatch during training . The probability of a sensor to drop is set to 30%, and the sensor to be dropped is selected randomly from a uniform distribution. This forces the classifier to learn representations that are not dependent on any one particular limb’s movement information. The results in  suggest Even though the sensor mounts of the Maiju jumpsuit are placed in fixed positions, the actually realized positioning of each sensor with relation to the infant’s body is affected by the body type of the infant. This effect can be simulated with artificial sensor rotation, where a 3 × 3 rotation matrix is used to mix the channels of each sensor. To perform random rotations to the sensors, we utilize the Euler rotation formula, where the yaw (A) are randomly sampled from a uniform distribution between . The synthesized timebase differential vector  to investigate the performance of different sensor encoder and time series modules, (2) to compare their performance with their computational and memory loads, and (3) to study the effects of data augmentation on system performance. The overall aim was to identify the best-performing solution for infant motility assessment using Maiju with reasonable computational requirements.For all of the experiments, each neural network combination was trained end-to-end with random initialization without any pretraining. To mitigate the effect of result variability due to the random initialization, each experiment was repeated three times and their average is reported as the result. The neural network training was performed with stochastic gradient descent using minibatches of 100 frames. The Adam algorithm  with parc, c, The unweighted average The first experiment compared the classifier performance of all of the encoder–time series module combinations presented in The results show that the best overall performance was achieved with the Conv2D-SI encoder with the WaveNet time series model. The choice of the encoder module is seen to have the largest impact on the classifier performance: the Conv2D-based encoders significantly outperform the competitors. Within the alternative Conv2D models, the simplest model, Conv2D-I, has the weakest performance. The Conv2D-SI model slightly outperforms the previously proposed Conv2D-IS model. The Conv2D-SI model also has the smallest performance variation across the various time series models, which suggests that the bottleneck representations learned by the encoder are the most robust .The choice of the time series model is seen to have a clear hierarchy in performance, where the WaveNet-based model systematically has the best performance. An interpretation for this effect is that the WaveNet model has more powerful modeling capabilities that learn to compensate some of the inefficiencies of inferior encoder modules. Surprisingly, the GRU module systematically outperforms the BGRU module, albeit with a minor margin.An interesting effect is also seen within the LSTM model: the worse the encoder performance is , the worse the LSTM also performs. With the best-performing encoder (Conv2D-SI), LSTM performance becomes on par with the rest of the RNN-based models. This finding is in line with the conventional wisdom regarding LSTM training instability, and suggests that RNN training might benefit from pretrained bottleneck features that would make the end-to-end training more stable.As further analysis of the first experiment systems, we explored the relationship of model size and model training time to classifier performance. Typically, smaller models have better generalization with a loss to detail of modeling capabilities, whereas larger models have better modeling capacity but are prone to overfitting during training. For research and development purposes, model training time is another feature of interest, as it determines a limit on the rate of experiments that can be performed given a limited number of computational resources. RNN-based systems are known to have considerably slower training times because the error backpropagation through time requires unraveling of the entire computational graph over all of the time steps of the minibatch . In contThe performance—model size—training time comparison of the systems is presented in the bubble chart of Within the time series models, the RNN-based modules exhibit considerably longer training times, and the dense and WaveNet time series module training times were roughly equivalent. From the fastest to slowest training times, the ratios are 1 (dense):1 (WaveNet):4.9 (GRU):6.5 (LSTM):7.6 (BGRU). The mean ratio between RNN and non-RNN training times is approximately 6:1. For the encoder models, the training times have ratios of 1 (dense):1.3 (Conv1D):1.4 (Conv2D-I):1.7 (Conv2D-IS):2.1 (Conv2D-SI).For the final model size experiment, we chose the best-performing system, Conv2D-SI + WaveNet, and tested its performance with a varying number of bottleneck features. As the Conv2D-SI encoder produces sensor-independent features, a decrease in bottleneck layer dimensionality directly reduces the number of features per sensor, thus also reducing the network size. This is an interesting avenue of investigation when considering embedded solutions that would perform the bottleneck feature extraction inside the sensor. Implementing such a scheme would allow data collection without online streaming of the raw data, which would significantly increase recording reliability and sensor battery life. The effect of varying bottleneck size to Conv2D-IS + WaveNet system performance is presented in The final set of experiments explored classifier model robustness to noise as well as the effect of various data augmentation methods. For these experiments, we chose the best-performing system, Conv2D-IS + WaveNet, alongside two of the systems with the lowest number of trainable parameters: Conv1D + dense and Conv1D + GRU. Robustness was tested for sensor-dropout and packet-loss cases under two conditions: moderate and severe.For sensor dropout, one (moderate condition) or two sensors (severe condition) were dropped for each recording. Every possible combination of the dropped sensors was tested, and the average performance across the tests is reported in the results. For packet loss, the moderate condition simulated 25% random dropout in four sample bursts per sensor. The severe condition used a dropout value of 50%. For both cases, the dropout simulation was repeated for five times, and the average result is reported.The results are presented in The results for the packet-loss case are somewhat more diverse: for the moderate case, the performance of the Conv2D-SI + Wavenet model is on par with the “no dropout” case, even without augmentation. This further suggests that the weight sharing in the Conv2D-SI encoder produces a robust low-dimensional representation for the movement sensor data. Rather surprisingly, input-level dropout does not increase performance of this system even in the severe packet loss case, but an increase in performance is observed with sensor dropout during training. For the Conv1D encoder-based systems, input-level dropout produces the greatest augmentation effect for the moderate and severe packet loss cases, whereas sensor dropout produces a smaller positive effect. In summary, the combination of input-level dropout with sensor dropout seems to be the most beneficial training strategy for the Maiju classifier, as it maintains the clean baseline performance while making the classifier considerably more robust in adverse conditions.This study shows that the choice of end-to-end neural network architectures has a major impact on the performance of human activity recognition from multisensor recordings. The choice of the encoder module (responsible for intra- and/or intersensor channel fusion) has the greatest significance in the resulting performance. Out of the tested encoders, the best performance was obtained with the “Conv2D-SI” model which uses parallel two-dimensional convolutions for intrasensor channel fusion with shared weights for all sensors. Furthermore, experiments regarding the bottleneck size of the the “Conv2D-SI” encoder indicate that a relatively compact feature representation is obtainable for within-sensor feature extraction without a drastic loss in classifier performance. Comparison of time series models reveals several key effects. First, the best-performing system, the “WaveNet” architecture based on feedforward dilated convolutions, outperforms the RNN-based models in performance, training time, and training stability, making it the preferred time series modeling method for the task. The same results also show the importance of input-feature robustness when training RNN-based models, especially LSTMs. This suggests that some level of pretraining (supervised or unsupervised) would be preferable before inserting an RNN module into an end-to-end classifier architecture.The experiments comparing data augmentation methods did not find additional benefit to classifier performance when using clean data as input. However, when studying model robustness in noisy conditions, such as simulated packet loss or dropped sensor scenarios, dropout-based (input dropout or sensor dropout) augmentation provided a considerable boost to performance without affecting the clean data performance. We speculate that the lack of performance boost from data augmentation is due to performance ceiling caused by the ambiguity in defining the gold-standard annotations of infant movement categories before the infants reach archetypal adult-like motor skills. Our previous study showed that the classifier output reaches the inter-rater agreement notators .In conclusion, this study suggests how to optimize end-to-end neural network training for multichannel movement sensor data using moderate-sized datasets. First, the design of the encoder/channel fusion component of the network greatly benefits from weight sharing and appropriate handling of data modalities from different sources. Second, feedforward convolutional approaches with wide receptive fields are well suited for time series modeling, and outperform RNNs in terms of accuracy, training speed, and robustness on our data. Finally, training data inflation by means of data augmentation is, at best, a secondary avenue in increasing classifier performance compared to the overall network structure and dataset design. Regarding the Maiju jumpsuit, our future research interests include the expansion of the training dataset to contain infants up to 14 months in age, and in exploring the effect of unsupervised representation learning techniques such as contrastive predictive coding  to the c


High-flow nasal cannula (HFNC) is a respiratory support measure for coronavirus 2019 (COVID-19) patients that has been increasingly used in the emergency department (ED). Although the respiratory rate oxygenation (ROX) index can predict HFNC success, its utility in emergency COVID-19 patients has not been well-established. Also, no studies have compared it to its simpler component, the oxygen saturation to fraction of inspired oxygen (SpO2/FiO2 [SF]) ratio, or its modified version incorporating heart rate. Therefore, we aimed to compare the utility of the SF ratio, the ROX index (SF ratio/respiratory rate), and the modified ROX index (ROX index/heart rate) in predicting HFNC success in emergency COVID-19 patients.We conducted this multicenter retrospective study at five EDs in Thailand between January–December 2021. Adult patients with COVID-19 treated with HFNC in the ED were included. The three study parameters were recorded at 0 and 2 hours. The primary outcome was HFNC success, defined as no requirement of mechanical ventilation at HFNC termination.A total of 173 patients were recruited; 55 (31.8%) had successful treatment. The two-hour SF ratio yielded the highest discrimination capacity , followed by two-hour ROX and modified ROX indices . The two-hour SF ratio also had the best calibration and overall model performance. At its optimal cut-point of 128.19, it gave a balanced sensitivity (65.3%) and specificity (61.8%). The two-hour SF≥128.19 was also significantly and independently associated with HFNC failure .The SF ratio predicted HFNC success better than the ROX and modified ROX indices in ED patients with COVID-19. With its simplicity and efficiency, it may be the appropriate tool to guide management and ED disposition for COVID-19 patients receiving HFNC in the ED. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 that has infected millions of individuals worldwide.High-flow nasal cannula (HFNC), an oxygen-delivering technique whereby heated and humidified air is delivered with positive pressure generated, has been proven to be an effective initial respiratory support measure for patients with AHRF of many etiologies in both inpatient and ED settings.2)/fraction of inspired oxygen (FiO2) to respiratory rate, has been demonstrated to be a reliable predictor of HFNC success for AHRF patients in the intensive care unit (ICU) and inpatient settings.The ROX (respiratory rate oxygenation) index, a ratio of oxygen saturation (SpO2/FiO2 (SF) ratio can also be employed as a predictive marker for HFNC outcomes.20The SpONo studies have validated and compared the SF ratio with the ROX index or its modified version in the ED setting, where HFNC is usually initiated earlier in the disease course. Consequently, we conducted this study to evaluate and compare the prognostic utility of the SF ratio, the ROX index, and the modified ROX index in predicting HFNC success in patients with AHRF secondary to COVID-19 in the ED.What do we already know about this issue?The respiratory rate oxygenation (ROX) index is a validated predictor of high-flow nasal cannula success only in non-COVID-19 patients.What was the research question?Our goal was to compare the prognostic utility of the SpO2/FiO2 ratio, ROX, and modified ROX index in COVID-19 patients.What was the major finding of the study?The two-hour SpO2/FiO2 ratio has the best discriminative ability .How does this improve population health?For emergency COVID-19 patients, the SpO2/FiO2 ratio should be used for prognostication instead of the ROX or modified ROX indices.This multicenter retrospective observational study was conducted between January 1–December 31, 2021 at five EDs in Thailand. A variety of EDs from various regions of the country, including those of university hospitals and secondary- and tertiary-level hospitals, participated in the study. The five study centers were Siriraj Hospital ; Banphaeo Hospital ; Ratchaburi Hospital ; Buddhachinaraj hospital ; and Prachuap Khiri Khan hospital . The Central Research Ethics Committee of Thailand approved the study (certificate number CREC044/2022). Due to its retrospective nature, informed consent was waived. The study was reported according to the STROBE guidelines.21Adult patients over 18 years of age diagnosed with AHRF due to COVID-19 who received HFNC in the ED were included. We excluded COVID-19 patients who did not receive HFNC therapy initiated in the ED. Also excluded were those with a do-not-intubate order who received HFNC for palliative purposes.th Revision, codes, we retrospectively reviewed consecutive patients visiting the participating EDs with the diagnosis of COVID-19 infection made before or within the index ED visit. Their electronic health records were reviewed to determine whether they had received HFNC in the ED. We used this data if all the inclusion and exclusion criteria were satisfied. With retrospective chart review performed by trained data abstractors at each study center,Using International Classification of Diseases, 10Parameters required for calculating the SF ratio, the ROX index, and the modified ROX index were recorded before HFNC application (hour 0) and at 2 hours after HFNC initiation. All these parameters were measured while the patients were still in the ED awaiting disposition. The decisions to initiate HFNC to the patients, adjust HFNC settings, and escalate the treatment toward a more invasive respiratory support measure were determined by the attending physicians at each study center. Another study coordinator double-checked the recorded data in the electronic case-report forms to ensure the reliability and accuracy of the study data.2 to FiO2.2/FiO2 to respiratory rate,24At 0 and 2 hours after HFNC initiation, we calculated three parameters and assessed them for their utility in predicting HFNC outcomes: the SF ratio; the ROX index; and the modified ROX index. The SF ratio was calculated from the ratio of SpOt-test or the Mann-Whitney U test for continuous data.We employed descriptive statistics to describe patients’ characteristics. Categorical data is reported as frequency and percentage. Continuous variables are reported as mean and standard deviation (SD) or median and interquartile range for normally distributed and non-normally distributed data, respectively, evaluated based on histograms and Q-Q plots. We compared these variables between the success and failure groups by using the chi-squared or Fisher exact test for categorical data and an independent As an external validation study, the predictive performance of the SF ratio, the ROX index, and the modified ROX index for the study outcomes were assessed primarily with their discrimination and calibration capacities, coupled with other additional analyses.30Moreover, we evaluated overall model performance using the Nagelkerke R-squared. A parameter that could yield a higher R-squared value should perform better than others.P-value <0.2 in the multivariate regression model for each outcome. Nonetheless, each multivariate model evaluated only one potential predictor value among the three parameters at one time point to avoid multicollinearity.Age, gender, body mass index, day of symptoms, Charlson Comorbidity Index, Sequential Organ Failure Assessment (SOFA) score, D-dimer, C-reactive protein, and steroid were determined a priori based as existing evidence as potential associating variables with HFNC outcomes to be adjusted for in the multivariate models. We included variables with univariate We performed all statistical analyses using SPSS version 18.0 , R version 3.6.1  with the rms, Hmisc, foreign, pROC, sciplot, and dca packages, and MedCalc for Windows version 19 .2 on HFNC, were on HFNC for a shorter duration, and had more complications and longer hospital length of stay than the success group  had do-not-intubate status. Consequently, 173 patients were included in the study. Their characteristics are shown in ss group .There were no missing values for any parameters evaluated at either the 0- or 2-hour time points. We included all 173 samples in the analyses for both time points because no outcome events occurred prior to the two-hour time point at which the second parameter values were measured. The mean values of the three indices were lower in the HFNC failure group than in the success group; however, only the parameters measured at two hours were significantly different between the groups for both study outcomes . DistribP-value for difference among AUROCs=0.80). Similarly, the two-hour SF ratio could yield higher AUROC for overall treatment failure than the two-hour ROX and modified ROX indices . The parameters measured at hour 0 all had lower discrimination than those at two hours for both study outcomes  and specificity (61.8%) compared to two-hour ROX≥3.23 and two-hour modified ROX≥4.27 . AlthougP=0.003) (P<0.001)  . For oveP<0.001) .To the best of our knowledge, this study was the first to directly compare the prognostic utility of the SF ratio, the ROX index, and the modified ROX index for AHRF patients secondary to COVID-19 in the ED setting. We found that the SF ratio measured at two hours post-HFNC application was the best predictor of HFNC and overall treatment success since it could yield the highest discriminating ability and overall performance index, as well as good calibration, well-balanced diagnostic accuracy indices, and strong association with HFNC and overall treatment failure.High-flow nasal cannula has been recommended as the respiratory and oxygenation support measure for patients with AHRF due to COVID-19 since it has been shown to provide many physiologic benefits and may reduce adverse outcomes, such as mechanical ventilation rate.The ROX index, the most widely validated prognostic marker of HFNC outcomes, has been shown by many studies to also have acceptable prognostic utility in COVID-19 patients.Consequently, the present study has added to the current body of evidence that the SF ratio, the simplest parameter among the three, could outperform the ROX and the modified ROX indices in predicting HFNC success for COVID-19 patients in the ED setting. Although the discrimination based on AUROC of the SF ratio was not significantly higher than those of the other parameters, it was still superior to the others by a wide range of other statistical analyses, including calibration, overall model performance, diagnostic accuracy indices based on the optimal cut-point, and associations with the outcome based on regression analyses. The superiority of the SF ratio over other more complex parameters could have been because patients with COVID-19 usually present with silent hypoxia, a condition in which other physiologic parameters can appear normal despite very low oxygenation.20However, it is important to note that although the SF ratio offered a more balanced sensitivity and specificity than the other two indices for HFNC success, the ROX index yielded a largely higher sensitivity and the proportion of detectable patients. This controversy might have been because the Youden index employed in these analyses may not be the most appropriate method to identify the optimal cut-point for this outcome as it only focused on the highest product of sensitivity combined with specificity without considering their balance. This matter was evidenced by a very high sensitivity and low specificity for the ROX index compared to the other two parameters.Interestingly, we found that the SF ratio clearly had better predictive ability than the other indices for overall treatment failure based on all statistical analyses performed. Its performance was even better than the SF ratio for HFNC success. This result adds to the current body of evidence that mortality could have been another measure of adverse clinical outcomes of COVID-19 in patients treated with HFNC that predictive scoring systems, especially the SF ratio, could be able to predict accurately. With its unique clinical progression, disease-specific mortality could imply severe disease deterioration despite initial successful HFNC weaning.24Nevertheless, despite the SF ratio having the highest AUROC, the AUROCs found in our study were generally lower than in other studies in COVID-19 patients.Nonetheless, from the present study, it was still appropriate to conclude that the SF ratio was superior to the ROX index and the modified ROX index in predicting HFNC success and overall treatment failure for emergency COVID-19 patients not only because of its superior performance over a wide range of statistical analytic methods but also because the SF ratio is easier to calculate at bedside, thereby being more efficient to be used in the ED.There were some limitations to this study. First, the study was conducted in a middle-income country, which may limit its generalizability even though it involved multiple EDs of hospitals with varying levels of care. Second, the data was collected retrospectively, which may have caused possible errors and corresponding bias associated with the nature of a retrospective study. Third, we only measured the parameters at two hours post-HFNC application and not at any later time points because it was the longest duration that all the patients were still in the EDs; therefore, the clinical utility of the parameters could also involve aiding in ED disposition decision-making. The other reason was that there were many missing variables at later time points because the physiologic parameters were not monitored simultaneously among inpatient units of participating hospitals. Nevertheless, had the parameters been followed for longer than two hours, their prognostic utility and their relative ability in prognostication could have changed. Regardless, the applicability of those findings to the ED setting may be limited.The SF ratio measured two hours after high-flow nasal cannula initiation was better than the ROX index and the modified ROX index at predicting HFNC success in patients with acute hypoxemic respiratory failure secondary to COVID-19 in the ED setting. Compared to the other two ROX indices, the two-hour SF ratio had the greatest prognostic utility, as well as the utmost simplicity and bedside efficiency. Therefore, it may be an appropriate tool to guide appropriate disposition, further management, and potential escalation therapy for COVID-19 patients treated with HFNC therapy in the ED.